研究活動情報

• 2012年 14th Young Investigator's Award

• Targeting KIFC1 to disrupt centrosome clustering and trigger anaphase catastrophe in small-cell lung cancer.

  Natsuki Nakagawa, Minemichi Toda, Akiko Kunita, Masafumi Horie, Masakatsu Tokunaga, Hiroaki Ikushima, Mirei Ka, Takahiro Iida, Manabu Shigeoka, Yukinobu Ito, Takahiro Ando, Kousuke Watanabe, Yasunori Ota, Xi Liu, Ethan Dmitrovsky, Hidenori Kage, Masanori Kawakami

  Supernumerary centrosomes are a hallmark of cancer. To maintain viability, cancer cells cluster these centrosomes during mitosis, enabling bipolar division similar to that of normal cells. Disruption of this centrosome clustering leads to multipolar anaphase and apoptosis (anaphase catastrophe), which selectively eliminates cancer cells harboring supernumerary centrosomes. In this context, because the motor protein KIFC1 contributes to centrosome clustering, we investigated whether targeting of this mechanism through KIFC1 inhibition could be exploited in small-cell lung cancer (SCLC), an aggressive malignancy with limited treatment options and poor prognosis. Through in silico and in vitro analyses, as well as IHC of clinical samples, we found that KIFC1 is overexpressed and that centrosome amplification occurs more frequently in SCLC compared with normal tissues and other cancer types. Pharmacological and genetic inhibition of KIFC1 disrupted the clustering of supernumerary centrosomes, triggered multipolar mitosis, and exerted antineoplastic effects in SCLC cells, with minimal effects on noncancerous cells. These findings were validated and extended in vivo using SCLC xenograft models. Finally, cotargeting KIFC1 and the centrosome duplication regulator PLK4 further enhanced growth suppression in SCLC cells. Together, these results suggest that disrupting centrosome clustering and triggering anaphase catastrophe via KIFC1 inhibition may represent a promising therapeutic strategy for SCLC.

  2026年04月, JCI insight, 11(7) (7), 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Thymic cyst: A clinicopathological, immunohistochemical, and molecular study of 36 cases focusing on squamous- and ciliated-type epithelium.

  So Takata, Masafumi Horie, Ken Miyabe, Yukinobu Ito, Yoichiro Nakatani, Yukitsugu Kudo-Asabe, Hiroto Ishida, Sohsuke Yamada, Akiteru Goto, Atsushi Kumanogoh, Yasushi Shintani, Eiichi Morii, Shinichi Yachida, Daichi Maeda

  BACKGROUND: Thymic cysts are benign mediastinal lesions lined by various epithelial types, but the distribution of each type is unknown. In this study, we aimed to evaluate the clinicopathological and immunohistochemical features of thymic cysts. DESIGN: We retrieved 36 resected primary thymic cysts. The lesions were initially evaluated morphologically, focusing on the type of epithelium. Immunohistochemical staining was performed for cytokeratin 7 (CK7), CK13, CK20, high molecular weight cytokeratin (HMWCK: CK34βE12), p63 and β5t. In addition, we investigated 15 occult cystic lesions (OCLs) associated with thymic epithelial tumors. RESULTS: Primary thymic cysts were classified as squamous/cuboidal (SC-type, N = 18), ciliated columnar (CC-type, N = 15), mucinous (N = 2), and mixed (N = 1) types. All cysts were CK7-positive. Linear-luminal pattern CK7 staining was observed more frequently in SC-type cysts (100%) than in CC-type cysts (40%) (P < 0.0001). CK20 was negative in all the cases except for the two mucinous cysts. Full-layer positivity for HMWCK was observed more frequently in SC-type cysts (78%) than in CC-type cysts (6.7%) (P < 0.0001). SC-type cysts were more frequently multilocular than CC-type (10/18, 55.6% vs 1/15, 6.7%; P = 0.0083). CK13 positivity was observed in 70.6% of SC-type cysts and 21.4% of CC-type cysts (P = 0.0113). Radiological findings showed that SC-type cysts were larger than CC-type cysts (P = 0.015), and the computed tomography (CT) values of SC-type cysts were markedly lower than those of CC-type cysts (P < 0.0001). The majority of OCLs were classified as SC-type (13/15). CONCLUSIONS: Based on morphological features, thymic cysts mainly comprise two types, SC-type and CC-type, which differ in their sizes, locularity, immunophenotypes, and CT features.

  2026年03月, Human pathology, 172, 106109 - 106109, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• BST2 promotes esophageal squamous cell carcinoma progression by mediating the cell-cell interaction between cancer cells and cancer-associated fibroblasts.

  Rikuya Torigoe, Yu-Ichiro Koma, Naozane Nomura, Hiroki Yokoo, Masaki Omori, Takashi Nakanishi, Shoji Miyako, Takaaki Nakanishi, Takayuki Kodama, Manabu Shigeoka, Yoshihiro Kakeji, Masafumi Horie

  Cancer-associated fibroblasts (CAFs) in the esophageal squamous cell carcinoma (ESCC) microenvironment promote cancer progression through cell‒cell interactions with cancer cells. A method has been established to generate CAF-like cells by direct co-culturing human bone marrow-derived mesenchymal stem cells (MSCs), a known source of CAFs, with ESCC cells. Using this method, cDNA microarray analyses were conducted on monocultured and co-cultured ESCCs or MSCs. In this study, bone marrow stromal cell antigen 2 (BST2) was studied, which is remarkably expressed in both ESCC cells and CAF-like cells after co-culture and may contribute to cell‒cell interactions. In a public database of single-cell RNA sequencing data from ESCC tissues, BST2 was markedly expressed in cancer cells and CAFs, and the results strongly suggested an interaction between CAFs and BST2-expressing cancer cells. The co-cultured ESCC cells and CAF-like cells showed enhanced proliferation, migration, and adhesion via the ERK signaling pathway, and BST2 was involved in these phenotypes. Furthermore, BST2 contributed to adhesion between MSCs and ESCC cells in direct co-culture. Immunohistochemistry demonstrated that high BST2 expression, especially in the cancer stroma, was significantly associated with adverse clinicopathological factors and poor prognosis in ESCC patients. In conclusion, BST2 contributes to ESCC progression by facilitating cell‒cell interactions between cancer cells and CAFs within the tumor microenvironment.

  2026年02月, The American journal of pathology, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Clinicopathological significance of loss of Y chromosome in male meningiomas.

  Maki Sakaguchi, Masafumi Horie, Yukinobu Ito, Shingo Tanaka, Hiroko Ikeda, Mitsutoshi Nakada, Akihiko Yoshizawa, Daichi Maeda

  Male meningiomas, comprising approximately 30% of all meningiomas, are more frequently high-grade and associated with poorer clinical outcomes compared to their female counterparts. Although Y chromosome alterations have been studied in various male-predominant tumors, a limited number of studies have evaluated their role in meningiomas. To evaluate the clinicopathological significance of Y chromosome loss in male meningiomas, we assessed the frequency of loss of the Y chromosome (LOY) using droplet digital polymerase chain reaction in combination with multiplex ligation-dependent probe amplification on tumor DNA from 93 male meningioma samples. LOY, detected in nine cases (9.7%), was significantly associated with a higher World Health Organization tumor grade (grade 2: 55.6% versus 14.3%; grade 1: 44.4% versus 85.7%; p = 0.009) and loss of the NF2 gene-encoded protein, moesin-ezrin-radixin-like protein (merlin) (loss: 88.9% versus 50.0%; retained: 11.1% versus 50.0%; p = 0.035). RNA in situ hybridization targeting KDM5D on formalin-fixed paraffin-embedded tissue sections demonstrated a sensitivity of 100% (9/9) and a specificity of 76.2% (64/84) for LOY detection, supporting its utility as a screening modality. Moreover, spatial transcriptomic analysis revealed significant differences in the expression of genes associated with epithelial-mesenchymal transition and extracellular matrix organization between LOY and non-LOY meningioma tumor cells. Our findings emphasize the presence of atypical pathological features and distinct transcriptional profiles in LOY-associated meningiomas. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

  2026年02月, The Journal of pathology, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Therapeutic Strategies to Overcome Payload Resistance of Trastuzumab Deruxtecan in HER2-Positive Cancers.

  Yuya Murase, Shigeki Nanjo, Sachiko Arai, Sota Kondo, Hayato Koba, Yifeng Liu, Koji Fukuda, Shigeki Sato, Jun Kinoshita, Noriyuki Inaki, Tsukasa Ueda, Shunichi Nomura, Yuichi Tambo, Takahiro Shimizu, Masafumi Horie, Daichi Maeda, Richard W Wong, Kazuyoshi Hosomichi, Takafumi Kobayashi, Satoshi Watanabe, Kenta Yamamura, Noriyuki Ohkura, Miki Abo, Seiji Yano

  Antibody-drug conjugates (ADCs) are emerging as a promising class of targeted cancer therapy. Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-directed ADC, has demonstrated clinical efficacy in HER2-positive gastric and breast cancers, as well as in HER2-mutant non-small cell lung cancer. However, the development of acquired resistance limits their long-term efficacy. To elucidate the resistance mechanism, we established T-DXd-resistant cell lines derived from HER2-amplified gastric xenografts (N87 acquired resistance [AR]) and leptomeningeal carcinomatosis (Calu-3 AR) lung cancer cells. N87 AR cells exhibited cross-resistance to T-DXd, payload DXd, and topoisomerase I inhibitor SN-38 despite preserved HER2 expression and intact drug internalization. As payload resistance-related molecules, ATP-binding cassette (ABC) transporter ABCG2 and ABCB1 were markedly upregulated in N87 AR and Calu-3 cells, respectively. Inhibition of ABCG2 and ABCB1 in N87 AR and Calu-3 cells, respectively, through siRNA-mediated knockdown restored T-DXd sensitivity in both models. As a strategy to overcome resistance, pharmacological inhibitors of ABCG2 and ABCB1 restored the T-DXd sensitivity of N87 AR and Calu-3 cells, respectively. Moreover, BB-1701, a novel HER2-ADC containing eribulin as a payload, to which N87 AR cells are sensitive, exhibited antitumor effects in N87 AR cells in vitro and in vivo. These findings indicate that ABC transporter-mediated drug efflux is an important mechanism underlying T-DXd resistance in HER2-positive gastric and lung cancer models. Furthermore, our study suggests that both targeting drug efflux pathways and utilizing alternative payloads may be effective strategies for overcoming T-DXd resistance in HER2-positive gastric and lung cancers.

  2026年01月, Cancer science, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• BGN Secreted by Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression via Activation of TLR4-Mediated Erk and NF-κB Signaling Pathways.

  Hiroki Yokoo, Yu-Ichiro Koma, Naozane Nomura, Rikuya Torigoe, Masaki Omori, Takashi Nakanishi, Shoji Miyako, Takaaki Nakanishi, Takayuki Kodama, Manabu Shigeoka, Yoshihiro Kakeji, Masafumi Horie

  Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis due to aggressive invasion and therapy resistance. Cancer-associated fibroblasts (CAFs) are key stromal components that promote tumor progression; however, their specific roles in ESCC remain unclear. Using a direct co-culture model of ESCC cell lines (TE-9, -10, and -15) and mesenchymal stem cells (MSCs) to generate CAF-like cells, we identified biglycan (BGN) as a significantly upregulated gene in CAF-like cells via cDNA microarray analysis. Public single-cell RNA sequencing data also demonstrated elevated BGN expression in CAF clusters. We confirmed that CAF-like cells exhibited elevated BGN expression and secretion at both the mRNA and protein levels. Recombinant human BGN enhanced ESCC cell proliferation and migration by activating Erk and NF-κB signaling pathways, effects abrogated by TLR4 blockade. Furthermore, BGN promoted CAF marker expression in MSCs, M2-like macrophage polarization, and enhanced proliferation and migration abilities in both cell types. Immunohistochemical analysis of 66 ESCC tissues revealed that high stromal BGN expression correlated with greater tumor invasion, lymphatic invasion, and shorter disease-free survival. These findings indicate that CAF-derived BGN promotes ESCC progression via TLR4-mediated signaling and modulates stromal cell behavior, highlighting its potential as a prognostic biomarker and therapeutic target.

  2025年12月, International journal of molecular sciences, 26(24) (24), 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Molecular characterization of chronic inflammatory diseases of the urinary bladder based on next-generation RNA sequencing and digital image analysis.

  Yoshiyuki Akiyama, Jimpei Miyakawa, Masafumi Horie, Tetsuichi Saito, Tomonori Minagawa, Tetsuo Ushiku, Akiteru Goto, Haruki Kume, Yukio Homma, Yi Luo, Daichi Maeda

  This study aimed to elucidate distinct cellular and immunological characteristics associated with chronic inflammatory conditions of the urinary bladder, including Hunner-type interstitial cystitis (HIC), bacillus Calmette-Guérin (BCG)-related cystitis, follicular cystitis (FC), and chronic bacterial cystitis (CBC). Transcriptomic analyses using next-generation RNA sequencing, along with quantitative polymerase chain reaction, were performed on mucosal bladder biopsies to assess the whole transcriptional and immune-response profiles. Furthermore, digital immunohistochemical quantification evaluated urothelial denudation and the densities of infiltrating immune cells, including T-lymphocytes, B-lymphocytes, mast cells, and plasma cells. HIC specimens exhibited a markedly distinct transcriptional profile, with 3,566 differentially expressed genes and enrichment of 116 biological processes particularly associated with microbial response and heightened autoimmunity with Th1/Th17 axis polarization. Histologically, HIC bladders demonstrated significant epithelial denudation, elevated IL-17-positive cell density, and increased plasma cell ratios compared to other cystitis types. No significant differences were observed in overall lymphoplasmacytic or mast cell densities, nor in B cell ratios among the groups. These findings underscore a unique immunopathological signature in HIC, characterized by plasma cell predominance within a Th1/17-polarized immune environment and epithelial denudation, offering new insights into its pathogenesis and therapeutic targeting.

  2025年10月, Scientific reports, 15(1) (1), 38169 - 38169, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Extracellular vesicles of cancer cells induce FOXP3+ fibroblasts and facilitate tumor invasion via the Wnt3-β-catenin pathway.

  Tomoaki Kimura, Kurara Takagane, Go Itoh, Sei Kuriyama, Kenji Meguro, Souichi Koyota, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Shuichi Tsukamoto, Naozane Nomura, Masafumi Horie, Motonobu Saito, Akiteru Goto, Masakazu Yashiro, Junichi Arita, Masamitsu Tanaka

  Forkhead-box-protein P3 (FOXP3) is a key transcription factor in T regulatory cells (Tregs). However, its expression and significance in non-immune stromal cells in the tumor microenvironment remain unclear. Here, we demonstrated FOXP3 expression in stromal fibroblasts of mouse and human gastrointestinal tumors. Immunohistological examination revealed FOXP3 expression in αSMA+ collagen I+ myofibroblasts. In the mouse omentum inoculated with gastric cancer cells, cytokeratin(-)/CD45(-)/FoxP3(+) stromal cells were identified via flow-cytometry, and high FOXP3 expression was noted in fibroblasts surrounding the tumor glands, where CD8+ T cells were exclusively infiltrated. Extracellular vesicles (EVs) from mouse gastric cancer cells upregulated Foxp3 transcription in fibroblasts, which partly depends on increase of transcription factors including NFAT1 and c-Rel, and activation of TGF-β and STAT5 pathways. In FOXP3(+) fibroblasts, immunosuppressive cytokines including IL-10 and CCL2 were upregulated. FOXP3 overexpression in NIH/3T3 fibroblasts enhanced Wnt3a-induced β-catenin responses, accompanied by cell growth and tumor invasion in mice stomach. As the mechanism, FOXP3 induced CDH11 expression in fibroblasts, which augmented the Wnt3/β-catenin pathway, and blocking of CDH11 suppressed tumor invasion mediated by FOXP3(+) fibroblasts. Our results suggest that cancer cell-derived EVs regulate FOXP3 expression in stromal fibroblasts, attenuating antitumor immunity, and facilitating tumor invasion.

  2025年09月, Oncogene, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Spatial TCR clonality and clonal expansion in the in situ microenvironment of non-small cell lung cancer.

  Hui Yu, Anastasia Magoulopoulou, Rose-Marie Amini, Maria Paraskevi Chatzinikolaou, Masafumi Horie, Amanda Lindberg, Artur Mezheyeuski, Max Backman, Andreas Metousis, Hans Brunnström, Millaray Marincevic, Johan Botling, Johanna Sofia Margareta Mattsson, Klas Kärre, Karin Leandersson, Mats Nilsson, Carina Strell, Patrick Micke

  BACKGROUND: T-cell activation and clonal expansion are essential to effective immunotherapy responses in non-small cell lung cancer (NSCLC). The distribution of T-cell clones may offer insights into immunogenic mechanisms and imply potential prognostic and predictive information. METHODS: We analyzed α/β T-cell receptor (TCR) clonality using RNA-sequencing of bulk frozen tumor tissue from 182 patients with NSCLC. The data was integrated with molecular and clinical characteristics, extensive in situ imaging, and spatial sequencing of the tumor immune microenvironment. TCR clonality was also determined in an independent cohort of nine patients with immune checkpoint-treated NSCLC. RESULTS: TCR clonality (Gini index) patterns ranged from high T-cell clone diversity with high evenness (low Gini index) to clonal dominance with low evenness (high Gini index). Generally, TCR clonality in cancer was lower than in matched normal lung parenchyma distant from the tumor (p=0.021). The TCR clonality distribution between adenocarcinoma and squamous cell carcinoma was similar; however, smokers showed a higher Gini index. While in the operated patient with NSCLC cohort, TCR clonality was not prognostic, in an immune checkpoint inhibitor-treated cohort, high TCR clonality was associated with better therapy response (p=0.016) and prolonged survival (p=0.003, median survival 13.8 vs 2.9 months). On the genomic level, a higher Gini index correlated strongly with a lower frequency of epidermal growth factor receptor (EGFR) and adenomatous polypsis coli (APC) gene mutations, but a higher frequency of P53 mutations, and a higher tumor mutation burden. In-depth characterization of the tumor tissue revealed that high TCR clonality was associated with an activated, inflamed tumor phenotype (PRF1, GZMA, GZMB, INFG) with exhaustion signatures (LAG3, TIGIT, IDO1, PD-1, PD-L1). Correspondingly, PD-1+, CD3+, CD8A+, CD163+, and CD138+immune cells infiltrated cancer tissue with high TCR clonality. In situ sequencing recovered single dominant T-cell clones within the patient tumor tissue, which were predominantly of the CD8 subtype and localized closer to tumor cells. CONCLUSION: Our robust analysis pipeline characterized diverse TCR repertoires linked to distinct genotypes and immunologic tumor phenotypes. The spatial clustering of expanded T-cell clones and their association with immunological activation underscores a functional, clinically relevant immune response, particularly in patients with NSCLC treated with checkpoint inhibitors.

  2025年08月, Journal for immunotherapy of cancer, 13(8) (8), 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Characteristic miRNA profiles represent clinicopathological diversity of small cell lung cancer.

  Masafumi Horie, Hiroshi Takumida, Hayato Koba, Tsukasa Ueda, Hidenori Tanaka, Masami Suzuki, Yukinobu Ito, Ayumi Ito, Mao Kondo, Hiroshi I Suzuki, Isao Matsumoto, Seiji Yano, Akira Saito, Daichi Maeda

  Small cell lung cancer (SCLC) is classified into distinct molecular subtypes based on the expression patterns of four transcription regulators: achaete-scute homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1). MicroRNAs (miRNAs) play critical roles in cancer cellular processes but their subtype-specific implications in SCLC remain underexplored. Out of 46 surgically resected SCLC samples, miRNA visualization through in situ hybridization identified high expression of miR-375 in the ASCL1, NEUROD1, and ASCL1/NEUROD1 subtypes, and miR-9-5p in the POU2F3 subtype. Comprehensive enhancer profiling using SCLC cell lines indicated that miR-375 and miR-9-5p were regulated by super-enhancers in a subtype-specific manner. Multiplex immunohistochemistry by imaging mass cytometry found that the miR-9-5p-high SCLC was characterized by a higher stromal area ratio, increased numbers of CD8+ T cells and CD163- macrophages in the intra-tumoral area, and an increased number of plasma cells in the stromal area, as compared with the miR-9-5p-low SCLC. Finally, clinicopathological analysis revealed that the miR-375-high SCLC was associated with YAP1 downregulation, increased serum pro-gastrin-releasing peptide levels, and poor prognosis. These findings highlight the critical role of super-enhancer-related miRNAs in the diversity of SCLC, and underscore the potential for novel diagnostic and prognostic biomarkers based on these subtype-specific miRNAs. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

  2025年08月, The Journal of pathology, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• Inhibition of ACVR1 in Cancer-Associated Fibroblasts Suppresses Colorectal Cancer Cell Growth.

  Shinya Kato, Norikatsu Miyoshi, Shiki Fujino, Masafumi Horie, Shinichi Yachida, Mitsunobu Takeda, Yuki Sekido, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Mamoru Uemura, Hirofumi Yamamoto, Masayoshi Yasui, Masayuki Ohue, Yuichiro Doki, Hidetoshi Eguchi

  BACKGROUND: Colorectal cancer (CRC) is the third most common malignancy worldwide and a leading cause of cancer-related mortality. Stromal signatures in CRC are correlated with poor prognosis and resistance to chemotherapy, affecting tumor progression and relapse. Although single-cell analyses have identified subpopulations of cancer-associated fibroblasts (CAFs), effective molecular targeted therapies against CAFs are lacking. MATERIALS AND METHODS: We employed organoid culture methods, focusing on two-dimensional organoids (2DOs) to mimic CRC histology. Using single-cell analysis, we investigated cancer-fibroblast crosstalk, with emphasis on activin receptor type I (ACVR1) in fibroblasts and bone morphogenetic protein 7 (BMP7) in cancer cells as potential therapeutic targets. The correlation between high ACVR1 and BMP7 expression levels and the prognosis of patients with stage II cancer was evaluated. RESULTS: The 2DO mouse xenograft model replicated the characteristics of the fibroblast subpopulations present in human CRC tumors. Single-cell RNA sequencing identified fibroblast clusters, with the BMP7-ACVR1 axis emerging as a potential therapeutic target. High BMP7 and ACVR1 expression was significantly correlated with poor disease-free survival and overall survival in stage II CRC. Administration of an ACVR1 inhibitor during the coculture of 2DOs and mouse stromal cells inhibited tumor growth. CONCLUSIONS: ACVR1 is a promising therapeutic target that inhibits CAF proliferation. High BMP7 and ACVR1 expression is a significant prognostic factor in stage II CRC.

  2025年07月, Annals of surgical oncology, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Integrative epigenome and transcriptome analyses reveal transcriptional programs differentially regulated by ASCL1 and NEUROD1 in small cell lung cancer.

  Hiroshi Takumida, Akira Saito, Yugo Okabe, Yasuhiro Terasaki, Yu Mikami, Hidenori Tanaka, Masami Suzuki, Yu Hamaguchi, Chao Zeng, Michiaki Hamada, Hiroshi I Suzuki, Hidenori Kage, Masafumi Horie

  Small cell lung cancer (SCLC), an aggressive neuroendocrine carcinoma, has an extremely poor prognosis. ASCL1 and NEUROD1 are key regulators of neuroendocrine features, and previous studies have suggested that SCLC plasticity occurs during the transition from ASCL1-positive (SCLC-A) to NEUROD1-positive (SCLC-N) subtypes. In this study, we attempted to understand the transcriptional programs governed by ASCL1 and NEUROD1 to identify markers of SCLC plasticity. Immunohistochemistry and epigenome and transcriptome analyses in ASCL1/NEUROD1 double-positive SCLC cells (SCLC-A/N) revealed co-expression of ASCL1 and NEUROD1 in almost half of SCLC cases. Genome-wide profiling of histone modifications, ASCL1 and NEUROD1 binding sites, and gene co-expression patterns revealed that both ASCL1 and NEUROD1 are active in SCLC-A/N and regulate partially distinct target genes. Furthermore, SCLC-A/N exhibited characteristics that were intermediate between SCLC-A and SCLC-N subtypes. NEUROD1 knockout, followed by RNA-seq, suggested an association between NEUROD and NHLH transcription factors that might shape the NEUROD1-mediated regulatory network. Small RNA-seq further indicated that miR-139-5p is specifically expressed in NEUROD1-positive SCLC, and transcriptomic studies suggested that miR-139-5p might regulate an array of pathologically relevant genes in collaboration with other NEUROD1-associated miRNAs. Our integrative analyses provide deeper insights into SCLC heterogeneity and multi-layered transcriptional programs differentially governed by ASCL1 and NEUROD1.

  2025年07月, Oncogene, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）

  神戸大学リポジトリ（Kernel）へのリンク


• CD31 expression in human cancers: a pan-cancer immunohistochemical study.

  Ayumi Ito, Yukinobu Ito, Hiroko Ikeda, Masafumi Horie, Yasufumi Omori, Akiteru Goto, Daichi Maeda

  AIMS: CD31 (platelet endothelial cell adhesion molecule 1) is a transmembrane glycoprotein involved in cell adhesion and signal transduction that is primarily expressed in vascular endothelial cells, platelets, neutrophils, and certain tumour cells. We investigated CD31 expression in cancer cells by conducting a pan-cancer gene expression analysis using data from cancer cell lines as well as an immunohistochemical analysis of surgically resected cancer specimens. The goal was to elucidate the frequency and distribution of CD31 expression across cancer types and its diagnostic significance. METHODS: Gene expression data from 1073 cancer cell lines were analysed to determine the frequency of CD31 expression across different cancer types. Immunohistochemical analysis was performed on 358 resected cancer specimens, focusing on adenocarcinomas and squamous cell carcinomas. The analysis compared the frequency of CD31 expression among specific cancer subtypes and between histological types. RESULTS: In gene expression analyses, adenocarcinomas showed a higher frequency of CD31 expression than did squamous cell carcinomas. Immunohistochemically, CD31 expression was observed in breast apocrine carcinomas (40.0%), hepatocellular carcinomas (18.8%), uterine endometrioid adenocarcinomas (31.6%), ovarian high-grade serous carcinomas (20.0%), ovarian clear cell carcinomas (40.0%) and urothelial carcinomas (25.0%). No CD31 expression was detected in oesophageal, renal, prostate or cervical cancers. CONCLUSIONS: CD31 expression is more frequent in adenocarcinomas than in squamous cell carcinomas, with variability among cancer subtypes. Recognising CD31-positive cancers is critical to avoid misdiagnosing them as endothelial-derived tumours. The mechanisms underlying CD31 expression in cancer remain unclear and warrant further investigation.

  2025年05月, Journal of clinical pathology, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• 血管疾患の病因・病理:アップデート In vivo動静脈奇形モデルを用いたヒト脳動静脈奇形のメカニズムの解明(Update of etiology and pathology of vascular disease Mechanisms of brain arteriovenous malformations using an in vivo arteriovenous malformation model)

  伊藤 行信, 吉田 誠, 南條 博, 増田 弘毅, 阪口 真希, 伊藤 歩美, 堀江 真史, 後藤 明輝, 前田 大地

  (一社)日本病理学会, 2025年03月, 日本病理学会会誌, 114(1) (1), 217 - 217, 英語


• 癌関連線維芽細胞との相互作用によって癌細胞において発現亢進するAREGは食道扁平上皮癌の進展を促進する(AREG upregulated in cancer cells by direct interaction with CAFs promotes ESCC progression via EGFR)

  狛 雄一朗, 中西 崇, 塚本 修一, 児玉 貴之, 西尾 真理, 重岡 学, 堀江 真史

  (一社)日本病理学会, 2025年03月, 日本病理学会会誌, 114(1) (1), 285 - 286, 英語


• pT1/T2舌癌において骨髄由来間葉系幹細胞は癌細胞との相互作用によりiCAF様形質を獲得する(BM-MSCs acquire iCAF-like phenotype by interaction with cancer cells in pT1/T2 tongue cancer)

  重岡 学, 塚本 修一, 児玉 貴之, 西尾 真理, 狛 雄一朗, 堀江 真史

  (一社)日本病理学会, 2025年03月, 日本病理学会会誌, 114(1) (1), 298 - 298, 英語


• 大腸癌の進展に伴うがん関連線維芽細胞の不均一性の解明(Challenges to cancer-associated fibroblasts' diversity in colorectal carcinoma along its progression)

  塚本 修一, 野村 尚志, 児玉 貴之, 西尾 真理, 重岡 学, 狛 雄一朗, 堀江 真史

  (一社)日本病理学会, 2025年03月, 日本病理学会会誌, 114(1) (1), 323 - 323, 英語


• 膵上皮内癌・微小浸潤癌の腫瘍免疫微小環境に関する免疫組織化学的検討(Tumor immune microenvironment in isolated high-grade PanIN and microinvasive PDAC: an IHC study)

  児玉 貴之, 塚本 修一, 西尾 真理, 重岡 学, 狛 雄一朗, 堀江 真史

  (一社)日本病理学会, 2025年03月, 日本病理学会会誌, 114(1) (1), 345 - 345, 英語


• マクロファージと肝細胞癌との間接共培養で発現上昇するCHI3L1とOPNの機能解析(Analysis of CHI3L1 and OPN upregulated in indirect co-culture system using HCC cells and macrophages)

  大森 將貴, 石原 伸明, 鳥越 陸矢, 横尾 拓樹, 藤本 修一, 児玉 貴之, 西尾 真理, 重岡 学, 狛 雄一朗, 堀江 真史

  (一社)日本病理学会, 2025年03月, 日本病理学会会誌, 114(1) (1), 350 - 350, 英語


• 癌関連線維芽細胞との相互作用により食道扁平上皮癌において発現亢進するBST2の機能解析(Analysis of BST2 upregulated in ESCC cells via interaction with cancer-associated fibroblasts)

  鳥越 陸矢, 横尾 拓樹, 大森 將貴, 中西 崇, 塚本 修一, 児玉 貴之, 西尾 真理, 重岡 學, 狛 雄一朗, 堀江 真史

  (一社)日本病理学会, 2025年03月, 日本病理学会会誌, 114(1) (1), 352 - 353, 英語


• 食道扁平上皮癌細胞と共培養した癌関連線維芽細胞において発現亢進するビグリカンの解析(Analysis of biglycan upregulated in cancer-associated fibroblasts co-cultured with ESCC cells)

  横尾 拓樹, 鳥越 陸矢, 大森 將貴, 中西 崇, 塚本 修一, 児玉 貴之, 西尾 真理, 重岡 学, 狛 雄一朗, 堀江 真史

  (一社)日本病理学会, 2025年03月, 日本病理学会会誌, 114(1) (1), 353 - 353, 英語


• 食道扁平上皮癌と癌関連線維芽細胞との直接共培養により発現誘導されるISG15の解析

  野村 尚志, 塚本 修一, 児玉 貴之, 西尾 真理, 重岡 学, 狛 雄一朗, 堀江 真史

  (一社)日本病理学会, 2025年03月, 日本病理学会会誌, 114(1) (1), 447 - 447, 日本語


• Characterizing the Tumor Immune Environment in Thymic Epithelial Tumors Using T-cell Receptor Repertoire Analysis and Gene Expression Profiling

  Hiroto Ishida, So Takata, Koichiro Aya, Yoichiro Nakatani, Masafumi Horie, Daichi Maeda, Soichiro Funaki, Yasushi Shintani, Shinichi Yachida

  OBJECTIVES: A thymoma is a functional thymic epithelial tumor wherein tumorigenic thymic epithelial cells possess T-cell differentiation and maturation potential. The tumor immune environment exhibits heterogeneous tumor immunity. The tumor immune environment of thymoma is characterized by its distinctive and complex immunological functions, requiring an analysis of the various factors involved. We aimed to evaluate the thymoma tumor immune environment and conduct a comprehensive immunogenomic profiling. METHODS: Ninety-seven patients undergoing surgery for primary thymoma were enrolled in the study. RNA was extracted from frozen tissue specimens, followed by analysis of T-cell receptor repertoire and RNA-seq. A clonality assessment of the T-cell receptor repertoire and shared clonotypes was also conducted. Gene expression profiling using digital cytometry (CIBERSORTx), T-cell inflammation signature, and Immunogram methodologies was performed. RESULTS: The analysis of T-cell receptor repertoire results indicated a higher level of clonality in B3 thymomas than in other histological types. The high-clonality group exhibited a worse prognosis than the low-clonality group. The results of digital cytometry revealed that type B3 thymomas were clustered and distinguished by a higher abundance of activated natural killer cells, macrophages, and resting mast cells than in other histological types. Additionally, the Immunogram gene signatures showed no correlation with the clonality of the T-cell receptor repertoire. CONCLUSIONS: Multiple immunological approaches to evaluate the tumor immune environment and immunogenomic profile of thymoma reveal a diverse and complex immune environment. B3 thymomas, despite being T-cell depleted, exhibit increased T-cell receptor clonality and expanded T-cell clones. Given the poor prognosis and the elevated expression of T-cell inhibitory markers, particularly CTLA4, this subset of patients may represent a critical target population for future clinical trials investigating T-cell checkpoint inhibitors.

  Elsevier BV, 2025年03月, JTCVS Open, 25, 435 - 465, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Adverse effects of progestin-primed ovarian stimulation: combination of clinical study and single-cell analysis.

  Mika Handa, Tsuyoshi Takiuchi, Sumika Kawaguchi, Chung-Chau Hon, Jonathan Moody, Yasushi Okazaki, Kokoro Ozaki, Masafumi Horie, Yasuhiro Ohara, Masakazu Doshida, Takumi Takeuchi, Hidehiko Matsubayashi, Fumie Saji, Tatsuya Miyake, Tomomoto Ishikawa, Yoshinari Ando, Sho Komukai, Tetsuhisa Kitamura, Jay W Shin, Tadashi Kimura

  RESEARCH QUESTION: Does progestin-primed ovarian stimulation (PPOS) have a negative effect on reproductive outcomes compared with a gonadotrophin-releasing hormone (GnRH) antagonist protocol? DESIGN: This retrospective cohort study included 907 patients aged <40 years with normal ovarian reserves undergoing either PPOS (n = 299) or a GnRH-antagonist protocol (n = 608) in their first IVF cycle between 2018 and 2020. An additional genetic analysis, single-cell RNA sequencing (scRNA-seq), was performed on the mural granulosa cells (mGC) of metaphase II oocyte follicles retrieved from 16 patients, with the above inclusion criteria, undergoing PPOS (n = 8) or a GnRH-antagonist protocol (n = 8) between 2021 and 2022. Inverse probability of treatment weighting (IPTW) was performed on the clinical data. Predetermined primary outcomes were the premature LH surge rate and the live birth rate of the first frozen embryo transfer cycle for the first and second IPTW analyses, respectively. RESULTS: The premature LH surge rate was lower in the PPOS group compared with the GnRH-antagonist group (3.1% versus 20.1%, OR 0.13, 95% CI 0.07-0.23; P < 0.001) in the first IPTW analysis. The good-quality cleavage embryo rate was lower in the PPOS group compared with the GnRH-antagonist group (37.2% versus 49.1%; P < 0.001). The live birth rate was lower in the PPOS group compared with the GnRH-antagonist group (31.5% versus 42.3%, OR 0.63, 95% CI 0.46-0.86; P = 0.004) in the second IPTW analysis. The scRNA-seq analysis demonstrated higher expression of 12 mitochondrial DNA (mtDNA) genes in the PPOS group compared with the GnRH-antagonist group. CONCLUSION: PPOS suppressed the premature LH surge rate but was associated with a lower live birth rate compared with the GnRH-antagonist protocol. The elevated expression of mtDNA genes in mGC may also indicate a decline in oocyte quality with PPOS.

  2025年01月, Reproductive biomedicine online, 104833 - 104833, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• APRIL/BAFF Upregulation is Associated with Clonal B-cell Expansion in Hunner-type Interstitial Cystitis

  Masafumi Horie, Yoshiyuki Akiyama, Hiroto Katoh, Satoru Taguchi, Masaki Nakamura, Keishi Mizuguchi, Yukinobu Ito, Takashi Matsushita, Tetsuo Ushiku, Shumpei Ishikaw, Akiteru Goto, Haruki Kume, Yukio Hom, Daichi Maed

  2024年08月, Journal of Pathology

  [査読有り]


• Comprehensive genomic analysis reveals clonal origin and subtype-specific evolution in a case of sporadic multiple meningiomas.

  Maki Sakaguchi, Masafumi Horie, Yukinobu Ito, Shingo Tanaka, Keishi Mizuguchi, Hiroko Ikeda, Etsuko Kiyokawa, Mitsutoshi Nakada, Daichi Maeda

  Meningioma is the most common primary intracranial tumor in adults, with up to 10% manifesting as multiple tumors. Data on the genomic and molecular changes in sporadic multiple meningiomas are scarce, leading to ongoing debates regarding their evolutionary processes. A comprehensive genetic analysis of a large number of lesions, including precursor lesions, is necessary to explore these two possible origins: clonal and independent. In the present study, we performed whole-exome sequencing and analyzed somatic single-nucleotide variants (SNVs), insertions/deletions (INDELs), and copy number alterations (CNAs) in a patient with sporadic multiple meningiomas. These meningiomas included two mass-forming lesions of different histological subtypes (transitional and chordoid) and two small meningothelial nests. Genetic analysis revealed CNAs on chromosomes 22q and Y as common abnormalities in the two largest tumors. Furthermore, we identified SNV/INDELs unique to each focus, with NF2 mutation prevalent in the transitional meningioma and CREBBP mutation in the chordoid meningioma. Loss of chromosome 22 was detected in two small meningothelial nests. Overall, we elucidated the clonal origin and subtype-specific evolution of multiple meningiomas in this case. CNAs may serve as the initial driving event in meningioma development.

  2024年07月, Brain tumor pathology, 英語, 国内誌

  [査読有り]

  研究論文（学術雑誌）


• ZFP36 family expression is suppressed by Th2 cells in asthma, leading to enhanced synthesis of inflammatory cytokines and cell surface molecules.

  Yuki Uehara, Maho Suzukawa, Masafumi Horie, Sayaka Igarashi, Masaaki Minegishi, Kazufumi Takada, Akira Saito, Hiroyuki Nagase

  Asthma is a chronic inflammatory airway disease, in which inflammatory cytokines play a pivotal role. The zinc finger binding protein 36 (ZFP36) family includes ZFP36, ZFP36L1, and ZFP36L2 and is among the RNA-binding proteins (RBPs) reported to cause inflammation. The present study aimed to clarify the roles of the ZFP36 family in asthma, particularly highlighting the relationship between the ZFP36 family and Th2 cells, which are key players in type 2 inflammation in asthma. Real-time PCR analysis revealed the preferential expression of ZFP36 family mRNAs in human white blood cells. Gene expression analysis using public datasets from the GEO database (https://www.ncbi.nlm.nih.gov/gds) showed significantly suppressed expression of ZFP36 family mRNAs in patients with asthma compared to that in healthy controls. Using multiple cytokine assays, Th2 cell transfection with ZFP36 family siRNAs enhanced the expression of inflammatory cytokines IL-8, IFN-γ, CCL3/MIP-1α, CCL4/MIP-1β, and TNF-α and cell surface molecules CCR4 (CD194) and PSGL-1 (CD162). Treatment with IL-2, 4, and 15 significantly suppressed, and corticosteroid significantly enhanced the expressions of ZFP36 family mRNAs by Th2 cells. In conclusion, the ZFP36 family expressed by Th2 cells was suppressed in patients with asthma, leading to the enhanced expression of cytokines and cell surface molecules. Suppressed ZFP36 expression in asthma may be involved in the enhancement of airway inflammation, and the ZFP36 family may be a therapeutic target for inflammatory diseases, including asthma.

  2024年07月, Cellular immunology, 403-404, 104859 - 104859, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Survival of Metastatic Human Papillomavirus (HPV)-Related Head and Neck Cancer Receiving Platinum-Based Triplet Induction Chemotherapy and Relevance of Circulating Tumor HPV DNA.

  Hirotaka Eguchi, Yukinori Takenaka, Hidenori Tanaka, Motoyuki Suzuki, Masafumi Horie, Haruka Kanai, Yuji Seo, Kazuhiko Ogawa, Shinichi Yachida, Hidenori Inohara

  Objectives We aimed to examine the effectiveness of platinum-based triplet induction chemotherapy in metastatic squamous cell carcinoma of the head and neck (HNSCC) at diagnosis in terms of tumor human papillomavirus (HPV) status and the clinical relevance of circulating tumor HPV DNA (ctHPVDNA) during induction chemotherapy. Methods  Twenty-one patients were included. ctHPVDNA was longitudinally quantified using optimized digital PCR in a subset of patients. Results HPV-related HNSCC patients (N=7) had a significantly better response to induction chemotherapy than HPV-unrelated HNSCC patients (N=14) (complete or partial response rate, 100% vs. 36%, P = 0.007). Following induction chemotherapy, more HPV-related HNSCC patients than HPV-unrelated patients received radiotherapy (86% vs. 36%, P = 0.06). With a median follow-up of 26 months in surviving patients, the two-year overall survival was 86% in HPV-related HNSCC patients and 43% in HPV-unrelated HNSCC patients (P = 0.04). In two patients, ctHPVDNA levels drastically decreased after the first cycle of induction chemotherapy but turned to continuous increase after the second cycle, suggesting the acquisition of drug resistance by the end of the second cycle. Radiographic imaging after induction chemotherapy failed to identify the drug resistance. In one patient, ctHPVDNA decreased gradually but remained detectable after induction chemotherapy despite no radiographic residual disease. ctHPVDNA became undetectable during radiotherapy. Conclusion HPV-related HNSCC patients with distant metastasis at diagnosis should be treated definitively. The ctHPVDNA level reflects real-time disease activity. ctHPVDNA monitoring during induction chemotherapy could help the decision-making of the therapeutic strategy.

  2024年05月, Cureus, 16(5) (5), e60547, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Genomic evolutional analysis of surgical resected specimen to assess osimertinib as a first‐line therapy in two patients with lung cancer harboring EGFR mutation: Case series

  Hayato Koba, Taro Yoneda, Hiroko Morita, Hideharu Kimura, Yuya Murase, Nanao Terada, Yuichi Tambo, Masafumi Horie, Kazuo Kasahara, Isao Matsumoto, Seiji Yano

  Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is crucial for patients with lung cancer harboring EGFR mutations. However, almost all patients experience disease progression, regardless of their response to the targeted therapy, necessitating the development of additional treatment options. Two patients with lung cancer harboring EGFR‐L858R mutations in exon 21 were treated by surgical resection during successful osimertinib treatment. Because the pathological diagnosis was suspected to be pleural metastasis, osimertinib treatment was continued until disease progression. We analyzed the evolution of genomic alterations and the levels of AXL using tumor specimens obtained by repeated biopsies during the course of treatment: initial diagnosis, operation, and disease progression. Genetic alterations detected at the three time points were dramatically changed and showed reductions in numbers, while EGFR‐L858R mutations were detected in all samples tested in both patients. Immunohistochemical expression of AXL remained positive from the beginning of analysis to disease progression. Clonal evolution under oncogenesis is related to gradual accumulation of genomic alterations during tumor growth. However, our case series revealed that volume reduction procedures may cause this phenomenon. Therefore, identification of intrinsic drug‐resistant cells in tumors may be as important as detection of acquired genetic alterations.

  Wiley, 2024年02月, Thoracic Cancer

  [査読有り]

  研究論文（学術雑誌）


• 高血流量が誘発する動脈リモデリングでの血管平滑筋細胞のリモデリング(Vascular smooth muscle cell remodeling in high-flow induced arterial remodeling)

  伊藤 行信, 吉田 誠, 堀江 真史, 前田 大地, 後藤 明輝, 増田 弘毅

  (一社)日本病理学会, 2024年02月, 日本病理学会会誌, 113(1) (1), 359 - 359, 英語


• 全エクソン解析による多発髄膜腫におけるクローナリティーの証明

  阪口 真希, 堀江 真史, 伊藤 行信, 田中 慎吾, 池田 博子, 前田 大地

  (一社)日本病理学会, 2024年02月, 日本病理学会会誌, 113(1) (1), 438 - 438, 日本語


• 剖検心30例を用いた心筋介在板の構造異常の検討

  要川 雄紀, 伊藤 行信, 熊田 雄仁, 伊藤 歩美, 阪口 真希, 堀江 真史, 吉田 誠, 前田 大地

  (一社)日本病理学会, 2024年02月, 日本病理学会会誌, 113(1) (1), 466 - 466, 日本語


• 包括的免疫ゲノムプロファイリングによるハンナ型間質性膀胱炎の本態解明(Comprehensive Immunogenomic Profiling of Hunner-type Interstitial Cystitis)

  堀江 真史, 秋山 佳之, 加藤 洋人, 水口 敬司, 牛久 哲男, 石川 俊平, 後藤 明輝, 本間 之夫, 前田 大地

  (一社)日本病理学会, 2024年02月, 日本病理学会会誌, 113(1) (1), 287 - 287, 英語


• 高血流量が誘発する動脈リモデリングでの血管平滑筋細胞のリモデリング(Vascular smooth muscle cell remodeling in high-flow induced arterial remodeling)

  伊藤 行信, 吉田 誠, 堀江 真史, 前田 大地, 後藤 明輝, 増田 弘毅

  (一社)日本病理学会, 2024年02月, 日本病理学会会誌, 113(1) (1), 359 - 359, 英語


• Identification of uromodulin deposition in the stroma of perinephric fibromyxoid nephrogenic adenoma by mass spectrometry.

  Kaori Yoshimura, Yukinobu Ito, Mina Suzuki, Masafumi Horie, Takumi Nishiuchi, Yukako Shintani-Domoto, Kazuyoshi Shigehara, Hiroko Oshima, Masanobu Oshima, Akiteru Goto, Takayuki Nojima, Toyonori Tsuzuki, Atsushi Mizokami, Hiroko Ikeda, Daichi Maeda

  Nephrogenic adenoma (NA) is an epithelial lesion that usually occurs in the mucosa of the urinary tract. Rare cases of deep infiltrative or perinephric lesions have also been reported. Recently, NA with characteristic fibromyxoid stroma (fibromyxoid NA) has been proposed as a distinct variant. Although shedding of distal renal tubular cells due to urinary tract rupture has been postulated as the cause of NA in general, the mechanism underlying extraurinary presentation of NA and fibromyxoid stromal change in fibromyxoid NA remains unknown. In this study, we performed mass spectrometry (MS) analysis in a case of perinephric fibromyxoid NA of an 82-year-old man who underwent right nephroureterectomy for distal ureteral cancer. The patient had no prior history of urinary tract injury or radiation. Periodic acid-Schiff staining-positive eosinophilic structureless deposits in the stroma of fibromyxoid NA were microdissected and subjected to liquid chromatography/MS. The analysis revealed the presence of a substantial amount of uromodulin (Tamm-Horsfall protein). The presence of urinary content in the stroma of perinephric fibromyxoid NA suggests that urinary tract rupture and engraftment of renal tubular epithelial cells directly cause the lesion.

  2024年01月, Pathology international, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Metastases and treatment-resistant lineages in patient-derived cancer cells of colorectal cancer.

  Shiki Fujino, Norikatsu Miyoshi, Aya Ito, Rie Hayashi, Masayoshi Yasui, Chu Matsuda, Masayuki Ohue, Masafumi Horie, Shinichi Yachida, Jun Koseki, Teppei Shimamura, Tsuyoshi Hata, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Tsunekazu Mizushima, Yuichiro Doki, Hidetoshi Eguchi

  Circulating tumor cells (CTCs) play an important role in metastasis and recurrence. However, which cells comprise the complex tumor lineages in recurrence and are key in metastasis are unknown in colorectal cancer (CRC). CRC with high expression of POU5F1 has a poor prognosis with a high incidence of liver metastatic recurrence. We aim to reveal the key cells promoting metastasis and identify treatment-resistant lineages with established EGFP-expressing organoids in two-dimensional culture (2DOs) under the POU5F1 promotor. POU5F1-expressing cells are highly present in relapsed clinical patients' blood as CTCs. Sorted POU5F1-expressing cells from 2DOs have cancer stem cell abilities and abundantly form liver metastases in vivo. Single-cell RNA sequencing of 2DOs identifies heterogeneous populations derived from POU5F1-expressing cells and the Wnt signaling pathway is enriched in POU5F1-expressing cells. Characteristic high expression of CTLA4 is observed in POU5F1-expressing cells and immunocytochemistry confirms the co-expression of POU5F1 and CTLA4. Demethylation in some CpG islands at the transcriptional start sites of POU5F1 and CTLA4 is observed. The Wnt/β-catenin pathway inhibitor, XAV939, prevents the adhesion and survival of POU5F1-expressing cells in vitro. Early administration of XAV939 also completely inhibits liver metastasis induced by POU5F1-positive cells.

  2023年11月, Communications biology, 6(1) (1), 1191 - 1191, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• GRAMD2 + alveolar type I cell plasticity facilitates cell state transitions in organoid culture.

  Hua Shen, Weimou Chen, Yixin Liu, Alessandra Castaldi, Jonathan Castillo, Masafumi Horie, Per Flodby, Shivah Sundar, Changgong Li, Yanbin Ji, Parviz Minoo, Crystal N Marconett, Beiyun Zhou, Zea Borok

  Alveolar epithelial regeneration is critical for normal lung function and becomes dysregulated in disease. While alveolar type 2 (AT2) and club cells are known distal lung epithelial progenitors, determining if alveolar epithelial type 1 (AT1) cells also contribute to alveolar regeneration has been hampered by lack of highly specific mouse models labeling AT1 cells. To address this, the Gramd2 CreERT2 transgenic strain was generated and crossed to Rosa mTmG mice. Extensive cellular characterization, including distal lung immunofluorescence and cytospin staining, confirmed that GRAMD2 + AT1 cells are highly enriched for green fluorescent protein (GFP). Interestingly, Gramd2 CreERT2 GFP + cells were able to form organoids in organoid co-culture with Mlg fibroblasts. Temporal scRNAseq revealed that Gramd2 + AT1 cells transition through numerous intermediate lung epithelial cell states including basal, secretory and AT2 cell in organoids while acquiring proliferative capacity. Our results indicate that Gramd2 + AT1 cells are highly plastic suggesting they may contribute to alveolar regeneration.

  2023年10月, bioRxiv : the preprint server for biology, 英語, 国際誌


• Distinct microRNA signature and suppression of ZFP36L1 define ASCL1-positive lung adenocarcinoma.

  Takayoshi Enokido, Masafumi Horie, Seiko Yoshino, Hiroshi I Suzuki, Rei Matsuki, Hans Brunnström, Patrick Micke, Takahide Nagase, Akira Saito, Naoya Miyashita

  Achaete-scute family bHLH transcription factor 1 (ASCL1) is a master transcription factor involved in neuroendocrine differentiation. ASCL1 is expressed in approximately 10% of lung adenocarcinomas and exerts tumor-promoting effects. Here, we explored microRNA (miRNA) profiles in ASCL1-positive lung adenocarcinomas and identified several miRNAs closely associated with ASCL1 expression, including miR-375, miR-95-3p/miR-95-5p, miR-124-3p, and members of the miR-17~92 family. Similar to small cell lung cancer, Yes1 associated transcriptional regulator (YAP1), a representative miR-375 target gene, was suppressed in ASCL1-positive lung adenocarcinomas. ASCL1 knockdown followed by miRNA profiling in a cell culture model further revealed that ASCL1 positively regulates miR-124-3p and members of the miR-17~92 family. Integrative transcriptomic analyses identified ZFP36 ring finger protein like 1 (ZFP36L1) as a target gene of miR-124-3p, and immunohistochemical studies demonstrated that ASCL1-positive lung adenocarcinomas are associated with low ZFP36L1 protein levels. Cell culture studies showed that ectopic ZFP36L1 expression inhibits cell proliferation, survival, and cell cycle progression. Moreover, ZFP36L1 negatively regulated several genes including E2F transcription factor 1 (E2F1) and snail family transcriptional repressor 1 (SNAI1). In conclusion, our study revealed that suppression of ZFP36L1 via ASCL1-regulated miR-124-3p could modulate gene expression., providing evidence that ASCL1-mediated regulation of miRNAs shapes molecular features of ASCL1-positive lung adenocarcinomas. Implications: Our study revealed unique miRNA profiles of ASCL1-positive lung adenocarcinomas and identified ASCL1-regulated miRNAs with functional relevance.

  2023年10月, Molecular cancer research : MCR, 22(1) (1), 29 - 40, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Whole Exome Sequencing of Thymoma Patients Exhibiting Exceptional Responses to Pemetrexed Monotherapy.

  Tomohiro Tanaka, Yasushi Goto, Masafumi Horie, Ken Masuda, Yuki Shinno, Yuji Matsumoto, Yusuke Okuma, Tatsuya Yoshida, Hidehito Horinouchi, Noriko Motoi, Yasushi Yatabe, Shunichi Watanabe, Noboru Yamamoto, Yuichiro Ohe

  BACKGROUND: Pemetrexed is used for the chemotherapy of advanced thymoma. Exceptional responses of thymoma to pemetrexed treatment are not frequently observed. The underlying genetic mechanism of the exceptional responses remains unclear. We used whole-exome sequencing to explore the specific genomic aberrations that lead to an extreme and durable response. METHODS: Whole-exome sequencing using NovaSeq6000 (150 bp paired-end sequencing) was performed on nine formalin-fixed paraffin-embedded tissues from patients with advanced thymomas treated with pemetrexed (two exceptional responders and seven typical responders). RESULTS: We identified 284 somatic single-nucleotide variants (SNVs; 272 missense, 8 missense/splice-site, 3 stop-gain, and 1 stop-gain/splice-site), 34 insertions and deletions (Indels; 33 frameshift and one splice region), and 21 copy number variations (CNVs; 15 gains and six losses). No difference in the number of SNVs variants and distribution of deleterious Indels was observed between the exceptional and typical responders. Interestingly, arm-level chromosomal CNVs (15 gains and six losses) were detected in four patients, including an exceptional responder. The highest number of arm-level CNVs was observed in an exceptional responder. CONCLUSION: Exceptional responders to pemetrexed for metastatic thymomas may be characterized by arm-level CNVs. Further, whole-genome and RNA sequencing studies should be performed.

  2023年08月, Cancers, 15(16) (16), 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Cancer Stem Cells Persist Despite Cellular Damage, Emergence of the Refractory Cell Population.

  Ayumi Nagae, Norikatsu Miyoshi, Shiki Fujino, Masafumi Horie, Shinichi Yachida, Masaru Sasaki, Yuki Sekido, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Hirofumi Yamamoto, Yuichiro Doki, Hidetoshi Eguchi

  PURPOSE: Cancer stem cells (CSCs) are responsible for chemotherapy resistance and have unique properties that protect them from chemotherapy. Investigating CSCs may help to identify the population that is more resistant to treatments, leading to recurrence. We evaluated persisting CSCs, emerging after chemotherapy that cause tumor recurrence. METHODS: Using human colorectal cancer organoids prepared from surgical specimens, we looked at changes in CSCs, the emergence and changes in the original population, which single-cell analysis identified. RESULTS: With regards to changes in cancer stem cell markers, CD44 showed low levels after 5-fluorouracil administration. Once the CD44-ve population was sorted and cultured, the CD44+ve population gradually emerged, and the CD44-ve population decreased. Compared with the CD44-ve population of an organoid parent, the CD44-ve population proliferated after chemotherapeutic agent stimulation. The CD44-ve population was derived from the CD44+ve population before chemotherapeutic agents. In addition, when the CD44 variants were evaluated, the CD44v9 population remained. In single-cell analysis, we found that POU5F1 was highly expressed in the CD44low population. Velocity analysis showed that the CD44-ve population was induced after chemotherapy and expressed POU5F1. POU5F1-EGFP-Casp9 transfected organoids resulted in the appearance of a CD44-ve population after administration of a chemotherapeutic reagent. Both in vivo and in vitro, the dimerizer administration inhibited tumor growth significantly. CONCLUSIONS: POU5F1 is involved in chemotherapy resistance in relation to stemness. For the treatment against refractory tumors, such as the recurrence after chemotherapy, the treatment should target the emerging specific population such as CD44 (or CD44v9) and proliferative cancer cells.

  2023年07月, Annals of surgical oncology, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• An integrative epigenomic approach identifies ELF3 as an oncogenic regulator in ASCL1-positive neuroendocrine carcinoma.

  Masafumi Horie, Hidenori Tanaka, Masami Suzuki, Yoshihiko Sato, So Takata, Erina Takai, Naoya Miyashita, Akira Saito, Yoichiro Nakatani, Shinichi Yachida

  Neuroendocrine carcinoma (NEC) is a highly aggressive subtype of the neuroendocrine tumor with an extremely poor prognosis. We have previously conducted a comprehensive genomic analysis of over 100 cases of NEC of the gastrointestinal system (GIS-NEC) and unraveled its unique and organ-specific genomic drivers. However, the epigenomic features of GIS-NEC remain unexplored. In this study, we have described the epigenomic landscape of GIS-NEC and small cell lung carcinoma (SCLC) by integrating motif enrichment analysis from the assay of transposase accessible chromatin sequencing (ATAC-seq) and enhancer profiling from a novel cleavage under targets and tagmentation (CUT&Tag) assay for H3K27ac and identified ELF3 as one of the super-enhancer-related transcriptional factors in NEC. By combining CUT&Tag and knockdown RNA sequencing for ELF3, we uncovered the transcriptional network regulated by ELF3 and defined its distinctive gene signature, including AURKA, CDC25B, CLDN4, ITGB6, and YWAHB. Furthermore, a loss-of-function assay revealed that ELF3 depletion led to poor cell viability. Finally, using gene expression of clinical samples, we successfully divided GIS-NEC patients into two subgroups according to the ELF3-signature, and demonstrated that tumor-promoting pathways were activated in the ELF3-signature high group. Our findings highlight the transcriptional regulation of ELF3 as an oncogenic transcription factor and its tumor-promoting properties in NEC.

  2023年02月, Cancer science, 114(6) (6), 2596 - 2608, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Clearance Profile of Circulating Tumor Human Papillomavirus DNA During Radiotherapy Predicts Clinical Outcomes in Human Papillomavirus-Related Oropharyngeal Cancer.

  Hidenori Tanaka, Atsuhiko Uno, Yukinori Takenaka, Motoyuki Suzuki, Yuji Seo, Norihiko Takemoto, Takahito Fukusumi, Hirotaka Eguchi, Haruka Kanai, Masafumi Horie, Fumiaki Isohashi, Kazuhiko Ogawa, Shinichi Yachida, Hidenori Inohara

  PURPOSE: This study aimed to examine whether circulating tumor human papillomavirus type 16 (HPV16) DNA (ctHPV16DNA) can help identify patients with locally advanced HPV16-related oropharyngeal squamous cell carcinoma who may benefit from deintensified treatment. MATERIALS AND METHODS: We serially collected blood samples before, during, and after treatment from 22 patients who received 70 Gy radiotherapy alone and longitudinally quantified ctHPV16DNA using droplet digital polymerase chain reaction. We correlated the clearance profile of ctHPV16DNA with clinical outcomes. RESULTS: The percentage of patients with detectable ctHPV16DNA decreased after every 10 Gy of radiotherapy. By contrast, the percentage of patients who later developed treatment failure among patients with detectable ctHPV16DNA gradually increased as radiotherapy proceeded, reaching 100% after 60 Gy of radiotherapy. We defined patients with and without detectable ctHPV16DNA after receiving 40 Gy as having slow and rapid clearance profiles, respectively. All 12 patients with a rapid clearance profile remained disease-free after radiotherapy. Of the 10 patients with a slow clearance profile, three had persistent or progressive disease at response evaluation after radiotherapy and one developed distant metastasis during follow-up (ie, four patients experienced treatment failure). The median follow-up for surviving patients was 38.6 months, and the 3-year failure-free survival rates of patients with rapid and slow clearance profiles were 100% and 58%, respectively (P = .02). Neither baseline ctHPV16DNA levels nor metabolic tumor volume was an independent predictor of the pattern of the clearance profile. CONCLUSION: In patients with HPV16-related oropharyngeal squamous cell carcinoma receiving radiotherapy, a slow ctHPV16DNA clearance profile could prelude unfavorable outcomes. Monitoring ctHPV16DNA is essential for determining the clearance profile, which might help optimize treatment intensity individually.

  2023年02月, JCO precision oncology, 7, e2200494, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Inhibition of Epithelial-Mesenchymal Transition Maintains Stemness in Human Amniotic Epithelial Cells.

  Chika Takano, Masafumi Horie, Isamu Taiko, Quang Duy Trinh, Kazunori Kanemaru, Shihoko Komine-Aizawa, Satoshi Hayakawa, Toshio Miki

  Human amniotic epithelial cells (hAECs), which are a type of placental stem cell, express stem cell marker genes and are capable of differentiating into all three germ layers under appropriate culture conditions. hAECs are known to undergo TGF-β-dependent epithelial-mesenchymal transition (EMT); however, the impact of EMT on the stemness or differentiation of hAECs has not yet been determined. Here, we first confirmed that hAECs undergo EMT immediately after starting primary culture. Comprehensive transcriptome analysis using RNA-seq revealed that inhibition of TGF-β-dependent EMT maintained the expression of stemness-related genes, including NANOG and POU5F1, in hAECs. Moreover, the maintenance of stemness did not affect the nontumorigenic characteristics of hAECs. We showed for the first time that TGF-β-dependent EMT negatively affected the stemness of hAECs, providing novel insight into cellular processes of placental stem cells.

  2022年08月, Stem cell reviews and reports, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• ASCL1 regulates super-enhancer-associated miRNAs to define molecular subtypes of small cell lung cancer.

  Kazuko Miyakawa, Naoya Miyashita, Masafumi Horie, Yasuhiro Terasaki, Hidenori Tanaka, Hirokazu Urushiyama, Kensuke Fukuda, Yugo Okabe, Takashi Ishii, Naomi Kuwahara, Hiroshi I Suzuki, Takahide Nagase, Akira Saito

  Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with dismal prognosis. Recently, molecular subtypes of SCLC have been defined by the expression status of ASCL1, NEUROD1, YAP1 and POU2F3 transcription regulators. ASCL1 is essential for neuroendocrine differentiation and is expressed in the majority of SCLC. Although previous studies investigated ASCL1 target genes in SCLC cells, ASCL1-mediated regulation of miRNAs and its relationship to molecular subtypes remain poorly explored. Here, we performed genome-wide profiling of chromatin modifications (H3K27me3, H3K4me3 and H3K27ac) by CUT&Tag assay and ASCL1 knockdown followed by RNA-sequencing and miRNA array analyses in SCLC cells. ASCL1 could preferentially regulate genes associated with super-enhancers (SEs) defined by enrichment of H3K27ac marking. Moreover, ASCL1 positively regulated several SE-associated miRNAs such as miR-7, miR-375, miR-200b-3p and miR-429, leading to repression of their targets whereas ASCL1 suppressed miR-455-3p, an abundant miRNA in other molecular subtypes. We further elucidated unique patterns of SE-associated miRNAs in different SCLC molecular subtypes, highlighting subtype-specific miRNA networks with functional relevance. Notably, we found apparent de-repression of common target genes of different miRNAs following ASCL1 knockdown, suggesting combinatorial action of multiple miRNAs underlying molecular heterogeneity of SCLC; for example, co-targeting of YAP1 by miR-9 and miR-375. Our comprehensive analyses provide novel insights into SCLC pathogenesis and a clue to understanding subtype-dependent phenotypic differences.

  2022年07月, Cancer science, 113(11) (11), 3932 - 3946, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System.

  Shinichi Yachida, Yasushi Totoki, Michael Noe, Yoichiro Nakatani, Masafumi Horie, Kenta Kawasaki, Hiromi Nakamura, Mihoko Saito-Adachi, Masami Suzuki, Erina Takai, Natsuko Hama, Ryota Higuchi, Seiko Hirono, Satoshi Shiba, Mamoru Kato, Eisaku Furukawa, Yasuhito Arai, Hirofumi Rokutan, Taiki Hashimoto, Shuichi Mitsunaga, Mitsuro Kanda, Hidenori Tanaka, So Takata, Ayaka Shimomura, Minoru Oshima, Wenzel M Hackeng, Tomoyuki Okumura, Keiichi Okano, Masakazu Yamamoto, Hiroki Yamaue, Chigusa Morizane, Koji Arihiro, Toru Furukawa, Toshiro Sato, Tohru Kiyono, Lodewijk A A Brosens, Laura D Wood, Ralph H Hruban, Tatsuhiro Shibata

  The neuroendocrine carcinoma of the gastrointestinal system (GIS-NEC) is a rare but highly malignant neoplasm. We analyzed 115 cases using whole-genome/exome sequencing, transcriptome sequencing, DNA methylation assays, and/or ATAC-seq and found GIS-NECs to be genetically distinct from neuroendocrine tumors (GIS-NETs) in the same location. Clear genomic differences were also evident between pancreatic NECs (Panc-NECs) and non-pancreatic GIS-NECs (Nonpanc-NECs). Panc-NECs could be classified into two subgroups (i.e., 'Ductal-type' and 'Acinar-type') based on genomic features. Alterations in TP53 and RB1 proved common in GIS-NECs and most Nonpanc-NECs with intact Rb demonstrated mutually exclusive amplification of CCNE1 or MYC. Alterations of the Notch gene family were characteristic of Nonpanc-NECs. Transcription factors for neuroendocrine differentiation, especially the SOX2 gene, appeared overexpressed in most GIS-NECs due to hypermethylation of the promoter region. This first comprehensive study of genomic alterations in GIS-NECs uncovered several key biological processes underlying genesis of this very lethal form of cancer.

  2021年12月, Cancer discovery, 12(3) (3), 692 - 711, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• TGF-β-mediated epithelial-mesenchymal transition and tumor-promoting effects in CMT64 cells are reflected in the transcriptomic signature of human lung adenocarcinoma.

  Naoya Miyashita, Takayoshi Enokido, Masafumi Horie, Kensuke Fukuda, Hirokazu Urushiyama, Carina Strell, Hans Brunnström, Patrick Micke, Akira Saito, Takahide Nagase

  Epithelial-mesenchymal transition (EMT) is a cellular process during which epithelial cells acquire mesenchymal phenotypes. Cancer cells undergo EMT to acquire malignant features and TGF-β is a key regulator of EMT. Here, we demonstrate for the first time that TGF-β could elicit EMT in a mouse lung adenocarcinoma cell line. TGF-β signaling activation led to cell morphological changes corresponding to EMT and enhanced the expression of mesenchymal markers and EMT-associated transcription factors in CMT64 lung cancer cells. RNA-sequencing analyses revealed that TGF-β increases expression of Tead transcription factors and an array of Tead2 target genes. TGF-β stimulation also resulted in alternative splicing of several genes including Cd44, tight junction protein 1 (Tjp1), and Cortactin (Cttn). In parallel with EMT, TGF-β enhanced cell growth of CMT64 cells and promoted tumor formation in a syngeneic transplantation model. Of clinical importance, the expression of TGF-β-induced genes identified in CMT64 cells correlated with EMT gene signatures in human lung adenocarcinoma tissue samples. Furthermore, TGF-β-induced gene enrichment was related to poor prognosis, underscoring the tumor-promoting role of TGF-β signaling in lung adenocarcinoma. Our cellular and syngeneic transplantation model would provide a simple and useful experimental tool to study the significance of TGF-β signaling and EMT.

  2021年11月, Scientific reports, 11(1) (1), 22380 - 22380, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Targeting hepatocyte growth factor in epithelial-stromal interactions in an in vitro experimental model of human periodontitis.

  Yoko Yamaguchi, Akira Saito, Masafumi Horie, Akira Aoki, Patrick Micke, Mitsuhiro Ohshima, Kai Kappert

  Periodontitis is a chronic inflammatory disease leading to progressive connective tissue degradation and loss of the tooth-supporting bone. Clinical and experimental studies suggest that hepatocyte growth factor (HGF) is involved in the dysregulated fibroblast-epithelial cell interactions in periodontitis. The aim of this study was to explore effects of HGF to impact fibroblast-induced collagen degradation. A patient-derived experimental cell culture model of periodontitis was applied. Primary human epithelial cells and fibroblasts isolated from periodontitis-affected gingiva were co-cultured in a three-dimensional collagen gel. The effects of HGF neutralizing antibody on collagen gel degradation were tested and transcriptome analyses were performed. HGF neutralizing antibody attenuated collagen degradation and elicited expression changes of genes related to extracellular matrix (ECM) and cell adhesion, indicating that HGF signaling inhibition leads to extensive impact on cell-cell and cell-ECM interactions. Our study highlights a potential role of HGF in periodontitis. Antagonizing HGF signaling by a neutralizing antibody may represent a novel approach for periodontitis treatment.

  2021年10月, Odontology, 109(4) (4), 912 - 920, 英語, 国内誌

  [査読有り]

  研究論文（学術雑誌）


• Performance of Oral HPV DNA, Oral HPV mRNA, and Circulating Tumor HPV DNA in the Detection of HPV-Related Oropharyngeal Cancer and Cancer of Unknown Primary.

  Hidenori Tanaka, Motoyuki Suzuki, Norihiko Takemoto, Takahito Fukusumi, Hirotaka Eguchi, Erina Takai, Haruka Kanai, Mitsuaki Tatsumi, Masafumi Horie, Yukinori Takenaka, Shinichi Yachida, Hidenori Inohara

  A biomarker that is useful for the detection of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) and cancer of unknown primary (CUP) is indispensable. We evaluated the diagnostic performance of HPV DNA and mRNA in oral gargle samples and circulating tumor HPV16 DNA (ctHPV16DNA) in blood samples. Oral HPV DNA and mRNA were analyzed using commercially available HPV assays of the GENOSEARCH HPV31 and Aptima, respectively. ctHPV16DNA was analyzed using in-house droplet digital PCR. Seventy-four patients with OPC and eight patients with CUP were included. The sensitivity and specificity of oral HPV DNA, oral HPV mRNA, and ctHPV16DNA were 82% (95% confidence interval [CI], 66-92) and 100% (95% CI, 88-100), 85% (95% CI, 69-94) and 94% (95% CI, 73-100), and 93% (95% CI, 81-99) and 97% (95% CI, 84-100), respectively, for HPV16-related OPC, while those were 20% (95% CI, 1-72) and 100% (95% CI, 3-100), 0% (95% CI, 0-52) and 100% (95% CI, 3-100), and 100% (95% CI, 54-100) and 100% (95% CI, 16-100), respectively, for HPV16-related CUP. The sensitivity of ctHPV16DNA for HPV16-related OPC was higher than that of oral biomarkers, though the difference was not statistically significant. ctHPV16DNA remarkably correlated with the anatomic extent of disease, total metabolic tumor volume, and HPV16 copy number per tumor genome in patients with HPV16-related OPC/CUP, whereas oral biomarkers did not. In conclusion, ctHPV16DNA is a potentially promising biomarker for HPV16-related OPC, while further studies are required for HPV16-related CUP. This article is protected by copyright. All rights reserved.

  2021年09月, International journal of cancer, 150(1) (1), 174 - 186, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network.

  Mathys Grapotte, Manu Saraswat, Chloé Bessière, Christophe Menichelli, Jordan A Ramilowski, Jessica Severin, Yoshihide Hayashizaki, Masayoshi Itoh, Michihira Tagami, Mitsuyoshi Murata, Miki Kojima-Ishiyama, Shohei Noma, Shuhei Noguchi, Takeya Kasukawa, Akira Hasegawa, Harukazu Suzuki, Hiromi Nishiyori-Sueki, Martin C Frith, Clément Chatelain, Piero Carninci, Michiel J L de Hoon, Wyeth W Wasserman, Laurent Bréhélin, Charles-Henri Lecellier

  Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism.

  2021年06月, Nature communications, 12(1) (1), 3297 - 3297, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Circulating tumor HPV DNA complements PET‐CT in guiding management after radiotherapy in HPV ‐related squamous cell carcinoma of the head and neck

  Hidenori Tanaka, Norihiko Takemoto, Masafumi Horie, Erina Takai, Takahito Fukusumi, Motoyuki Suzuki, Hirotaka Eguchi, Sho Komukai, Mitsuaki Tatsumi, Fumiaki Isohashi, Kazuhiko Ogawa, Shinichi Yachida, Hidenori Inohara

  Positron emission tomography and computed tomography (PET-CT) is widely used to assess the response to radiotherapy. However, the ability of PET-CT to predict treatment failure in human papillomavirus (HPV)-related squamous cell carcinoma of the head and neck (HNSCC) is unsatisfactory. We quantified circulating tumor HPV type16 DNA (ctHPV16DNA) using optimized droplet digital PCR in 35 patients with HPV16-related HNSCC, who received radiotherapy with or without chemotherapy, and prospectively correlated ctHPV16DNA and metabolic response with treatment failure. After a median follow-up of 21 months, ctHPV16DNA and PET-CT had similar negative predictive values (89.7% vs 84.0%), whereas the positive predictive value was much higher in ctHPV16DNA than in PET-CT (100% vs 50.0%). Notably, six patients who had detectable posttreatment ctHPV16DNA all had treatment failure irrespective of metabolic response, whereas none of five patients who had partial metabolic response without detectable posttreatment ctHPV16DNA had treatment failure. The risk of treatment failure was high in patients who had incomplete metabolic response with detectable posttreatment ctHPV16DNA (hazard ratio [HR], 138.8; 95% confidence interval [CI], 15.5-3366.4; P < .0001) and intermediate in patients who had discordant results between metabolic response and posttreatment ctHPV16DNA (HR, 4.7; 95% CI, 0.8-36.2, P = .09) as compared with patients who had complete metabolic response without detectable posttreatment ctHPV16DNA. One-year event-free survival rates of each risk group were 0%, 88% (95% CI, 46-98) and 95% (95% CI, 72-99), respectively (P < .0001). In conclusion, posttreatment ctHPV16DNA complements PET-CT and helps guide decisions managing patients with HPV16-related HNSCC after radiotherapy.

  Wiley, 2021年02月, International Journal of Cancer, 148(4) (4), 995 - 1005, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• E74-Like Factor 3 Is a Key Regulator of Epithelial Integrity and Immune Response Genes in Biliary Tract Cancer.

  Masami Suzuki, Mihoko Saito-Adachi, Yasuhito Arai, Yuko Fujiwara, Erina Takai, Shinsuke Shibata, Masahide Seki, Hirofumi Rokutan, Daichi Maeda, Masafumi Horie, Yutaka Suzuki, Tatsuhiro Shibata, Tohru Kiyono, Shinichi Yachida

  The transcription factor E74-like factor 3 (ELF3) is inactivated in a range of cancers, including biliary tract cancer (BTC). Here, we investigated the tumor-suppressive role of ELF3 in bile duct cells by identifying several previously unknown direct target genes of ELF3 that appear to be implicated in biliary duct carcinogenesis. ELF3 directly repressed ZEB2, a key regulator of epithelial-mesenchymal transition, and upregulated the expression of CGN, an integral element in lumen formation. Loss of ELF3 led to decreased cell-cell junctions and enhanced cell motility. ALOX5 and CXCL16 were also identified as additional direct targets of ELF3; their corresponding proteins 5-lipoxygenase and CXCL16 play a role in the immune response. Conditioned medium from cells overexpressing ELF3 significantly enhanced the migration of natural killer cells and CD8+ T cells toward the conditioned medium. Gene expression profiling for BTC expressing high levels of ELF3 revealed significant enrichment of the ELF3-related genes. In a BTC xenograft model, activation of ELF3 increased expression of ELF3-related genes, enhanced the tubular structure of the tumors, and led to a loss of vimentin. Overall, our results indicate that ELF3 is a key regulator of both epithelial integrity and immune responses in BTC. SIGNIFICANCE: Thease finding shows that ELF3 regulates epithelial integrity and host immune responses and functions as a tumor suppressor in biliary tract cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/2/489/F1.large.jpg.

  2021年01月, Cancer research, 81(2) (2), 489 - 500, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• A mouse model of asthma‐chronic obstructive pulmonary disease overlap induced by intratracheal papain

  Kensuke Fukuda, Hirotaka Matsuzaki, Yu Mikami, Kosuke Makita, Kazuko Miyakawa, Naoya Miyashita, Keisuke Hosoki, Takashi Ishii, Satoshi Noguchi, Hirokazu Urushiyama, Masafumi Horie, Akihisa Mitani, Yasuhiro Yamauchi, Eri Shimura, Susumu Nakae, Akira Saito, Takahide Nagase, Yoshihisa Hiraishi

  Wiley, 2021年01月, Allergy, 76(1) (1), 390 - 394, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• FOXL1 Regulates Lung Fibroblast Function via Multiple Mechanisms

  Naoya Miyashita, Masafumi Horie, Hiroshi I. Suzuki, Minako Saito, Yu Mikami, Kenichi Okuda, Richard C. Boucher, Maho Suzukawa, Akira Hebisawa, Akira Saito, Takahide Nagase

  Fibroblasts provide a structural framework for multiple organs and are essential for wound repair and fibrotic processes. Here, we demonstrate functional roles of FOXL1 (forkhead box L1), a transcription factor that characterizes the pulmonary origin of lung fibroblasts. We detected high FOXL1 transcripts associated with DNA hypomethylation and super-enhancer formation in lung fibroblasts, which is in contrast with fibroblasts derived from other organs. RNA in situ hybridization and immunohistochemistry in normal lung tissue indicated that FOXL1 mRNA and protein are expressed in submucosal interstitial cells together with airway epithelial cells. Transcriptome analysis revealed that FOXL1 could control a broad array of genes that potentiate fibroblast function, including TAZ (transcriptional coactivator with PDZ-binding motif)/YAP (Yes-associated protein) signature genes and PDGFRα (platelet-derived growth factor receptor-α). FOXL1 silencing in lung fibroblasts attenuated cell growth and collagen gel contraction capacity, underscoring the functional importance of FOXL1 in fibroproliferative reactions. Of clinical importance, increased FOXL1 mRNA expression was found in fibroblasts of idiopathic pulmonary fibrosis lung tissue. Our observations suggest that FOXL1 regulates multiple functional aspects of lung fibroblasts as a key transcription factor and is involved in idiopathic pulmonary fibrosis pathogenesis.

  American Thoracic Society, 2020年12月, American Journal of Respiratory Cell and Molecular Biology, 63(6) (6), 831 - 842, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Integrated Single-Cell RNA-Sequencing Analysis of Aquaporin 5-Expressing Mouse Lung Epithelial Cells Identifies GPRC5A as a Novel Validated Type I Cell Surface Marker.

  Masafumi Horie, Alessandra Castaldi, Mitsuhiro Sunohara, Hongjun Wang, Yanbin Ji, Yixin Liu, Fan Li, Thomas A Wilkinson, Long Hung, Hua Shen, Hidenori Kage, Ite A Offringa, Crystal N Marconett, Per Flodby, Beiyun Zhou, Zea Borok

  Molecular and functional characterization of alveolar epithelial type I (AT1) cells has been challenging due to difficulty in isolating sufficient numbers of viable cells. Here we performed single-cell RNA-sequencing (scRNA-seq) of tdTomato+ cells from lungs of AT1 cell-specific Aqp5-Cre-IRES-DsRed (ACID);R26tdTomato reporter mice. Following enzymatic digestion, CD31-CD45-E-cadherin+tdTomato+ cells were subjected to fluorescence-activated cell sorting (FACS) followed by scRNA-seq. Cell identity was confirmed by immunofluorescence using cell type-specific antibodies. After quality control, 92 cells were analyzed. Most cells expressed 'conventional' AT1 cell markers (Aqp5, Pdpn, Hopx, Ager), with heterogeneous expression within this population. The remaining cells expressed AT2, club, basal or ciliated cell markers. Integration with public datasets identified three robust AT1 cell- and lung-enriched genes, Ager, Rtkn2 and Gprc5a, that were conserved across species. GPRC5A co-localized with HOPX and was not expressed in AT2 or airway cells in mouse, rat and human lung. GPRC5A co-localized with AQP5 but not pro-SPC or CC10 in mouse lung epithelial cell cytospins. We enriched mouse AT1 cells to perform molecular phenotyping using scRNA-seq. Further characterization of putative AT1 cell-enriched genes revealed GPRC5A as a conserved AT1 cell surface marker that may be useful for AT1 cell isolation.

  2020年11月, Cells, 9(11) (11), 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Detection of MEAF6-PHF1 translocation in an endometrial stromal nodule.

  Yusuke Nomura, Daisuke Tamura, Masafumi Horie, Masakazu Sato, Shinya Sasaki, Yohei Yamamoto, Yukitsugu Kudo-Asabe, Michinobu Umakoshi, Kei Koyama, Kenichi Makino, Shinogu Takashima, Kazuhiro Imai, Yoshihiro Minamiya, Satoru Munakata, Shinichi Yachida, Yukihiro Terada, Akiteru Goto, Daichi Maeda

  Endometrial stromal nodule (ESN) and low-grade endometrial stromal sarcoma (LG-ESS) are rare uterine tumors known as endometrial stromal tumors (ESTs). In addition to their similarity in morphological features, recent studies have shown that these two tumors share common genetic alterations. In particular, JAZF1-SUZ12 fusion is found with high frequency in both ESN and LG-ESS. In LG-ESS, some minor fusions have also been described, which include rearrangements involving PHF1 and its partner genes, such as JAZF1, EPC1, MEAF6, BRD8, EPC2, and MBTD1. Because of the rarity of ESN, genetic alterations other than JAZF1 fusion have not been investigated in detail. In this study, we performed a next-generation sequencing-based analysis in a case of ESN with peripheral metaplastic bone formation and detected MEAF6-PHF1 fusion, which has been reported in a small subset of uterine LG-ESSs and soft tissue ossifying fibromyxoid tumors. The finding that MEAF6-PHF1 fusion is a background genetic abnormality detected both in ESN and LG-ESS, along with JAZF1-SUZ12, provides further support for the similarity and continuum between these two types of ESTs. Furthermore, the association between metaplastic bone formation and MEAF6-PHF1 fusion may not be limited to soft tissue tumors.

  2020年08月, Genes, chromosomes & cancer, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Genome-wide integration of microRNA and transcriptomic profiles of differentiating human alveolar epithelial cells.

  Alessandra Castaldi, Masafumi Horie, Megan E Rieger, Mickael Dubourd, Mitsuhiro Sunohara, Kusum Pandit, Beiyun Zhou, Ite A Offringa, Crystal N Marconett, Zea Borok

  The alveolar epithelium is comprised of two cell types, alveolar epithelial type 1 (AT1) and type 2 (AT2) cells, the latter being capable of self-renewal and transdifferentiation into AT1 cells for normal maintenance and restoration of epithelial integrity following injury. MicroRNAs (miRNAs) are critical regulators of several biological processes, including cell differentiation; however, their role in establishment/maintenance of cellular identity in adult alveolar epithelium is not well understood. To investigate this question, we performed genome-wide analysis of sequential changes in miRNA and gene expression profiles using a well-established model in which human AT2 (hAT2) cells transdifferentiate into AT1-like cells over time in culture that recapitulates many aspects of transdifferentiation in vivo. We defined three phases of miRNA expression during the transdifferentiation process as "early," "late," and "consistently" changed, which were further subclassified as up- or downregulated. miRNAs with altered expression at all time points during transdifferentiation were the largest subgroup, suggesting the need for consistent regulation of signaling pathways to mediate this process. Target prediction analysis and integration with previously published gene expression data identified glucocorticoid signaling as the top pathway regulated by miRNAs. Serum/glucocorticoid-regulated kinase 1 (SGK1) emerged as a central regulatory factor, whose downregulation correlated temporally with gain of hsa-miR-424 and hsa-miR-503 expression. Functional validation demonstrated specific targeting of these miRNAs to the 3'-untranslated region of SGK1. These data demonstrate the time-related contribution of miRNAs to the alveolar transdifferentiation process and suggest that inhibition of glucocorticoid signaling is necessary to achieve the AT1-like cell phenotype.

  2020年07月, American journal of physiology. Lung cellular and molecular physiology, 319(1) (1), L173-L184, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Exophilin-5 regulates allergic airway inflammation by controlling IL-33-mediated Th2 responses.

  Katsuhide Okunishi, Hao Wang, Maho Suzukawa, Ray Ishizaki, Eri Kobayashi, Miho Kihara, Takaya Abe, Jun-Ichi Miyazaki, Masafumi Horie, Akira Saito, Hirohisa Saito, Susumu Nakae, Tetsuro Izumi

  A common variant in the RAB27A gene in adults was recently found to be associated with the fractional exhaled nitric oxide level, a marker of eosinophilic airway inflammation. The small GTPase Rab27 is known to regulate intracellular vesicle traffic, although its role in allergic responses is unclear. We demonstrated that exophilin-5, a Rab27-binding protein, was predominantly expressed in both of the major IL-33 producers, lung epithelial cells, and the specialized IL-5 and IL-13 producers in the CD44hiCD62LloCXCR3lo pathogenic Th2 cell population in mice. Exophilin-5 deficiency increased stimulant-dependent damage and IL-33 secretion by lung epithelial cells. Moreover, it enhanced IL-5 and IL-13 production in response to TCR and IL-33 stimulation from a specific subset of pathogenic Th2 cells that expresses a high level of IL-33 receptor, which exacerbated allergic airway inflammation in a mouse model of asthma. Mechanistically, exophilin-5 regulates extracellular superoxide release, intracellular ROS production, and phosphoinositide 3-kinase activity by controlling intracellular trafficking of Nox2-containing vesicles, which seems to prevent the overactivation of pathogenic Th2 cells mediated by IL-33. This is the first report to our knowledge to establish the significance of the Rab27-related protein exophilin-5 in the development of allergic airway inflammation, and provides insights into the pathophysiology of asthma.

  2020年07月, The Journal of clinical investigation, 130(7) (7), 3919 - 3935, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• ASCL1 promotes tumor progression through cell-autonomous signaling and immune modulation in a subset of lung adenocarcinoma.

  Naoya Miyashita, Masafumi Horie, Yu Mikami, Hirokazu Urushiyama, Kensuke Fukuda, Kazuko Miyakawa, Hirotaka Matsuzaki, Kosuke Makita, Yasuyuki Morishita, Hiroaki Harada, Max Backman, Cecilia Lindskog, Hans Brunnström, Patrick Micke, Takahide Nagase, Akira Saito

  The master regulator of neuroendocrine differentiation, achaete-scute complex homolog 1 (ASCL1) defines a subgroup of lung adenocarcinoma. However, the mechanistic role of ASCL1 in lung tumorigenesis and its relation to the immune microenvironment is principally unknown. Here, the immune landscape of ASCL1-positive lung adenocarcinomas was characterized by immunohistochemistry. Furthermore, ASCL1 was transduced in mouse lung adenocarcinoma cell lines and comparative RNA-sequencing and secretome analyses were performed. The effects of ASCL1 on tumorigenesis were explored in an orthotopic syngeneic transplantation model. ASCL1-positive lung adenocarcinomas revealed lower infiltration of CD8+, CD4+, CD20+, and FOXP3+ lymphocytes and CD163+ macrophages indicating an immune desert phenotype. Ectopic ASCL1 upregulated cyclin transcript levels, stimulated cell proliferation, and enhanced tumor growth in mice. ASCL1 suppressed secretion of chemokines, including CCL20, CXCL2, CXCL10, and CXCL16, indicating effects on immune cell trafficking. In accordance with lower lymphocytes infiltration, ASCL1-positive lung adenocarcinomas demonstrated lower abundance of CXCR3-and CCR6-expressing cells. In conclusion, ASCL1 mediates its tumor-promoting effect not only through cell-autonomous signaling but also by modulating chemokine production and immune responses. These findings suggest that ASCL1-positive tumors represent a clinically relevant lung cancer entity.

  2020年06月, Cancer letters, 489, 121 - 132, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Epithelial Expression of YAP and TAZ Is Sequentially Required in Lung Development.

  Hideaki Isago, Akihisa Mitani, Yu Mikami, Masafumi Horie, Hirokazu Urushiyama, Ryuji Hamamoto, Yasuhiro Terasaki, Takahide Nagase

  TAZ (transcriptional coactivator with PDZ-binding motif) and YAP (Yes-associated protein) are key molecules of the Hippo pathway. Recent studies revealed that these molecules are essential in lung development; however, the precise signaling cascade involving these molecules and the differences in their roles during lung development remain unknown. We aimed to investigate YAP and TAZ functions using lung epithelium-specific Taz and Yap conditional knockout mice. We generated lung epithelium-specific Taz and Yap conditional knockout mice and investigated the functions of YAP and TAZ in lung development. Selective TAZ deficiency in mouse lung epithelial cells resulted in abnormal alveolarization, which mimics lung emphysema, in adults, whereas YAP deficiency caused disruption of bronchial morphogenesis during the embryonic stage. We report that TAZ and YAP are sequentially expressed in the lung and that this could explain their different phenotypes. Furthermore, we report that YAP stimulates Shh (Sonic hedgehog) expression and regulates the FGF (fibroblast growth factor)-SHH feedback loop, thereby contributing to normal bronchial morphogenesis. We also found that TGF-β (transforming growth factor-β) stimulation induced Shh expression in the lung epithelial cells, and both TAZ and YAP are essential in this novel pathway. Our results provide a novel insight into the molecular mechanisms underlying lung development and contribute to a better understanding of the characteristics of TAZ and YAP.

  2020年02月, American journal of respiratory cell and molecular biology, 62(2) (2), 256 - 266, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Grp78 Loss in Epithelial Progenitors Reveals an Age-Linked Role for ER Stress in Pulmonary Fibrosis.

  Borok Z, Horie M, Flodby P, Wang H, Liu Y, Ganesh S, Ryan Firth AL, Minoo P, Li C, Beers MF, Lee AS, Zhou B

  Rationale: Alveolar epithelial cell (AEC) injury and dysregulated repair are implicated in the pathogenesis of pulmonary fibrosis. Endoplasmic reticulum (ER) stress in AEC has been observed in idiopathic pulmonary fibrosis (IPF), a disease of aging.Objectives: To investigate a causal role for ER stress in the pathogenesis of pulmonary fibrosis (PF) and therapeutic potential of ER stress inhibition in PF.Methods: The role of ER stress in AEC dysfunction and fibrosis was studied in mice with tamoxifen (Tmx)-inducible deletion of ER chaperone Grp78, a key regulator of ER homeostasis, in alveolar type II (AT2) cells, progenitors of distal lung epithelium, and in IPF lung slice cultures.Measurements and Main Results: Grp78 deletion caused weight loss, mortality, lung inflammation, and spatially heterogeneous fibrosis characterized by fibroblastic foci, hyperplastic AT2 cells, and increased susceptibility of old and male mice, all features of IPF. Fibrosis was more persistent in more severely injured Grp78 knockout (KO) mice. Grp78 KO AT2 cells showed evidence of ER stress, apoptosis, senescence, impaired progenitor capacity, and activation of TGF-β (transforming growth factor-β)/SMAD signaling. Glucose-regulated protein 78 is reduced in AT2 cells from old mice and patients with IPF, and ER stress inhibitor tauroursodeoxycholic acid ameliorates ER stress and fibrosis in Grp78 KO mouse and IPF lung slice cultures.Conclusions: These results support a causal role for ER stress and resulting epithelial dysfunction in PF and suggest ER stress as a potential mechanism linking aging to IPF. Modulation of ER stress and chaperone function may offer a promising therapeutic approach for pulmonary fibrosis.

  2019年11月, American journal of respiratory and critical care medicine, 201(2) (2), 198 - 211, 英語, 国際誌

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  研究論文（学術雑誌）


• CNOT3 targets negative cell cycle regulators in non-small cell lung cancer development.

  Shirai YT, Mizutani A, Nishijima S, Horie M, Kikuguchi C, Elisseeva O, Yamamoto T

  Lung cancer is one of the major causes of cancer death and clarification of its molecular pathology is highly prioritized. The physiological importance of mRNA degradation through the CCR4-NOT deadenylase has recently been highlighted. For example, mutation in CNOT3, a gene coding for CNOT3 subunit of the CCR4-NOT complex, is found to be associated with T-cell acute lymphoblastic leukemia, T-ALL, though its contribution to other cancers has not been reported. Here, we provide evidence suggesting that CNOT3 is required for the growth of non-small cell lung cancer. Depletion of CNOT3 suppresses proliferation of A549 human non-small cell lung cancer cells with enhanced mRNA stability and subsequent elevated expression of p21. In addition, we identified the mRNA for Krüppel-like factor 2 transcription factor, an inducer of p21, as a novel mRNA degradation target of CNOT3 in non-small cell lung cancer cells. Aberrant up-regulation of Krüppel-like factor 2 by CNOT3 depletion leads to impairment in the proliferation of A549 cells. Consistent with these findings, elevated mRNA expression of CNOT3 in non-small cell lung cancer in comparison with the paired normal lung epithelium was confirmed through scrutinization of the RNA-sequencing datasets from The Cancer Genome Atlas. Moreover, we found an inverse correlation between CNOT3 and CDKN1A (encoding p21) mRNA expression using the combined datasets of normal lung epithelium and non-small cell lung cancer. Thus, we propose that the up-regulation of CNOT3 facilitates the development of non-small cell lung cancer through down-regulation of Krüppel-like factor 2 and p21, contrary to tumor suppressive functions of CNOT3 in T-ALL.

  2019年04月, Oncogene, 38(14) (14), 2580 - 2594, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• CISH is a negative regulator of IL-13-induced CCL26 production in lung fibroblasts.

  Hideyuki Takeshima, Masafumi Horie, Yu Mikami, Kosuke Makita, Naoya Miyashita, Hirotaka Matsuzaki, Satoshi Noguchi, Hirokazu Urushiyama, Yoshihisa Hiraishi, Akihisa Mitani, Zea Borok, Takahide Nagase, Yasuhiro Yamauchi

  BACKGROUND: Bronchial asthma is a chronic airway disease characterized by eosinophilic airway inflammation. Lung fibroblasts activated by IL-13 serve as important sources of chemokines, such as eotaxins, contributing to persistent eosinophilic inflammation. Src-homology 2-containing protein (CISH), belonging to the suppressor of cytokine signaling (SOCS) family, acts as a negative regulator of cytokine induction. The aim of this study was to elucidate the role of CISH in the production of eosinophil chemotactic chemokines in human lung fibroblasts. METHODS: Normal human lung fibroblasts were stimulated by IL-13, and global gene expression profile was assessed by cDNA microarray. Expression changes and downstream of IL-13 signaling were evaluated by quantitative RT-PCR, ELISA or western blotting. Loss- and gain-of-function analyses of CISH were performed by small interfering RNA and vector overexpression, respectively. RESULTS: Ingenuity pathway analysis revealed that IL-13 induced chemokine signaling, including the eotaxin family, while significantly suppressing IFN-α/β signaling. Among eight SOCS family members, CISH was most strongly induced by IL-13 via phosphorylation of signal transducer and activator of transcription 6 (STAT6). Loss- and gain-of-function studies demonstrated that CISH negatively regulated the expression of CCL26. CONCLUSIONS: These findings suggest that CISH plays a key role in the eosinophilic inflammation associated with bronchial asthma by regulating IL-13-induced CCL26 production. Augmentation of CISH function could be a novel approach for treating eosinophilic inflammation in severe asthma.

  2019年01月, Allergology international : official journal of the Japanese Society of Allergology, 68(1) (1), 101 - 109, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• The Role of TGF-β Signaling in Lung Cancer Associated with Idiopathic Pulmonary Fibrosis.

  Akira Saito, Masafumi Horie, Patrick Micke, Takahide Nagase

  Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown etiology and dismal prognosis. IPF patients are known to have an increased risk of lung cancer and careful decision-making is required for the treatment of lung cancer associated with IPF. Transforming growth factor (TGF)-β signaling plays a central role in tissue fibrosis and tumorigenesis. TGF-β-mediated pathological changes that occur in IPF lung tissue may promote the process of field cancerization and provide the microenvironment favorable to cancer initiation and progression. This review summarizes the current knowledge related to IPF pathogenesis and explores the molecular mechanisms that underlie the occurrence of lung cancer in the background of IPF, with an emphasis on the multifaceted effects of TGF-β signaling.

  2018年11月, International journal of molecular sciences, 19(11) (11), 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas.

  Naoya Miyashita, Masafumi Horie, Hiroshi I Suzuki, Masahito Yoshihara, Dijana Djureinovic, Johan Persson, Hans Brunnström, Cecilia Lindskog, Hedvig Elfving, Patrick Micke, Akira Saito, Takahide Nagase

  INTRODUCTION: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1), common to high-grade neuroendocrine tumors, small-cell lung cancer and large cell neuroendocrine carcinoma. METHODS: The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas. RESULTS: The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal-proliferative molecular subtype. Gene expression profiling of ASCL1-positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 protein expression. Genome-wide methylation analysis showed global DNA hypomethylation in ASCL1-positive cases. ASCL1 was associated with super-enhancers in ASCL1-positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super-enhancer-associated genes, suggesting that ASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. CONCLUSIONS: These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super-enhancer-mediated transcriptional programs.

  2018年11月, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 13(11) (11), 1676 - 1691, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• An integrative transcriptome analysis reveals a functional role for thyroid transcription factor-1 in small cell lung cancer.

  Masafumi Horie, Naoya Miyashita, Johanna Sofia Margareta Mattsson, Yu Mikami, Martin Sandelin, Hans Brunnström, Patrick Micke, Takahide Nagase, Akira Saito

  Small cell lung cancer (SCLC) is a neuroendocrine tumour that exhibits rapid growth and metastatic spread. Although SCLC represents a prototypically undifferentiated cancer type, thyroid transcription factor-1 (TTF-1, gene symbol NKX2-1), a master regulator for pulmonary epithelial cell differentiation and lung morphogenesis, is strongly upregulated in this aggressive cancer type. The aim of this study was to evaluate a functional role for TTF-1 in SCLC. We demonstrated that achaete-scute complex homolog 1 (ASCL1), an essential transcription factor for neuroendocrine differentiation, positively regulated TTF-1 in SCLC cell lines. Subsequently, we described genes and microRNAs (miRNAs) that were possibly controlled by TTF-1 and identified nuclear factor IB (NFIB), a recently characterised driver of SCLC progression, as a transcriptional target of TTF-1. Our findings shine light on a regulatory axis in SCLC consisting of ASCL1/TTF-1/NFIB that potentially contributes to the tumourigenesis of SCLC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  2018年10月, The Journal of pathology, 246(2) (2), 154 - 165, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• TGF-β Signaling in Lung Health and Disease.

  Akira Saito, Masafumi Horie, Takahide Nagase

  Transforming growth factor (TGF)-β is an evolutionarily conserved pleiotropic factor that regulates a myriad of biological processes including development, tissue regeneration, immune responses, and tumorigenesis. TGF-β is necessary for lung organogenesis and homeostasis as evidenced by genetically engineered mouse models. TGF-β is crucial for epithelial-mesenchymal interactions during lung branching morphogenesis and alveolarization. Expression and activation of the three TGF-β ligand isoforms in the lungs are temporally and spatially regulated by multiple mechanisms. The lungs are structurally exposed to extrinsic stimuli and pathogens, and are susceptible to inflammation, allergic reactions, and carcinogenesis. Upregulation of TGF-β ligands is observed in major pulmonary diseases, including pulmonary fibrosis, emphysema, bronchial asthma, and lung cancer. TGF-β regulates multiple cellular processes such as growth suppression of epithelial cells, alveolar epithelial cell differentiation, fibroblast activation, and extracellular matrix organization. These effects are closely associated with tissue remodeling in pulmonary fibrosis and emphysema. TGF-β is also central to T cell homeostasis and is deeply involved in asthmatic airway inflammation. TGF-β is the most potent inducer of epithelial-mesenchymal transition in non-small cell lung cancer cells and is pivotal to the development of tumor-promoting microenvironment in the lung cancer tissue. This review summarizes and integrates the current knowledge of TGF-β signaling relevant to lung health and disease.

  2018年08月, International journal of molecular sciences, 19(8) (8), 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling.

  Suzuki HI, Horie M, Mihira H, Saito A

  Phenotypic plasticity of endothelial cells underlies cardiovascular system development, cardiovascular diseases, and various conditions associated with organ fibrosis. In these conditions, differentiated endothelial cells acquire mesenchymal-like phenotypes. This process is called endothelial-mesenchymal transition (EndMT) and is characterized by downregulation of endothelial markers, upregulation of mesenchymal markers, and morphological changes. EndMT is induced by several signaling pathways, including transforming growth factor (TGF)-β, Wnt, and Notch, and regulated by molecular mechanisms similar to those of epithelial-mesenchymal transition (EMT) important for gastrulation, tissue fibrosis, and cancer metastasis. Understanding the mechanisms of EndMT is important to develop diagnostic and therapeutic approaches targeting EndMT. Robust induction of EndMT in vitro is useful to characterize common gene expression signatures, identify druggable molecular mechanisms, and screen for modulators of EndMT. Here, we describe an in vitro method for induction of EndMT. MS-1 mouse pancreatic microvascular endothelial cells undergo EndMT after prolonged exposure to TGF-β and show upregulation of mesenchymal markers and morphological changes as well as induction of multiple inflammatory chemokines and cytokines. Methods for the analysis of microRNA (miRNA) modulation are also included. These methods provide a platform to investigate mechanisms underlying EndMT and the contribution of miRNAs to EndMT.

  2018年08月, Journal of visualized experiments : JoVE, (138) (138), 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• TBX4 is involved in the super-enhancer-driven transcriptional programs underlying features specific to lung fibroblasts.

  Masafumi Horie, Naoya Miyashita, Yu Mikami, Satoshi Noguchi, Yasuhiro Yamauchi, Maho Suzukawa, Takeshi Fukami, Ken Ohta, Yoshihide Asano, Shinichi Sato, Yoko Yamaguchi, Mitsuhiro Ohshima, Hiroshi I Suzuki, Akira Saito, Takahide Nagase

  Lung fibroblasts participate in the pathogenesis of respiratory diseases, including lung cancer and pulmonary fibrosis. Although fibroblasts are ubiquitous constituents of various organs, their cellular diversity among different organs has been poorly characterized. Here, we aimed to investigate the distinct gene signature of lung fibroblasts that represents its pulmonary origin and the underlying gene regulatory networks. Promoter-level differential expression analysis by cap analysis of gene expression (CAGE) sequencing revealed distinct gene expression patterns of fibroblasts derived from different anatomical sites and identified 88 coding genes with higher expression in lung fibroblasts relative to other fibroblasts. Multiple key transcription factors important for lung mesenchyme development, including the T-box transcription factors TBX2, TBX4, and TBX5 were enriched in this lung-specific signature and were associated with super-enhancers. TBX4 showed highly specific expression in lung fibroblasts and was required for cell proliferation and collagen gel contraction capacity. Transcriptome analysis revealed that TBX4 could broadly regulate fibroblast-related pathways and partly contribute to super-enhancer-mediated transcriptional programs. Of pathological importance, lung fibroblast-specific genes were globally downregulated in lung cancer-associated fibroblasts (CAFs). Notably, TBX2, TBX4, and TBX5 were downregulated and hypermethylated in lung CAFs, suggesting an association between epigenetic silencing of these factors and phenotypic alteration of lung fibroblasts in cancer. Our study highlights the importance of T-box transcription factors, especially TBX4, and super-enhancers in the roles of lung fibroblasts in pulmonary physiology and pathogenesis.

  2018年01月, American journal of physiology. Lung cellular and molecular physiology, 314(1) (1), L177-L191 - L191, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Mechanism of Periostin Production in Human Bronchial Smooth Muscle Cells.

  Kosuke Makita, Yu Mikami, Hirotaka Matsuzaki, Naoya Miyashita, Hideyuki Takeshima, Satoshi Noguchi, Masafumi Horie, Hirokazu Urushiyama, Motoyasu Iikura, Masayuki Hojo, Takahide Nagase, Yasuhiro Yamauchi

  BACKGROUND: Asthma is a chronic airway inflammatory disease characterized by airway remodeling, in which the bronchial smooth muscle (BSM) cells play an important role. Periostin, a biomarker that reflects Th2-driven inflammatory diseases such as asthma, may play an important role in the asthmatic airway. Although periostin is mainly produced in airway epithelial cells and fibroblasts after interleukin (IL)-13 stimulation, whether BSM cells produce periostin remains unclear. Therefore, we investigated periostin production in BSM cells and the mechanisms involved. METHODS: Human BSM cells were cultured, and the effect of IL-13 stimulation on periostin production was evaluated using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). We evaluated the phosphorylation of signal transducer and activator of transcription factor 6 (STAT6), extracellular signal-regulated kinase (ERK)1/2, and Akt after IL-13 stimulation. Furthermore, using ELISA, we evaluated the influence of several phosphorylation inhibitors on periostin production. RESULTS: Periostin mRNA expression increased in a dose- and time-dependent manner after IL-13 stimulation; periostin production was induced 24 and 48 h after stimulation. IL-13 stimulation induced the phosphorylation of STAT6, ERK1/2, and Akt. IL-13-induced periostin production was attenuated by inhibiting STAT6 phosphorylation and strongly suppressed by inhibiting mitogen-activated protein kinase kinase 1/2 phosphorylation or phosphatidylinositol 3-kinase (PI3K) phosphorylation. CONCLUSIONS: BSM cells produced periostin after IL-13 stimulation, via the JAK/STAT6, ERK1/2, and PI3K/Akt pathways. Understanding the mechanism of periostin production in BSM cells may help to clarify asthma pathogenesis.

  2018年, International archives of allergy and immunology, 175(1-2) (1-2), 26 - 35, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• The incidence and risk factors of asymptomatic primary spontaneous pneumothorax detected during health check-ups

  Akihisa Mitani, Yukichika Hakamata, Megumi Hosoi, Masafumi Horie, Yoko Murano, Akira Saito, Shintaro Yanagimoto, Shoji Tsuji, Kazuhiko Yamamoto, Takahide Nagase

  2017年12月, BMC PULMONARY MEDICINE, 17(1) (1), 177 - 177, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC

  Masafumi Horie, Bogumil Kaczkowski, Mitsuhiro Ohshima, Hirotaka Matsuzaki, Satoshi Noguchi, Yu Mikami, Marina Lizio, Masayoshi Itoh, Hideya Kawaji, Timo Lassmann, Piero Carninci, Yoshihide Hayashizaki, Alistair R. R. Forrest, Daiya Takai, Yoko Yamaguchi, Patrick Micke, Akira Saito, Takahide Nagase

  2017年10月, MOLECULAR CANCER RESEARCH, 15(10) (10), 1354 - 1365, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• MicroRNA profiling in gingival crevicular fluid of periodontitis-a pilot study

  Akira Saito, Masafumi Horie, Kenichiro Ejiri, Akira Aoki, Sayaka Katagiri, Shogo Maekawa, Shinta Suzuki, Sophannary Kong, Tsuneto Yamauchi, Yoko Yamaguchi, Yuichi Izumi, Mitsuhiro Ohshima

  2017年07月, FEBS OPEN BIO, 7(7) (7), 981 - 994, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Regulation of TGF-β-mediated endothelial-mesenchymal transition by microRNA-27.

  Suzuki HI, Katsura A, Mihira H, Horie M, Saito A, Miyazono K

  2017年05月, Journal of biochemistry, 161(5) (5), 417 - 420, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• TAZ contributes to pulmonary fibrosis by activating profibrotic functions of lung fibroblasts

  Satoshi Noguchi, Akira Saito, Yu Mikami, Hirokazu Urushiyama, Masafumi Horie, Hirotaka Matsuzaki, Hideyuki Takeshima, Kosuke Makita, Naoya Miyashita, Akihisa Mitani, Taisuke Jo, Yasuhiro Yamauchi, Yasuhiro Terasaki, Takahide Nagase

  2017年02月, SCIENTIFIC REPORTS, 7, 42595 - 42595, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• YAP and TAZ modulate cell phenotype in a subset of small cell lung cancer

  Masafumi Horie, Akira Saito, Mitsuhiro Ohshima, Hiroshi I. Suzuki, Takahide Nagase

  2016年12月, CANCER SCIENCE, 107(12) (12), 1755 - 1766, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Serum Reactive Oxygen Metabolite Levels Predict Severe Exacerbations of Asthma

  Keitaro Nakamoto, Masato Watanabe, Mitsuru Sada, Toshiya Inui, Masuo Nakamura, Kojiro Honda, Hiroo Wada, Yu Mikami, Hirotaka Matsuzaki, Masafumi Horie, Satoshi Noguchi, Yasuhiro Yamauchi, Hikari Koyama, Toshiyuki Kogane, Tadashi Kohyama, Hajime Takizawa

  2016年10月, PLOS ONE, 11(10) (10), e0164948 - e0164948

  研究論文（学術雑誌）


• Serum Reactive Oxygen Metabolite Levels Predict Severe Exacerbations of Asthma

  Keitaro Nakamoto, Masato Watanabe, Mitsuru Sada, Toshiya Inui, Masuo Nakamura, Kojiro Honda, Hiroo Wade, Yu Mikami, Hirotaka Matsuzaki, Masafumi Horie, Satoshi Noguchi, Yasuhiro Yamauchi, Hikari Koyama, Toshiyuki Kogane, Tadashi Kohyama, Hajime Takizawal

  2016年10月, PLoS One, 11(10) (10), e0164948, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Transcriptome analysis of periodontitis-associated fibroblasts by CAGE sequencing identified DLX5 and RUNX2 long variant as novel regulators involved in periodontitis

  Masafumi Horie, Yoko Yamaguchi, Akira Saito, Takahide Nagase, Marina Lizio, Masayoshi Itoh, Hideya Kawaji, Timo Lassmann, Piero Carninci, Alistair R. R. Forrest, Yoshihide Hayashizaki, Tatsuo Suzutani, Kai Kappert, Patrick Micke, Mitsuhiro Ohshima

  2016年09月, SCIENTIFIC REPORTS, 6, 33666 - 33666, 英語, 国際誌

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  研究論文（学術雑誌）


• Profiling cancer testis antigens in non-small-cell lung cancer.

  Djureinovic D, Hallström BM, Horie M, Mattsson JSM, La Fleur L, Fagerberg L, Brunnström H, Lindskog C, Madjar K, Rahnenführer J, Ekman S, Ståhle E, Koyi H, Brandén E, Edlund K, Hengstler JG, Lambe M, Saito A, Botling J, Pontén F, Uhlén M, Micke P

  Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.

  2016年07月, JCI insight, 1(10) (10), e86837, 英語, 国際誌

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  研究論文（学術雑誌）


• Integrated pathway-based transcription regulation network mining and visualization based on gene expression profiles

  Nelson Kibinge, Naoaki Ono, Masafumi Horie, Tetsuo Sato, Tadao Sugiura, Md. Altaf-Ul-Amin, Akira Saito, Shigehiko Kanaya

  2016年06月, JOURNAL OF BIOMEDICAL INFORMATICS, 61, 194 - 202, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Fibroblast VEGF-receptor 1 expression as molecular target in periodontitis

  Mitsuhiro Ohshima, Yoko Yamaguchi, Kimiharu Ambe, Masafumi Horie, Akira Saito, Takahide Nagase, Keisuke Nakashima, Hidero Ohki, Toshihisa Kawai, Yoshimitsu Abiko, Patrick Micke, Kai Kappert

  2016年02月, JOURNAL OF CLINICAL PERIODONTOLOGY, 43(2) (2), 128 - 137, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Role of canstatin in early fibrotic lesions of idiopathic interstitial pneumonias and migration of lung fibroblasts

  Urushiyama H, Terasaki Y, Nagasaka S, Kokuho N, Terasaki M, Kunugi S, Mikami Y, Noguchi S, Horie M, Nagahama K, Yamauchi Y, Shimizu A, Nagase T

  2016年, International Journal of Clinical and Experimental Pathology, 9(12) (12), 12714 - 12722

  [査読有り]


• Nonspecific elevation of serum Aspergillus galactomannan antigen levels in patients with rheumatoid arthritis

  Masafumi Horie, Hiroyuki Tamiya, Yasushi Goto, Masaru Suzuki, Hirotaka Matsuzaki, Wakae Tanaka Hasegawa, Satoshi Noguchi, Masaki Kawakami, Kunio Matsuta, Takahide Nagase, Yoshio Sakamoto

  Elsevier, 2016年01月, Respiratory Investigation, 54(1) (1), 44 - 49, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Interleukin-17A and Toll-Like Receptor 3 Ligand Poly(I:C) Synergistically Induced Neutrophil Chemoattractant Production by Bronchial Epithelial Cells

  Hirotaka Matsuzaki, Yu Mikami, Kousuke Makita, Hideyuki Takeshima, Masafumi Horie, Satoshi Noguchi, Taisuke Jo, Osamu Narumoto, Tadashi Kohyama, Hajime Takizawa, Takahide Nagase, Yasuhiro Yamauchi

  2015年10月, PLOS ONE, 10(10) (10), e0141746, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Three-dimensional Co-culture Model for Tumor-stromal Interaction

  Masafumi Horie, Akira Saito, Yoko Yamaguchi, Mitsuhiro Ohshima, Takahide Nagase

  2015年02月, JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, (96) (96), 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Lymphotoxin β receptor signaling induces IL-8 production in human bronchial epithelial cells.

  Mikami Y, Matsuzaki H, Horie M, Noguchi S, Jo T, Narumoto O, Kohyama T, Takizawa H, Nagase T, Yamauchi Y

  2014年12月, PloS one, 9(12) (12), e114791, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• An Integrative Analysis of the Tumorigenic Role of TAZ in Human Non-Small Cell Lung Cancer

  Satoshi Noguchi, Akira Saito, Masafumi Horie, Yu Mikami, Hiroshi I. Suzuki, Yasuyuki Morishita, Mitsuhiro Ohshima, Yoshimitsu Abiko, Johanna Sofia Margareta Mattsson, Helena Koenig, Miriam Lohr, Karolina Edlund, Johan Botling, Patrick Micke, Takahide Nagase

  2014年09月, CLINICAL CANCER RESEARCH, 20(17) (17), 4660 - 4672, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Differential knockdown of TGF-β ligands in a three-dimensional co-culture tumor- stromal interaction model of lung cancer.

  Horie M, Saito A, Noguchi S, Yamaguchi Y, Ohshima M, Morishita Y, Suzuki HI, Kohyama T, Nagase T

  2014年08月, BMC cancer, 14, 580 - 580, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Histamine induces human lung fibroblast-mediated collagen gel contraction via histamine H1 receptor

  Masafumi Horie, Akira Saito, Yasuhiro Yamauchi, Yu Mikami, Makiko Sakamoto, Taisuke Jo, Jun Nakajima, Hajime Takizawa, Takahide Nagase, Tadashi Kohyama

  2014年06月, EXPERIMENTAL LUNG RESEARCH, 40(5) (5), 222 - 236, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Relationships among Smoking Habits, Airflow Limitations, and Metabolic Abnormalities in School Workers

  Masafumi Horie, Satoshi Noguchi, Wakae Tanaka, Yasushi Goto, Hisanao Yoshihara, Masaki Kawakami, Masaru Suzuki, Yoshio Sakamoto

  2013年11月, PLOS ONE, 8(11) (11), e81145, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• An integrated expression profiling reveals target genes of TGF-β and TNF-α possibly mediated by microRNAs in lung cancer cells.

  Saito A, Suzuki HI, Horie M, Ohshima M, Morishita Y, Abiko Y, Nagase T

  2013年02月, PloS one, 8(2) (2), e56587, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Tumor necrosis factor superfamily member LIGHT induces epithelial-mesenchymal transition in A549 human alveolar epithelial cells

  Yu Mikami, Yasuhiro Yamauchi, Masafumi Horie, Makiko Kase, Taisuke Jo, Hajime Takizawa, Tadashi Kohyama, Takahide Nagase

  2012年11月, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 428(4) (4), 451 - 457, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Characterization of human lung cancer-associated fibroblasts in three-dimensional in vitro co-culture model

  Masafumi Horie, Akira Saito, Yu Mikami, Mitsuhiro Ohshima, Yasuyuki Morishita, Jun Nakajima, Tadashi Kohyama, Takahide Nagase

  2012年06月, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 423(1) (1), 158 - 163, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Diagnostic and Prognostic Value of Procalcitonin in Community-Acquired Pneumonia

  Masafumi Horie, Motoi Ugajin, Masaru Suzuki, Satoshi Noguchi, Wakae Tanaka, Hisanao Yoshihara, Masaki Kawakami, Yoshiko Kichikawa, Yoshio Sakamoto

  2012年01月, AMERICAN JOURNAL OF THE MEDICAL SCIENCES, 343(1) (1), 30 - 35, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）


• Primary Malignant Pericardial Mesothelioma Mimicking Pericardial Metastasis from Adenocarcinoma

  Masafumi Horie, Satoshi Noguchi, Wakae Tanaka, Hisanao Yoshihara, Masaki Kawakami, Masaru Suzuki, Yoshio Sakamoto, Teruaki Oka

  2010年12月, JOURNAL OF THORACIC ONCOLOGY, 5(12) (12), 2012 - 2014, 英語, 国際誌

  [査読有り]

  研究論文（学術雑誌）

• 肺多形癌におけるシングルセル解析を用いた成因解明と新規マーカーの探索

  和田 崇志, 結城 浩考, 西川 悟司, 寺田 百合子, 齋藤 大輔, 懸川 誠一, 松本 勲, 堀江 真史, 前田 大地

  (NPO)日本肺癌学会, 2025年11月, 肺癌, 65(5) (5), 441 - 441, 日本語


• 小細胞肺癌におけるサブタイプ特異的なmicroRNAの解析

  工田 啓史, 堀江 真史, 齋藤 朗, 上田 宰, 木場 隼人, 矢野 聖二, 田宮 浩之, 鈴木 洋, 鹿毛 秀宣

  (NPO)日本肺癌学会, 2025年11月, 肺癌, 65(5) (5), 483 - 483, 日本語


• Ide-cel投与後に運動毒性および神経認知毒性を呈した骨髄腫患者の剖検所見

  吉野 裕貴, 東 大貴, 貫井 友貴, 細川 晃平, 山田 真也, 中川 俊一郎, 酒井 悟臣, 藤井 俊, 平塚 杏奈, 畑田 達哉, 鎧高 健志, 井美 達也, 材木 義隆, 吉田 晶代, 丸山 裕之, 堀江 真史, 前田 大地, 高松 博幸, 宮本 敏浩

  (一社)日本血液学会, 2025年10月, 日本血液学会学術集会, 87回, P3 - 5, 英語


• 小細胞肺癌におけるmicroRNAプロファイリングと臨床病理学的検討

  堀江真史, 工田啓史, 木場隼人, 伊藤行信, 伊藤歩美, 齋藤朗, 前田大地

  2025年, 日本病理学会会誌, 114(1) (1)


• 男性髄膜腫におけるY染色体欠失(LOY)の検討

  阪口真希, 堀江真史, 堀江真史, 伊藤行信, 田中慎吾, 池田博子, 前田大地

  2025年, 日本病理学会会誌, 114(1) (1)


• 口腔癌の転移形成初期段階において惹起される癌細胞と間質細胞の分布・位置関係の変化

  重岡学, 児玉貴之, 狛雄一朗, 堀江真史

  2025年, 日本がん転移学会学術集会・総会プログラム抄録集, 34th


• 経過中に肉芽腫性炎症を生じ診断に難渋した眼窩内脂肪肉腫の一例

  西尾真理, 村井佑輔, 安積淳, 塚本修一, 児玉貴之, 重岡学, 狛雄一朗, 堀江真史

  2025年, 日本病理学会会誌, 114(1) (1)


• がんゲノムプロファイリング検査の意義と次世代シークエンサー

  堀江真史

  2024年06月, 細胞診のベーシックサイエンスと臨床の実際


• 喘息・COPDオーバーラップモデルの多層的オミックス解析による病態解明と新規エンドタイピングマーカー探索

  福田健介, 松崎博崇, 松崎博崇, 槇田広佑, 三上優, 田中秀憲, 齋藤朗, 鹿毛秀宣, 堀江真史

  2024年, アレルギー, 73(6/7) (6/7)


• 全ゲノム解析等の網羅的ゲノム解析による膵・消化管神経内分泌腫瘍の病態解明

  堀江真史, 谷内田真一

  2022年12月, 病理と臨床, 40(12) (12), 1237 - 1246


• トランスクリプトーム解析によるAsthma-COPD Ovcerlap(ACO)の分子病態の解明

  堀江真史, 福田健介, 松崎博崇, 田中秀憲, 三上優, 鹿毛秀宣, 齋藤朗, 長瀬隆英, 平石尚久

  2022年, 日本呼吸器学会誌(Web), 11


• 難治性呼吸器疾患・肺高血圧症に関する調査研究 肺線維芽細胞におけるCISHのIL-13誘導性CCL26産生調整機構の検討

  長瀬隆英, 竹島英之, 堀江真史, 三上優, 槇田広佑, 宮下直也, 松崎博崇, 野口智史, 漆山博和, 平石尚久, 三谷明久, 山内康宏

  2019年, 難治性呼吸器疾患・肺高血圧症に関する調査研究 平成30年度 総括・分担研究報告書(Web)


• 健康診断の胸部X線検査における胸膜肥厚所見に関する検討

  齋藤 朗, 堀江 真史, 垂井 愛, 春原 光宏, 村野 陽子, 三谷 明久, 田中 君枝, 柳元 伸太郎, 小池 和彦

  (公社)全国大学保健管理協会, 2017年11月, 全国大学保健管理研究集会プログラム・抄録集, 55回, 47 - 47, 日本語


• 線維芽細胞と肺がん

  堀江 真史, 山内 康宏, 長瀬 隆英

  (株)先端医学社, 2017年02月, 炎症と免疫, 25(2) (2), 161 - 167, 日本語


• トランスクリプトーム解析による肺線維芽細胞におけるIL13シグナリングの解明

  竹島英之, 堀江真史, 宮下直也, 槇田広佑, 松崎博崇, 野口智史, 三上優, 漆山博和, 三谷明久, 長瀬隆英, 山内康宏

  2017年, 日本呼吸器学会誌(Web), 6


• 本学における自然気胸の定期健診発見症例のまとめ

  細井 恩, 三谷 明久, 岩崎 翔也, 古田 明子, 関根 早苗, 菊池 優子, 袴田 千愛, 堀江 真史, 村野 葉子, 齋藤 朗, 柳元 伸太郎, 辻 省次, 長瀬 隆英, 山本 一彦

  (公社)全国大学保健管理協会, 2016年09月, 全国大学保健管理研究集会プログラム・抄録集, 54回, 77 - 77, 日本語


• 呼吸器疾患に関する細胞生物学: 気道上皮細胞

  堀江 真史, 山内 康宏

  (株)先端医学社, 2016年01月, Respiratory Medical Research, 4(1) (1), 65 - 70, 日本語


• DNA adduct formation by diesel exhaust and its relevance to carcinogenesis.

  Masafumi Horie

  2015年, Pm2.5 : Role of Oxidative Stress in Health Effects and Prevention Strategy, 81 - 102


• 呼吸器の検査: 喀痰検査

  堀江 真史, 幸山 正

  (株)日本評論社, 2011年02月, からだの科学, (268) (268), 43 - 47, 日本語


• 骨髄異形成症候群に粟粒陰影、脳神経麻痺を生じた高齢者サルコイドーシスの1例

  堀江 真史, 野口 智史, 田中 若恵, 吉原 久直, 川上 真樹, 鈴木 勝, 坂本 芳雄, 岡 輝明

  (一社)日本呼吸器学会, 2010年12月, 日本呼吸器学会雑誌, 48(12) (12), 938 - 943, 日本語


• 肺扁平上皮癌と縦隔腫瘍を合併したKartagener症候群の1例

  堀江 真史, 新井 秀宜, 野口 智史, 鈴木 勝, 坂本 芳雄, 岡 輝明

  (一社)日本呼吸器学会, 2010年05月, 日本呼吸器学会雑誌, 48(5) (5), 375 - 378, 日本語


• 多発結節性肺陰影、腹部リンパ節腫大、脾腫を呈した結核症の1例

  堀江 真史, 垂井 愛, 加志崎 史大, 川島 正裕, 鈴木 純子, 島田 昌裕, 荒木 孝介, 小宮 幸作, 松井 芳憲, 大島 信治, 益田 公彦, 田村 厚久, 長山 直弘, 豊田 恵美子, 永井 英明, 赤川 志のぶ, 中島 由槻

  94歳男。健診で胸部異常陰影を指摘され、精査目的で入院となった。胸部単純CTで両肺上葉を中心に多発結節影を認め、また上縦隔上部リンパ節の腫大を認めた。悪性腫瘍を疑って腹骨盤造影CTを施行したところ、累々と腫大する腹部リンパ節と脾腫が認められた。肺多発結節影についての精査として気管支鏡検査を行い、気管支洗浄液の所見が抗酸菌塗抹1+、結核菌DNA-PCR陽性であったことから肺結核と診断した。腹部リンパ節腫大と脾腫の存在により悪性リンパ腫との鑑別が問題となったが、確定診断には開腹生検が必要であり、高齢であることを考慮して、まず抗結核薬への反応を観察した。その結果、RFP・INH・EBの投与によって肺結核の改善とともに腹部リンパ節の縮小と脾腫の改善が認められ、腹部リンパ節腫大と脾腫は結核によるものであったと判断した。

  (一社)日本結核・非結核性抗酸菌症学会, 2009年10月, 結核, 84(10) (10), 675 - 679, 日本語


• 両側精巣上体腫瘤にて発見されたサルコイドーシスの1例

  堀江 真史, 坂本 芳雄, 大圃 美穂, 野口 智史, 田宮 浩之, 吉原 久直, 吉川 理子, 鈴木 勝, 大野 烈士, 石坂 和博, 岡 輝明

  75歳男性。患者は両側陰嚢内の無痛性腫瘤を主訴に、はじめ著者らの施設にある泌尿器科にて両側精巣上体切除術が施行されたところ、同時に前立腺癌も認められた。病理組織学的に結核性精巣上体炎と診断され、胸部CTでは縦隔・肺門リンパ節腫大(BHL)、肺野に多発小結節も認められ、呼吸器内科へ紹介となった。本症例は関節リウマチ合併例であり、MTX投与が結核発症に関与した可能性も考え、MTXを中止し、抗結核薬4剤HREZにて治療を開始した。しかし、治療開始約1ヵ月より視力低下が出現し、左網膜血管炎・乳頭炎、ACEの上昇、肺の小結節の増大が認められた。そこで、抗結核薬を中止し、左肺S10の小結節に対し胸腔鏡下肺生検術を行った結果、多発性の非乾酪性類上皮細胞肉芽腫が確認され、サルコイドーシスと診断された。以後、プレドニゾロンの内服治療を開始し、BHLとACE値の改善を認めたものの、眼症状は残存した。

  (一社)日本内科学会, 2009年05月, 日本内科学会雑誌, 98(5) (5), 1117 - 1119, 日本語

• 肺腺癌におけるRIPK3によるケモカイン産生と腫瘍免疫微小環境の調節

  小岩智大, 石井崇史, 齋藤朗, 三上優, 宮下直也, 工田啓史, Hans Brunnström, 鈴川真穂, Patrick Micke, 堀江真史, 鹿毛秀宣

  第65回日本呼吸器学会学術講演会, 2025年04月


• 間質マクロファージのサブタイプと代償性肺再生における役割

  渡辺知志, 武藤篤, 加瀬一政, 堀江真史, 射場智大, 内藤尚道, 矢野聖二

  第65回日本呼吸器学会学術講演会, 2025年04月


• in vivo動静脈奇形モデルを用いたヒト脳動静脈奇形のメカニズムの解明

  伊藤行信, 吉田誠, 南條博, 増田弘毅, 阪口真希, 伊藤歩美, 堀江真史, 後藤明輝, 前田大地

  第114回日本病理学会総会, 2025年04月


• 男性髄膜腫におけるY染色体欠失（LOY）の検討

  阪口真希, 堀江真史, 伊藤行信, 田中慎吾, 池田博子, 前田大地

  第114回日本病理学会総会, 2025年04月


• 子宮内膜癌84例の分子病理学的検討 ～POLE変異群に焦点をあてて～

  今井歩美, 堀江真史, 伊藤行信, 阪口真希, 前田大地

  第114回日本病理学会総会, 2025年04月


• 早期胃がんESD切除検体を用いた粘膜筋板の厚さに関する検討

  小池知生, 堀江真史, 伊藤行信, 阪口真希, 前田大地

  第114回日本病理学会総会, 2025年04月


• 食道扁平上皮癌と癌関連線維芽細胞との直接共培養により発現誘導されるISG15の解析

  野村尚志, 塚本修一, 児玉貴之, 西尾真理, 重岡学, 狛雄一朗, 堀江真史

  第114回日本病理学会総会, 2025年04月


• マクロファージと肝細胞癌との間接共培養で発現上昇するCHI3L1とOPNの機能解析

  大森將貴, 石原伸朗, 鳥越陸矢, 横尾拓樹, 塚本修一, 児玉貴之, 西尾真理, 重岡学, 狛雄一朗, 堀江真史

  第114回日本病理学会総会, 2025年04月


• 癌関連線維芽細胞との相互作用により食道扁平上皮癌において発現亢進するBST2の機能解析

  鳥越陸矢, 横尾拓樹, 大森將貴, 中西崇, 塚本修一, 児玉貴之, 西尾真理, 重岡学, 狛雄一朗, 堀江真史

  第114回日本病理学会総会, 2025年04月


• 食道扁平上皮癌細胞と共培養した癌関連線維芽細胞において発現亢進するビグリカンの解析

  横尾拓樹, 鳥越陸矢, 大森將貴, 中西崇, 塚本修一, 児玉貴之, 西尾真理, 重岡学, 狛雄一朗, 堀江真史

  第114回日本病理学会総会, 2025年04月


• 大腸癌の進展に伴うがん関連線維芽細胞の不均一性の解明

  塚本修一, 野村尚志, 児玉貴之, 西尾真理, 重岡学, 狛雄一朗, 堀江真史

  第114回日本病理学会総会, 2025年04月


• 膵上皮内癌・微小浸潤癌の腫瘍免疫微小環境に関する免疫組織化学的検討

  児玉貴之, 塚本修一, 西尾真理, 重岡学, 狛雄一朗, 堀江真史

  第114回日本病理学会総会, 2025年04月


• 経過中に肉芽腫性炎症を生じ診断に難渋した眼窩内脂肪肉腫の一例

  西尾真理, 村井佑輔, 安積淳, 塚本修一, 児玉貴之, 重岡学, 狛雄一朗, 堀江真史

  第114回日本病理学会総会, 2025年04月


• pT1/T2舌癌において骨髄由来間葉系幹細胞は癌細胞との相互作用によりiCAF様形質を獲得する

  重岡学, 塚本修一, 児玉貴之, 西尾真理, 狛雄一朗, 堀江真史

  第114回日本病理学会総会, 2025年04月


• 癌関連線維芽細胞との相互作用によって癌細胞において発現亢進するAREGは食道扁平上皮癌の進展を促進する

  狛雄一朗, 中西崇, 塚本修一, 児玉貴之, 西尾真理, 重岡学, 堀江真史

  第114回日本病理学会総会, 2025年04月


• 小細胞肺癌におけるmicroRNAプロファイリングと臨床病理学的検討

  堀江真史, 工田啓史, 木場隼人, 伊藤行信, 伊藤歩美, 齋藤朗, 前田大地

  第114回日本病理学会総会, 2025年04月


• ランチョンセミナー9 病理学の未来を切り拓く！シングルセル空間解析で新たな世界へ 空間トランスクリプトームを活用したがん研究

  堀江真史

  第114回日本病理学会総会, 2025年04月

  [招待有り]


• シンポジウム4 新しい時代の病理解剖を模索する 剖検検体を活用したがん研究の実際

  堀江真史

  第114回日本病理学会総会 シンポジウム4 新しい時代の病理解剖を模索する, 2025年04月

  [招待有り]


• LAT1蛋白発現と原発性肺がん

  木場隼人, 堀江真史, 新井祥子, 村瀬裕哉, 上田宰, 寺田七朗, 野村俊一, 南條成輝, 丹保裕一, 矢野聖二

  第22回日本臨床腫瘍学会学術集会, 2025年03月


• 喘息・COPDオーバーラップモデルの多層的オミックス解析による病態解明と新規エンドタイピングマーカー探索

  福田健介, 松崎博崇, 槇田広佑, 三上優, 田中秀憲, 齋藤朗, 鹿毛秀宣, 堀江真史

  第73回日本アレルギー学会学術大会, 2024年10月


• G-CSFを介したCAFと乳がん幹細胞の相互作用は、トリプルネガティブ乳がんの原発腫瘍形成と骨転移に重要である

  竹内康人, 張華姿, 村山貴彦, 池田和博, 井上聡, 堀江公仁子, 矢野正雄, 田辺真彦, 太田哲生, 洲崎悦生, 平田英周, 堀江真史, 前田大地, 岡本康司, 東條有伸, 後藤典子, 田辺真彦

  第83回日本癌学会学術総会, 2024年09月


• 顆粒球コロニー刺激因子受容体（G-CSFR）発現乳癌幹細胞と骨転移ニッチにおける周囲細胞との相互作用の解析

  張華姿, 竹内康人, 村山貴彦, 池田和博, 井上聡, 堀江公仁子, 矢野正雄, 田辺真彦, 太田哲生, 洲崎悦生, 平田英周, 堀江真史, 前田大地, 岡本康司, 東條有伸, 後藤典子

  第83回日本癌学会学術総会, 2024年09月


• Deciphering NEUROD1's target genes and miRNAs: an integrative analysis in small cell lung cancer

  Hiroshi Takumida, Akira Saito, Yasuhiro Terasaki, Yugo Okabe, Yu Mikami, Hidenori Tanaka, Hidenori Kage, Masafumi Horie

  European Respiratory Society Congress 2024, 2024年09月


• PD-L1タンパク発現のクライオバイオプシーによる変化の検討

  村瀬裕哉, 木場隼人, 上田宰, 武藤篤, 古林崇史, 新井祥子, 加瀬一政, 武田仁浩, 寺田七朗, 山村健太, 丹保裕一, 大倉徳幸, 原丈介, 阿保未来, 渡辺知志, 南條成輝, 矢野聖二, 堀江真史, 前田大地, 鈴木淳也, 芝靖貴, 岩佐桂一, 柴田和彦

  第78回日本肺癌学会北陸支部学術集会, 2024年07月


• Claudin-18 Regulates Airway Progenitor Cell Homeostasis and Differentiation.

  Castaldi A, Samimi K, Arias N, Pinson-Rose W, Allen A, Solaimanpour K, Zamani P, Xie M, Ma B, Horie M, Liu Y, Ji Y, Shen H, Flodby P, Ryan AL, Borok Z

  American Thoracic Society International Conference (ATS)., 2024年05月


• Monocyte-derived Interstitial Macrophages Promote Lung Regeneration by Regulating Extracellular Matrix Degradation and Angiogenesis.

  Watanabe S, Kase K, Saeki K, Iwasaki K, Muto A, Ohkura N, Abo M, Horie M, Naito H, Yano S

  American Thoracic Society International Conference (ATS)., 2024年05月


• Claudin-18 Regulates Alveolar Epithelial Cell Plasticity and Regeneration.

  Castaldi A, Chin J, Ma B, Samimi K, Arias N, Allen A, Pinson-Rose W, Zamani P, Xie M, Solaimanpour K, Chang M, Castillo J, Liu Y, Ji Y, Shen H, Horie M, Flodby P, Benner C, Marconett CN, Sun X, Zhou B, Borok Z

  American Thoracic Society International Conference (ATS)., 2024年05月


• Large scale, transcriptome-based analysis of TCR clonality reveals functional immunity in non-small cell lung cancer.

  Yu H, Magoulopoulou A, Horie M, Lindberg A, Backman M, Brunström H, Zuniga M, Mattsson J, Saito A, Leandersson K, Nilsson M, Amini RM, Micke P, Strell C

  American Association for Cancer Research (AACR)., 2024年04月


• FGFR2 splice variant as a cell fate adjudicator determines clinical outcomes in non-small cell lung cancer.

  Yu H, Horie M, Lindberg A, Backman M, Hekmati N, Mattsson J, Miyashita N, Brunnström H, Ponten F, Saito A, Strell C, Micke P

  American Association for Cancer Research (AACR)., 2024年04月


• Comprehensive Proteomic Analysis of Cervical Adeno carcinoma Reveals Annexin A10 and Cathepsin E as Potential Biomarkers of Gastric - type Adenocarcinoma.

  Suzuki M, Horie M, Koyama K, Goto A, Maeda D

  United States and Canadian Academy of Pathology (USCAP)., 2024年03月


• Comprehensive Immunogenomic Profiling Reveals Association of BAFF/APRIL Upregulation with Clonal B-cell Expansion in Hunner-type Interstitial Cystitis.

  Horie M, Akiyama Y, Ushiku T, Homma Y, Maeda D

  United States and Canadian Academy of Pathology (USCAP)., 2024年03月


• 剖検心３０例を用いた心筋介在板の構造異常の検討

  要川 雄紀, 伊藤 行信, 伊藤 歩美, 阪口 真希, 堀江 真史, 吉田 誠, 前田 大地

  日本病理学会総会, 2024年


• 高血流量が誘発する動脈リモデリングでの血管平滑筋細胞のリモデリング

  伊藤 行信, 吉田 誠, 堀江 真史, 前田 大地, 後藤 明輝, 増田 弘毅

  日本病理学会総会, 2024年


• 全エクソン解析による多発髄膜腫におけるクローナリティーの証明

  阪口 真希, 堀江 真史, 伊藤 行信, 田中 慎吾, 池田 博子, 前田 大地

  日本病理学会総会, 2024年


• 包括的免疫ゲノムプロファイリングによるハンナ型間質性膀胱炎の本態解明

  堀江 真史, 秋山 佳之, 加藤 洋人, 水口 敬司, 牛久 哲男, 石川 俊平, 後藤 明輝, 本間 之夫, 前田 大地

  日本病理学会総会, 2024年


• The RNA Sensor MDA5 Regulates The Inflammatory and Profibrotic Responses Of Immune Cells In Bleomycin-induced Lung Fibrosis

  Ishii T, Horie M, Murakami Y, Narita T, Yamashita N, Kumano K, Kage H, Saito A

  日本呼吸器学会学術講演会, 2024年


• Monocyte-derived Interstitial Macrophages Stimulate Angiogenesis to Promote Lung Regeneration following Pneumonectomy

  Watanabe S, Kase K, Saeki K, Kobayashi T, Takeda Y, Ohkura N, Abo M, Horie M, Naito H, Yano S

  日本呼吸器学会学術講演会, 2024年


• Deciphering NEUROD1's Target Genes and miRNAs：An Integrative Analysis in SCLC

  Takumida H, Mikami Y, Terasaki Y, Tanaka H, Urushiyama H, Okabe Y, Kuwahar N, Saito A, Horie M

  日本呼吸器学会学術講演会, 2024年


• ZFP36ファミリーによるTh2細胞の制御と気管支喘息における気道炎症との関連性の解析

  上原 有貴, 鈴川 真穂, 堀江 真史, 髙田 和典, 五十嵐 彩夏, 峰岸 正明, 齋藤 朗, 長瀬 洋之

  日本呼吸器学会学術講演会, 2024年


• 多面的な単一細胞解析による肺小細胞癌の本態解明の試み～FFPE検体の活用へ～

  堀江 真史

  日本呼吸器学会学術講演会, 2024年


• Monocyte-derived Interstitial Macrophages Stimulate Angiogenesis to Promote Lung Regeneration Following Pneumonectomy

  Watanabe S, Kase K, Saeki K, Kobayashi T, Takeda Y, Ohkura N, Abo M, Horie M, Naito H, Yano S.

  American Thoracic Society International Conference, 2023年05月


• ASCL1型肺小細胞癌におけるエピゲノムの全貌解明

  堀江 真史, 田中 秀憲, 伊藤 行信, 宮下 直也, 齋藤 朗, 前田 大地

  第112回 日本病理学会総会, 2023年04月


• Thymic Cyst: A Clinicopathological, Immunohistochemical, and Molecular Study of 38 Cases Focusing on Squamous- and Ciliated-Type Epithelium.

  Takata S, Horie M, Goto A, Shintani Y, Kumanogoh A, Yachida S, Maeda D

  United States and Canadian Academy of Pathology (USCAP)., 2023年


• Claudin-18 Regulates Airway Progenitor Cell Homeostasis and Differentiation.

  Castaldi A, Samimi K, Arias N, Pinson-Rose W, Allen A, Solaimanpour K, Zamani P, Xie M, Ma B, Horie M, Liu Y, Ji Y, Shen H, Flodby P, Ryan AL, Borok Z

  American Thoracic Society International Conference (ATS)., 2023年


• シングルセル解析を用いたヒト羊膜上皮細胞の系統学的多様性の解明

  高野 智圭, 堀江 真史, エルディーブ ダリア, 早川 智, 三木 敏生

  日本胎盤学会学術集会, 2023年


• 肺線維症におけるGremlin 1の役割の検討

  松木 怜, 野口 智史, 齋藤 朗, 堀江 真史, 三上 優, 福田 健介, 榎戸 貴祥, 佐藤 雅昭, 此枝 千尋, 寺崎 泰弘, 岡部 友吾, 漆山 博和, 長瀬 隆英

  日本呼吸器学会学術講演会, 2023年


• ヒト歯周炎のin vitro実験モデルでの上皮-間葉相互作用における肝細胞増殖因子の役割

  山口 洋子, 齋藤 朗, 堀江 真史, 青木 章, Micke Patrick, Kappert Kai

  第95回 日本生化学会大会, 2022年11月


• がん抑制遺伝子であるELF3は上皮管腔形成の維持と免疫反応に関与する遺伝子発現を制御する

  鈴木 雅美, 足立 美保子, 新井 康仁, 堀江 真史, 柴田 龍弘, 清野 透, 谷内田 真一

  第81回 日本癌学会学術総会, 2022年09月


• がん幹細胞による治療抵抗性細胞の再構築

  藤野 志季, 武田 和, 團野 克樹, 山本 慧, 東口 公哉, 野口 幸藏, 豊田 泰弘, 平尾 隆文, 岡 義雄, 堀江 真史, 谷内田 真一, 大植 雅之, 土岐 祐一郎, 江口 英利, 三吉 範克

  第81回 日本癌学会学術総会, 2022年09月


• Deletion of Claudin-18 Accelerates Alveolar Epithelial Cell Repair Following Injury

  Castaldi A, Samimi K, Arias N, Allen A, Pinson-Rose W, Zamani P, Solaimanpour K, Liu Y, Ji Y, Shen H, Horie M, Flodby P, Minoo P, Carraro G, Stripp BR, Zhou B, Borok Z

  American Thoracic Society International Conference, 2022年05月


• トランスクリプトーム解析によるAsthma-COPD Overlap(ACO)の分子病態の解明

  堀江 真史, 福田 健介, 松崎 博崇, 田中 秀憲, 三上 優, 鹿毛 秀宣, 齋藤 朗, 長瀬 隆英, 平石 尚久

  第62回 日本呼吸器学会学術講演会, 2022年04月


• 肺小細胞癌サブタイプにおけるmiR-455-3pの関与

  田中 和子, 宮下 直也, 堀江 真史, 漆山 博和, 岡部 友吾, 福田 健介, 石井 崇史, 齋藤 朗, 長瀬 隆英

  第62回 日本呼吸器学会学術講演会, 2022年04月


• Single-cell RNA sequencing of patient-derived organoid reveals treatment-induced tumor resistance through cancer stem cells.

  Fujino S, Ito A, Yasui M, Matsuda C, Ohue M, Horie M, Yachida S, Doki Y, Eguchi H, Miyoshi N

  American Association for Cancer Research (AACR)., 2022年


• Monocyte-derived Interstitial Macrophages Promote Lung Regeneration by Regulating Extracellular Matrix Degradation and Angiogenesis.

  Watanabe S, Kase K, Saeki K, Iwasaki K, Muto A, Ohkura N, Abo M, Horie M, Naito H, Yano S

  American Thoracic Society International Conference (ATS), 2022年


• ヒト羊膜上皮細胞における上皮間葉転換と多能性に関する網羅的遺伝子解析

  高野 智圭, 堀江 真史, 早川 智, 三木 敏生

  第29回 日本胎盤学会学術集会, 2021年11月


• Inhibition of epithelial mesenchymal transition maintains stemness in human amniotic epithelial cells

  Takano C, Horie M, Miki T

  Joint IXA-CTRMS Virtual Congress 2021, 2021年09月


• 2次元培養オルガノイドを利用したシングルセル解析による癌多様性の解明

  藤野 志季, 武田 和, 團野 克樹, 山本 慧, 野口 幸藏, 豊田 泰弘, 徳永 俊照, 平尾 隆文, 杉本 圭司, 岡 義雄, 堀江 真史, 谷内田 真一, 大植 雅之, 土岐 祐一郎, 江口 英利, 三吉 範克

  第80回 日本癌学会学術総会, 2021年09月


• Claudin-18 Regulates Alveolar Epithelial Regeneration Following Injury

  Castaldi A, Allen A, Pinson-Rose W, Samimi K, Zamani P, Solaimanpour K, Liu Y, Ji Y, Shen H, Horie M, Flodby P, Minoo P, Zhou B, Borok Z.

  American Thoracic Society International Conference, 2021年05月


• 歯周炎病因論の再考 FANTOM5プロジェクトによる歯周炎関連線維芽細胞の解析

  堀江 真史

  第63回 春季日本歯周病学会学術大会, 2020年05月


• ASCL1 suppress ZFP36L1 expression by regulating miR124-3p expression in lung adenocarcinoma.

  Enokido T, Miyashita N, Horie M, Saito A, Nagase T

  European Respiratory Society International Congress (ERS)., 2020年


• Regulation of Airway Progenitor Homeostasis and Cell Composition by Tight Junction Protein Claudin-18.

  Castaldi A, Arias N, Pinson-Rose W, Samimi K, Allen A, Horie M, Li C, Minoo P, Zhou B, Stripp B, Ryan A, Borok Z

  Experimental Biology., 2020年


• Claudin-18 Is a Novel Regulator of Airway Progenitor Cell Homeostasis and Differentiation.

  Castaldi A, Arias N, Pinson-Rose W, Samimi K, Allen A, Solaimanpour K, Zamani P, Xie M, Horie M, Li C, Minoo P, Zhou B, Stripp B, Ryan A, Borok Z

  American Thoracic Society International Conference (ATS)., 2020年


• Single-cell transcriptomes reveal phylogenetic diversification of human amniotic epithelial cells.

  Takano C, Horie M, Eldeeb D, Taiko I, Miki T

  IPITA-IXA-CTRMA Join;Congress, 2020年


• Effects of ASCL1 expression on tumorigenesis and immune cell infiltration in a syngenic mouse model of lung adenocarcinoma

  Miyashita N, Horie M, Mikami Y, Urushiyama H, Fukuda K, Makita K, Matsuzaki H, Saito A, Nagase T

  European Respiratory Society International Congress, 2019年09月


• The Hippo pathway effectors TAZ and YAP are sequentially required in lung development.

  Isago H, Mitani A, Hohno S, Nagoshi H, Ishimori T, Saito M, Tamiya H, Mikami Y, Horie M, Urushiyama H, Jo T, Tanaka G, Hamamoto R, Terasaki Y, Nagase T

  European Respiratory Society International Congress, 2019年09月


• Transcriptomic Analysis Identifies Pathways Mediating Alveolar Epithelial Type II (AT2) Cell Dysfunction and Fibrosis in Response to ER Stress Following Grp78 Knockout (KO).

  Zhou B, Horie M, Flodby P, Wang H, Liu Y, Lee A, Borok Z

  American Thoracic Society International Conference, 2019年05月


• Single-Cell RNA Sequencing of Aquaporin 5 (Aqp5)-Positive Epithelial Cells in Adult Mouse Lung Reveals Heterogeneity of Type I Cells and Facilitates Identification of Gprc5a as a Potential Novel Type I Cell Marker.

  Horie M, Sunohara M, Castaldi A, Wang H, Ji Y, Li F, Kage H, Crandall E, Flodby P, Zhou B, Borok Z

  American Thoracic Society International Conference, 2019年05月


• 非小細胞肺癌におけるASCL1陽性群の解析

  宮下 直也, 堀江 真史, 齋藤 朗, 長瀬 隆英

  肺癌, 2018年10月, 日本語


• Mechanism of Periostin Production in Human Bronchial Smooth Muscle Cells.

  Makita K, Mikami Y, Matsuzaki H, Miyashita N, Takeshima H, Noguchi S, Horie M, Urushiyama H, Iikura M, Hojo M, Yamauchi Y, Nagase T

  American Thoracic Society International Conference, 2018年05月


• Analysis of ASCL1-Positive Subgroup of Non-Small Cell Lung Cancer.

  Miyashita N, Horie M, Saito A, Nagase T

  American Thoracic Society International Conference, 2018年05月


• 非小細胞肺癌におけるASCL1陽性群の解析

  宮下 直也, 堀江 真史, 齋藤 朗, 長瀬 隆英

  日本呼吸器学会誌, 2018年03月, 日本語


• 健康診断の胸部X線検査における胸膜肥厚所見に関する検討

  齋藤 朗, 堀江 真史, 垂井 愛, 春原 光宏, 村野 陽子, 三谷 明久, 田中 君枝, 柳元 伸太郎, 小池 和彦

  CAMPUS HEALTH, 2018年03月, 日本語


• 健康診断の胸部X線検査における胸膜肥厚所見に関する検討

  齋藤 朗, 堀江 真史, 垂井 愛, 春原 光宏, 村野 陽子, 三谷 明久, 田中 君枝, 柳元 伸太郎, 小池 和彦

  全国大学保健管理研究集会プログラム・抄録集, 2017年11月, 日本語


• Naftopidil, a selective α1 adrenoceptor antagonist, inhibits the growth of lung fibroblasts and attenuates bleomycin-induced lung fibrosis in mice.

  Urushiyama H, Terasaki Y, Nagasaka S, Yamauchi Y, Kokuho N, Kunugi S, Matsuzaki H, Hiraishi Y, Mikami Y, Noguchi S, Horie M, Nagase T

  European Respiratory Society International Congress, 2017年09月


• Transcriptome analysis revealed IL-13 signaling pathway in human lung fibroblasts.

  Takeshima H, Horie M, Miyashita N, Makita K, Matsuzaki H, Noguchi S, Mikami Y, Urushiyama H, Mitani A, Nagase T, Yamauchi Y

  American Thoracic Society International Conference, 2017年05月


• The Incidence and Risk Factors of Asymptomatic Spontaneous Pneumothorax (ASP) Detected During Health Check-Ups.

  Mitani A, Hakamata Y, Hosoi M, Horie M, Murano Y, Saito A, Yanagimoto S, Tsuji S, Yamamoto K, Nagase T

  American Thoracic Society International Conference, 2017年05月


• 若年男子における非アルコール性脂肪性肝疾患と動脈硬化の関連

  井上 有希子, 柳元 伸太郎, 八尾 厚史, 弓削田 晃弘, 岩澤 邦明, 碓井 知子, 斎藤 朗, 坂本 愛子, 柴山 修, 西本 菜穂子, 堀江 真史, 道下 和也, 村野 陽子, 三谷 明久, 山田 朋英, 岡崎 佐智子, 池田 均, 辻 省次, 山本 一彦

  CAMPUS HEALTH, 2017年03月, 日本語


• 本学における自然気胸の定期健診発見症例まとめ

  細井 恩, 袴田 千愛, 三谷 明久, 岩崎 翔也, 古田 明子, 関根 早苗, 菊池 優子, 堀江 真史, 村野 陽子, 齋藤 朗, 柳元 伸太郎, 辻 省次, 長瀬 隆英, 山本 一彦

  CAMPUS HEALTH, 2017年03月, 日本語


• トランスクリプトーム解析による肺線維芽細胞におけるIL13シグナリングの解明

  竹島 英之, 堀江 真史, 宮下 直也, 槇田 広佑, 松崎 博崇, 野口 智史, 三上 優, 漆山 博和, 三谷 明久, 長瀬 隆英, 山内 康宏

  日本呼吸器学会誌, 2017年03月, 日本語


• 定期健診発見の自然気胸症例のまとめ

  三谷 明久, 袴田 千愛, 細井 恵, 堀江 真史, 村野 陽子, 齋藤 朗, 柳元 伸太郎, 辻 省次, 山本 一彦, 長瀬 隆英

  日本呼吸器学会誌, 2017年03月, 日本語


• 歯肉溝滲出液miRNAによる新しい歯周炎診断法

  齋藤 朗, 堀江 真史, 江尻 健一郎, 青木 章, 鈴木 伸太, 前川 省吾, 片桐 さやか, Kong Sophannary, 山内 恒人, 山口 洋子, 和泉 雄一, 大島 光宏

  みちのく歯学会雑誌, 2016年12月, 日本語


• Mechanism Of Periostin Production In Bronchial Smooth Muscle Cells.

  Makita K, Yamauchi Y, Mikami Y, Matsuzaki H, Miyashita N, Takeshima H, Noguchi S, Horie M, Urushiyama H, Nagase T

  Asian Pacific Society of Respirology Congress, 2016年11月


• 肺小細胞癌のトランスクリプトーム解析

  堀江 真史, 齋藤 朗, 長瀬 隆英

  日本癌学会総会記事, 2016年10月, 英語


• 本学における自然気胸の定期健診発見症例のまとめ

  細井 恩, 三谷 明久, 岩崎 翔也, 古田 明子, 関根 早苗, 菊池 優子, 袴田 千愛, 堀江 真史, 村野 葉子, 齋藤 朗, 柳元 伸太郎, 辻 省次, 長瀬 隆英, 山本 一彦

  全国大学保健管理研究集会プログラム・抄録集, 2016年09月, 日本語


• 若年男子における非アルコール性脂肪性肝疾患と動脈硬化の関連

  井上 有希子, 柳元 慎太郎, 八尾 厚史, 弓削田 晃弘, 岩澤 邦明, 碓井 智子, 斎藤 朗, 坂本 愛子, 柴山 修, 西本 菜穂子, 堀江 真史, 道下 和也, 村野 陽子, 辻 省次, 山本 一彦

  全国大学保健管理研究集会プログラム・抄録集, 2016年09月, 日本語


• COPDにおける大気汚染とバイオマーカーの検討

  佐田 充, 渡辺 雅人, 乾 俊哉, 中本 啓太郎, 中村 益夫, 本多 紘二郎, 和田 裕雄, 堀江 真史, 三上 優, 野口 智史, 山内 康弘, 滝澤 始

  日本職業・環境アレルギー学会雑誌, 2016年06月, 日本語


• Transcriptome Analysis of Small Cell Lung Cancer.

  Horie M, Saito A, Nagase T

  American Thoracic Society International Conference, 2016年05月


• 入院中の血液悪性疾患患者における呼吸器合併症と、その診断における気管支鏡検査の寄与についての検討

  三上 優, 槇田 広佑, 成本 治, 堀江 真史, 野口 智史, 長瀬 隆英

  気管支学, 2016年05月, 日本語


• 気管支喘息とCOPDにおけるバイオマーカーと大気汚染物質 GSTP1遺伝子多型の影響

  乾 俊哉, 中本 啓太郎, 佐田 充, 辻 晋吾, 平田 彩, 小出 卓, 高田 佐織, 横山 琢磨, 石井 晴之, 三上 優, 堀江 真史, 滝澤 始

  気管支学, 2016年05月, 日本語


• 気管支喘息、COPDにおけるバイオマーカーと大気汚染物質 GSTP1遺伝子多型の影響

  乾 俊哉, 中本 啓太郎, 佐田 充, 辻 晋吾, 中村 益夫, 本多 紘二郎, 渡辺 雅人, 小川 ゆかり, 小出 卓, 高田 佐織, 横山 琢磨, 倉井 大輔, 皿谷 健, 石井 晴之, 松崎 博崇, 野口 智史, 三上 優, 堀江 真史, 金 俊行, 小山 ひかり, 和田 裕雄, 山内 康宏, 幸山 正, 滝澤 始

  日本職業・環境アレルギー学会雑誌, 2016年05月, 日本語


• Hippo pathwayの構成因子であるTAZの肺線維症における役割

  野口 智史, 齋藤 朗, 三上 優, 漆山 博和, 寺崎 泰弘, 堀江 真史, 松崎 博崇, 竹島 英之, 槇田 広佑, 三谷 明久, 山内 康宏, 長瀬 隆英

  日本呼吸器学会誌, 2016年03月, 日本語


• 口腔がん浸潤に関与する遺伝子発現プロファイルの検討

  山口 洋子, 大島 光宏, 石井 輝彦, 大木 秀郎, 堀江 真史, Micke Partrick

  日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 2015年12月, 日本語


• CAGE revealed novel biomarker of periodontitis-associated fibroblasts.

  Horie M, Yamaguchi Y, Saito A, Nagase T, Itoh M, Kawaji H, Lassmann T, Carninci P, Hayashizaki Y, Forrest A, The FANTOM consortium, Lizio M, Kondo M, Suzutani T, Micke P, Ohshima M

  International Mammalian Genome Conference, 2015年11月


• Influence of gene polymorphism on biological markers in patients with asthma and COPD associated with air pollutants.

  Inui T, Nakamoto K, Sada M, Ishii H, Kogane T, Koyama H, Matsuzaki H, Noguchi S, Mikami Y, Horie M, Yamauchi Y, Kohyama T, Takizawa H

  Asian Pacific Society of Respirology Congress, 2015年11月


• Respiratory manifestations in hospitalized patients with hematological malignancies.

  Mikami Y, Takai D, Horie M, Noguchi S, Matsuzaki H, Makita K, Takeshima H, Yamauchi Y, Tanaka G, Nagase T

  European Respiratory Society International Congress, 2015年09月


• 喘息、COPD及びオーバーラップにおけるバイオマーカーと大気汚染物質 GSTP1遺伝子多型の影響

  乾 俊哉, 中本 啓太郎, 佐田 充, 辻 晋吾, 中村 益夫, 渡辺 雅人, 小川 ゆかり, 小出 卓, 高田 佐織, 横山 琢磨, 皿谷 健, 倉井 大輔, 石井 晴之, 松崎 博崇, 野口 智史, 三上 優, 堀江 真史, 金 俊行, 小山 ひかり, 和田 裕雄, 山内 康宏, 幸山 正, 滝澤 始

  日本職業・環境アレルギー学会雑誌, 2015年06月, 日本語


• Montelukast Inhibits Transforming Growth Factor-β1-Induced Fibroblast To Myofibroblast Differentiation.

  Mikami Y, Matsuzaki H, Horie M, Noguchi S, Jo T, Mitani A, Yamauchi Y, Nagase T

  American Thoracic Society International Conference, 2015年05月


• Evaluation Of Intracellular Signaling Of Synergistic Chemokines Production From Bronchial Epithelial Cells By Co-Stimulation With IL-17A And TLR3 Ligand.

  Matsuzaki H, Yamauchi Y, Mikami Y, Noguchi S, Horie M, Narumoto O, Hirota N, Jo T, Takami K, Nagase T

  American Thoracic Society International Conference, 2015年05月


• TGF-βは肺線維芽細胞における神経栄養因子の産生を増強する

  堀江 真史, 三上 優, 野口 智史, 松崎 博崇, 垂井 愛, 成本 治, 三谷 明久, 齋藤 朗, 城 大祐, 坂本 真樹子, 高見 和孝, 幸山 正, 滝澤 始, 長瀬 隆英, 山内 康宏

  日本呼吸器学会誌, 2015年03月, 日本語


• 気管支喘息患者におけるGSTP1遺伝子多型と大気汚染の影響

  佐田 充, 和田 裕雄, 乾 俊哉, 中本 啓太郎, 中村 益夫, 本多 紘二郎, 堀江 真史, 三上 優, 野口 智史, 山内 康弘, 滝澤 始

  日本呼吸器学会誌, 2015年03月, 日本語


• Influence of gene polymorphism on air pollutants-induced airway oxidative stress among asthmatic patients.

  Inui T, Wada H, Nakamoto K, Sada M, Tsuji S, Nakamura M, Honda K, Tanaka Y, Koide T, Takata S, Yokoyama T, Kurai D, Saraya T, Ishii H, Koyama H, Kogane T, Horie M, Mikami Y, Noguchi S, Matsuzaki H, Yamauchi Y, Kohyama T, Goto H, Takizawa H

  Asian Pacific Society of Respirology Congress, 2014年11月


• Transforming growth factor-beta induces the production of neurotrophins in lung fibroblasts via Smad pathway.

  Horie M, Mikami Y, Noguchi S, Matsuzaki T, Tarui M, Narumoto O, Hirota N, Mitani A, Saito A, Jo T, Sakamoto M, Takami K, Kohyama T, Takizawa H, Nagase T, Yamauchi Y

  Asian Pacific Society of Respirology Congress, 2014年11月


• The influence of bronchial asthma as a comorbidity of COPD on the COPD assessment test (CAT).

  Jo T, Yamauchi Y, Okudaira R, Saito A, Hirota N, Goto Y, Narumoto O, Watanabe K, Sunohara M, Amano Y, Horie M, Mikami Y, Noguchi S, Matsuzaki H, Tanaka G, Takami K, Ohishi N, Kohyama T, Nagase T

  European Respiratory Society International Congress, 2014年09月


• Lymphotoxin β Receptor Signal Induces IL-8 From Bronchial Epithelial Cells Via Erk And NF-κB Activation.

  Mikami Y, Yamauchi Y, Hirota N, Matsuzaki H, Horie M, Noguchi S, Jo T, Narumoto O, Kohyama T, Takizawa H, Nagase T

  American Thoracic Society International Conference, 2014年05月


• IL-17A And TLR3 Ligand Poly (i:c). Synergistically Induce The Production Of Chemokines From Bronchial Epithelial Cells.

  Matsuzaki H, Yamauchi Y, Mikami Y, Noguchi S, Horie M, Narumoto O, Hirota N, Jo T, Takami K, Nagase T

  American Thoracic Society International Conference, 2014年05月


• 軽度から中程度のCOPD患者ではFOTにより測定した指数は肺活量測定による細気道の狭窄度を反映する指数と相関している(Parameters by FOT correlate with parameters reflecting small airway narrowing by spirometry in patients with mild to moderate COPD)

  山内 康宏, 城 大祐, 後藤 悌, 堀江 真史, 三上 優, 野口 智史, 松崎 博崇, 高見 和孝, 長瀬 隆英

  日本呼吸器学会誌, 2014年03月, 英語


• 気道上皮細胞での酸化ストレス及びIL-17Aによるケモカイン産生の影響

  松崎 博崇, 山内 康宏, 三上 優, 堀江 真史, 野口 智史, 成本 治, 城 大祐, 高見 和孝, 幸山 正, 滝澤 始, 長瀬 隆英

  アレルギー, 2013年10月, 日本語


• The ratio of inspiratory ΣRrs to expiratory ΣRrs measured by forced oscillation technique correlates with the parameters reflecting narrowing of small airway measured by spirometry in patients with mild to moderate COPD.

  Yamauchi Y, Jo T, Goto Y, Horie M, Mikami Y, Noguchi S, Takami K, Kohyama T, Nagase T

  European Respiratory Society International Congress, 2013年09月


• FLT-1が歯周炎原因候補遺伝子である可能性

  大島 光宏, 山口 洋子, 堀江 真史, 齋藤 朗, 長瀬 隆英, 安孫子 宜光

  日本生化学会大会プログラム・講演要旨集, 2013年09月, 日本語


• Tumor Necrosis Factor Super Family Member LIGHT Induces CXCL8 Production In BEAS-2B Human Bronchial Epithelial Cells Via Erk1/2 Pathway.

  Mikami Y, Yamauchi Y, Horie M, Noguchi S, Narumoto O, Jo T, Kohyama T, Takizawa H, Nagase T

  American Thoracic Society International Conference, 2013年05月


• An Integrated Expression Profiling Reveals Target Genes Of TGF-β And TNF-α Possibly Mediated By microRNAs In Lung Cancer Cells.

  Saito A, Horie M, Nagase T

  American Thoracic Society International Conference, 2013年05月


• Interleukin-17A Enhances Interferon-Gamma-Induced CXCL10/IP-10 Production In BEAS-2B Human Bronchial Epithelial Cells.

  Yamauchi Y, Jo T, Horie M, Mikami Y, Noguchi S, Narumoto O, Takami K, Kohyama T, Takizawa H, Nagase T

  American Thoracic Society International Conference, 2013年05月


• Functional Roles Of TAZ In Lung Cancer Cell Proliferation.

  Noguchi S, Horie M, Mikami Y, Saito A, Nagase T

  American Thoracic Society International Conference, 2013年05月


• Lentivirus-Mediated Knockdown Of TGF-β Ligands Inhibits Lung Cancer Invasion And Tumorigenesis: An Experimental Model For Tumor-Stromal Interaction.

  Horie M, Saito A, Noguchi S, Nagase T, Kohyama T

  American Thoracic Society International Conference, 2013年05月


• Tumor necrosis factor super family member LIGHT induces IL-6, MCP-1 and IL8 in Beas2B human bronchial epithelial cells.

  Mikami Y, Yamauchi Y, Horie M, Noguchi S, Jo T, Kohyama T, Takizawa H, Nagase T

  Asian Pacific Society of Respirology Congress, 2012年11月


• 腫瘍壊死因子スーパーファミリーLIGHTは気道上皮細胞でのIL-8分泌を促進する

  三上 優, 山内 康宏, 堀江 真史, 城 大祐, 幸山 正, 滝澤 始, 長瀬 隆英

  アレルギー, 2012年10月, 日本語


• Chemokine profiles of A549 human alveolar epithelial cells that underwent epithelial-mesenchymal transition by TGF-b and/or TNF-a.

  Horie M, Yamauchi Y, Saito A, Jo T, Mikami Y, Takizawa H, Nagase T, Kohyama T

  European Respiratory Society International Congress, 2012年09月


• Difference of respiratory reactance between mild and moderate COPD by forced oscillation technique using a MostGraph-01.

  Yamauchi Y, Kohyama T, Jo T, Horie M, Mikami Y, NagaseT

  European Respiratory Society International Congress, 2012年09月


• Difference Of Chemokines Production From Airway Epithelial Cells And The Cells That Underwent Epithelial Mesenchymal Transition.

  Horie M, Yamauchi Y, Kohyama T, Jo T, Mikami Y, Takizawa H, Nagase T

  American Thoracic Society International Conference, 2012年05月


• Tumor Necrosis Factor Superfamily Member LIGHT (TNFSF14) Induces Epithelial-Mesenchymal Transition In A549 Human Airway Epithelial Cells

  Mikami Y, Yamauchi Y, Kohyama T, Horie M, Saito A, Jo T, Takizawa H, Nagase T

  American Thoracic Society International Conference, 2012年05月


• TNF superfamilyのLIGHTは肺胞上皮細胞でのTGF-β1刺激による上皮間葉転換(EMT)を増強する

  三上 優, 山内 康宏, 幸山 正, 堀江 真史, 齋藤 朗, 城 大祐, 滝澤 始, 長瀬 隆英

  日本呼吸器学会誌, 2012年03月, 日本語


• COPD患者の吸気・呼気相における呼吸抵抗の検討

  山内 康宏, 幸山 正, 城 大祐, 堀江 真史, 三上 優, 長瀬 隆英

  日本呼吸器学会誌, 2012年03月, 日本語


• Tumor necrosis factor superfamily member LIGHT enhances epithelial-mesenchymal transition induced in A549 human alveolar epithelial cells by TGF-β1.

  Mikami Y, Yamauchi Y, Kohyama T, Horie M, Saito A, Jo T, Takizawa H, Nagase T

  Asian Pacific Society of Respirology Congress, 2011年11月


• ヒスタミンは肺線維芽細胞の収縮能を増強し線維化に影響する

  堀江 真史, 幸山 正, 山内 康宏, 三上 優, 齋藤 朗, 城 大祐, 滝澤 始, 長瀬 隆英

  アレルギー, 2011年10月, 日本語


• Evaluation of respiratory impedance in COPD by forced oscillation technique using a MostGraph.

  Yamauchi Y, Kohyama T, Takizawa H, Kase M, Horie M, Mikami Y, Nagase T

  European Respiratory Society International Congress, 2011年09月


• The Effect Of Fluticasone And Salmeterol On TNF-Alpha-Induced Chemokine Production In Airway Epithelial Cells.

  Mikami Y, Yamauchi Y, Kohayama T, Horie M, Saito R, Jo T, Takizawa H, Nagase T

  American Thoracic Society International Conference, 2011年05月


• Histamine Stimulates Human Lung Fibroblast Mediated Gel Contraction.

  Horie M, Kohyama T, Yamauchi Y, Mikami Y, Saito A, Jo T, Takizawa H, Nagase T

  American Thoracic Society International Conference, 2011年05月


• 多発骨転移・皮下転移により発見され、原発巣診断に免疫染色が有効だった肺腺癌、大腸癌の重複癌の1例

  遠藤 聡, 三上 優, 鹿毛 秀宣, 堀江 真史, 河崎 伸, 幸山 正, 大石 展也, 長瀬 隆英

  日本内科学会関東地方会, 2011年03月, 日本語


• 心膜液細胞診にて腺癌と診断され、剖検にて原発性心膜悪性中皮腫と判明した1例

  田村 公嗣, 堀江 真史, 松崎 博崇, 野口 智史, 田中 若恵, 小島 康弘, 川上 真樹, 鈴木 勝, 坂本 芳雄

  日本内科学会関東地方会, 2010年06月, 日本語


• Effects Of Smoking cessation On Airflow Limitation And Metabolic Abnormalities Among The Population Of School Workers.

  Noguchi S, Sakamoto Y, Suzuki M, Kichikawa Y, Kawakami M, Yoshihara H, Tanaka W, Horie M, Horiuchi T

  American Thoracic Society International Conference, 2010年05月


• 重症の肝機能障害を伴いステロイドおよび免疫グロブリン療法により治療した薬剤過敏症症候群の1例

  漆畑 真理, 成田 明子, 堀江 真史

  日本皮膚科学会雑誌, 2010年04月, 日本語


• 高度閉塞性換気障害と炎症性偽腫瘍を認めたIgG4関連疾患の一例

  吉原 久直, 野口 智史, 田中 若恵, 堀江 真史, 川上 真樹, 吉川 理子, 鈴木 勝, 坂本 芳雄, 堀内 正, 大田 健

  アレルギー, 2010年04月, 日本語


• シェーグレン症候群に合併し、4年間に渡りBALF所見の変化を観察しえた慢性好酸球性肺炎の1例

  野口 智史, 坂本 芳雄, 田中 若恵, 堀江 真史, 吉原 久直, 川上 真樹, 吉川 理子, 鈴木 勝

  アレルギー, 2010年04月, 日本語


• 12年の経過で再燃を繰り返したChurg-Strauss症候群(CSS)の1例

  田中 若恵, 川上 真樹, 野口 智史, 堀江 真史, 吉原 久直, 鈴木 勝, 坂本 芳雄, 日野 治子, 堀内 正

  アレルギー, 2010年04月, 日本語


• メソトレキサート長期内服中に呼吸困難を来し、中止により自然軽快した1例

  竹島 英之, 吉原 久直, 野口 智史, 田中 若恵, 堀江 真史, 川上 真樹, 鈴木 勝, 坂本 芳雄

  日本内科学会関東地方会, 2009年12月, 日本語


• Diagnostic and prognostic utility of procalcitonin (PCT) measurements in patients with hospitalized community-acquired pneumonia (CAP).

  Horie M, Ugajin M, Suzuki M, Ohata M, Noguchi S, Tamiya H, Yoshihara H, Kichikawa Y, Sakamoto Y

  European Respiratory Society International Congress, 2009年09月


• 気管支喘息 診断と管理 疫学と実態調査 気管支喘息と喘鳴を伴う慢性閉塞性肺疾患との比較

  吉原 久直, 川上 真樹, 吉川 理子, 堀江 真史, 野口 智史, 田中 若江, 鈴木 勝, 坂本 芳雄, 倉光 薫, 永田 真

  アレルギー, 2009年09月, 日本語


• 関節リウマチ(RA)患者における血清中アスペルギルス抗原の測定

  田宮 浩之, 野口 智史, 大圃 美穂, 堀江 真史, 吉原 久直, 吉川 理子, 鈴木 勝, 坂本 芳雄, 堀内 正, 松多 邦雄

  日本呼吸器学会雑誌, 2009年05月, 日本語


• 人間ドックにおける気流制限の検出頻度

  堀江 真史, 野口 智史, 大圃 美穂, 田宮 浩之, 吉原 久直, 吉川 理子, 鈴木 勝, 坂本 芳雄, 堀内 正

  日本呼吸器学会雑誌, 2009年05月, 日本語


• 毛嚢炎に起因すると考えられる敗血症性肺塞栓症を来した1例

  山口 敏弘, 吉原 久直, 大圃 美穂, 野口 智史, 堀江 真史, 田宮 浩之, 吉川 理子, 鈴木 勝, 坂本 芳雄

  日本内科学会関東地方会, 2009年03月, 日本語


• 人間ドックからみた気管支喘息有症率の推定

  吉原 久直, 田宮 浩之, 堀江 真史, 野口 智史, 吉川 理子, 鈴木 勝, 坂本 芳雄, 堀内 正

  アレルギー, 2008年10月, 日本語


• 両側精巣上体腫瘤にて発見されたサルコイドーシスの1例

  堀江 真史, 野口 智史, 田宮 浩之, 吉原 久直, 吉川 理子, 鈴木 勝, 坂本 芳雄, 大野 烈士, 石坂 和博, 岡 輝明

  日本内科学会関東地方会, 2008年09月, 日本語


• 急性下気道感染症での血清プロカルシトニン値測定の有用性についての検討

  宇賀神 基, 堀江 真史, 鈴木 智史, 中山 一誠, 吉川 理子, 新井 秀宜, 鈴木 勝, 坂本 芳雄

  日本呼吸器学会雑誌, 2008年05月, 日本語


• 肺扁平上皮癌および縦隔腫瘍を合併したKartagener症候群の1例

  白川 純, 新井 秀宜, 鈴木 勝, 吉川 理子, 鈴木 智史, 宇賀神 基, 堀江 真史, 中山 一誠, 岡 輝明, 坂本 芳雄

  日本内科学会関東地方会, 2008年02月, 日本語


• 喉頭ファイバー検査施行直後に呼吸困難・皮疹を発症した薬物過敏の1症例

  鈴川 真穂, 立田 彩, 堀江 真史, 原田 広顕, 川上 綾子, 纐纈 力也, 小宮 明子, 山田 浩和, 山口 正雄, 三崎 義堅, 竹内 二士夫, 山本 一彦, 鈴木 越, 木村 美和子, 二藤 隆春

  アレルギーの臨床, 2006年05月, 日本語

• 日本病理学会

  - 現在


• 日本バイオインフォマティクス学会


• 日本内科学会


• 日本肺癌学会


• 日本アレルギー学会


• 日本呼吸器学会

• 性差に着目した間質性膀胱炎の病態解明研究

  前田 大地, 堀江 真史

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2026年04月 - 2029年03月


• 単一細胞マルチオミックスによるクロマチン動態と脳動静脈奇形発生機構の解明

  伊藤 行信, 堀江 真史

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 金沢大学, 2026年04月 - 2029年03月


• 小細胞肺癌における系統可塑性と治療抵抗性の統合的解析

  神保 直江, 堀江 真史

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2026年04月 - 2029年03月


• 広島・神戸・熊本 医療革新・研究共同推進イニシアティブ（HK2-MIRAI）

  田中 順子 尾池 雄一 岡田 賢 田中 靖人 見前 隆洋 田中 靖人 小柳 三千代 安永 純一朗 本園 千尋 岡 志郎 西尾 瑞穂 堀江 真史 岩槻 政晃 岡田 賢 植田 光晴 大平 真裕 中佐 智幸 宮西 正憲 近添 淳一 橋本 浩一 菊田 順一 千原 典夫 尾池 雄一 阪口 雅司 中村 優子 大竹 寛雅 篠原 正和 小野 悠介

  日本医療研究開発機構研究費（AMED）, 医学系研究支援プログラム 特色型, 2025年10月 - 2028年03月, 研究分担者


• 甲状腺濾胞癌の遠隔転移に関連する分子異常の解明と転移予測マーカーの探索

  江口 博孝, 堀江 真史, 鈴木 雅美

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 大阪大学, 2025年04月 - 2028年03月, 研究分担者


• 肺神経内分泌細胞の機能解析および呼吸器疾患病態における役割の解明

  齋藤朗, 福田健介, 三上優, 堀江真史, 鹿毛秀宣

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 東京大学, 2025年04月 - 2028年03月, 研究分担者


• 間質性膀胱炎の患者登録と診療ガイドラインに関する研究

  秋山 佳之, 堀江 真史

  厚生労働科学研究費, 難治性疾患政策研究事業, 2026年04月 - 2027年03月, 研究分担者


• 特発性肺線維症の急性増悪に対する新規治療薬の創出を目指した研究

  渡辺 知志, 堀江 真史

  日本医療研究開発機構（AMED）, 橋渡し研究プログラム「橋渡し研究推進による未来医療創出」, 2026年04月 - 2027年03月, 研究分担者


• 癌微小転移の早期発見と治療戦略の構築

  藤野 志季, 堀江 真史, 植村 守, 三吉 範克, 林 理絵

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 大阪大学, 2024年04月 - 2027年03月, 研究分担者


• 肺線維症患者における肺癌発生予防を目指した革新的基盤構築

  堀江真史

  小林がん学術振興会 公益目的事業4, 2025年07月 - 2026年06月, 研究代表者


• Imaging Mass Cytometryを活用した肺小細胞癌の分子サブタイプにおける免疫プロファイルの比較検討

  堀江真史, Micke Patrick, 木場 隼人

  日本肺癌学会 肺癌研究助成申請書, 2024年11月 - 2025年10月


• B細胞クローン動態に着目した間質性膀胱炎(ハンナ型)の治療標的探索

  堀江真史, 秋山佳之

  日本医療研究開発機構研究費（AMED）・難治性疾患実用化研究事業, 2025年01月, 研究代表者


• 自然免疫系-ネクロトーシスのクロストークと気管支喘息病態の解明

  石井 崇史, 堀江 真史, 鈴川 真穂, 齋藤 朗

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 東京大学, 2024年, 研究分担者


• マスター転写因子に注目した肺癌における腫瘍免疫環境の解明と新規治療法の開発

  堀江真史, 矢野聖二

  金沢大学がん進展制御研究所共同研究, 2024年, 研究代表者


• 臓器横断的マルチオミックス解析による神経内分泌腫瘍におけるエピゲノムと転写制御の全容解明

  堀江 真史, 田中 秀憲, 源 利成

  武田科学振興財団, 医学系研究継続助成 がん領域（基礎）, 2023年09月, 研究代表者


• 血管内皮幹細胞を標的とした虚血性疾患の革新的治療法の開発

  内藤 尚道, 堀江 真史, 田中 里佳, 射場 智大

  日本医療研究開発機構（AMED）・革新的先端研究開発支援事業, 2023年04月, 研究分担者


• S100A8―RAGEシグナルに着目した肥満関連喘息の病態の解明

  松崎 博崇, 堀江 真史, 石井 崇史, 福田 健介, 齋藤 朗

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 東京大学, 2023年04月, 研究分担者


• 剖検検体を活用した肺癌におけるエピゲノム不均一性の解明と新規治療法の探索

  堀江 真史, 田中 秀憲, 齋藤 朗

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 金沢大学, 2023年04月, 研究代表者


• Ⅱ型肺胞上皮細胞の不均一性に注目したAsthma-COPD overlapの本態解明と新規治療標的の探索

  堀江 真史, 福田 健介, 松崎 博崇, 齋藤 朗, 田中 秀憲

  日本アレルギー学会 基礎研究支援プログラム, 2023年04月, 研究代表者


• IL-5/IL-13高産生性病原性Th2細胞の分化誘導機構の解明

  堀江 真史, 奥西 勝秀

  群馬大学 生体調節研究所, 内分泌・代謝学共同研究拠点共同研究, 2023年04月, 研究代表者


• 肺の気腫化、線維化の発症機序の解明

  渡辺 知志, 堀江 真史, 田中 利恵

  金沢大学 令和5年度戦略的研究推進プログラム「自己超克プロジェクト」, 2023年, 研究分担者


• 気管支喘息、COPD、およびAsthma and COPD Overlap（ACO）の単一細胞レベルでの多層的オミックス解析による病態解明

  堀江 真史, 福田 健介, 松崎 博崇, 齋藤 朗, 田中 秀憲

  公益財団法人 MSD生命科学財団, 呼吸器・アレルギー領域 研究助成金, 2023年01月, 研究代表者


• 細胞間ミトコンドリア移送開始シグナルの解明

  三木 敏生, 堀江 真史, 太向 勇

  日本学術振興会, 科学研究費助成事業, 挑戦的研究(萌芽), 日本大学, 2022年06月, 研究分担者

  本研究の目的は、ミトコンドリアの細胞間水平移動のメカニズムについて、特にミトコンドリアの移動がどのように開始されるのかについて解明し、細胞間コミュニケーションを制御するための知見を得ることである。これにより、がん細胞の耐性獲得の阻止や酸化ダメージを受けた組織の修復を目的とする新しい治療方法の開発が期待される。本研究では、レンチウイルスベクターを用いて遺伝的に蛍光ラベルしたミトコンドリアを持つ細胞株を用いる。この実験系により、ミトコンドリアを受け取った細胞と受け取らなかった細胞をフローサイトメーターを用いて分別することが可能になり、それぞれのトランスクリプトームを網羅的に解析して、ミトコンドリア移送開始の契機となるシグナルを探求する。令和４年度は、予備実験としてDsRed、mCherry、TurboRFP、mKOkの４種類の異なる赤色蛍光タンパクのミトコンドリアへの移送とラベル効率について検討した。その結果、一般的によく使われている Discosoma sp由来の赤色蛍光タンパク（DsRed、mCherry）は細胞内において凝集塊を作成する傾向があるため、本研究においては偽陽性をきたす可能性があるという知見を得た。 また、予備的にフローサイトメーターを用いて分別した細胞のRNAseq解析を行い差次的遺伝子発現の解析を行っている。


• 線維芽細胞・マクロファージの相互作用に着目した肺線維化の病態解明

  齋藤 朗, 堀江 真史, 漆山 博和, 鹿毛 秀宣

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 東京大学, 2022年04月, 研究分担者


• 臓器横断的マルチオミックス解析による神経内分泌腫瘍におけるエピゲノムと転写制御の全容解明

  堀江 真史

  武田科学振興財団, 医学系研究助成 がん領域（基礎）, 2021年09月, 研究代表者


• 新規マスター転写因子ＥＬＦ３による肺小細胞癌のサブタイプ化とその臨床的意義の解明

  堀江 真史

  日本学術振興会, 科学研究費助成事業, 若手研究, 大阪大学, 2020年04月, 研究代表者

  本年度はCUT＆Tagアッセイの実験系の構築を行った。CUT&Tagとは、Cleavage Under Targets and Tagmentationの略で、ChIP-seqよりより簡便、高感度でシーケンスコストを抑えられる近年注目されている実験系である。肺小細胞癌細胞株・DMS53を中心とした数種類の細胞株に対して、ヒストン3種類（プロモーター：H3K4me3, エンハンサー：H3K27ac, リプレッサー：H3K27me3）のCUT&Tagアッセイを行った。pilot的に行っていたChIP-seqのデータから想定されていた通り、ELF3のゲノム領域周辺にH3K4me3とH3K27acのピークがしっかり出現していることが確認できた。


• シングルセル解析によるAsthma-COPD Overlap (ACO) の分子病態の解明

  堀江 真史, 齋藤 朗, 平石 尚久, 鹿毛 秀宣, 長瀬 隆英

  公益財団法人 日本呼吸器財団, 2020年04月, 研究代表者

  競争的資金


• 間質性肺炎における肺胞上皮修復異常の機序の解明

  堀江 真史

  公益財団法人 上原記念生命科学財団, 海外留学助成リサーチフェローシップ, 2017年, 研究代表者

  競争的資金


• 歯肉上皮細胞の特殊性に基づいた新規歯周炎治療薬の開発

  山口 洋子, 大島 光宏, 堀江 真史, 齋藤 朗

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 日本大学, 2016年04月, 連携研究者

  歯周炎に対する治療薬、とくに歯肉上皮に塗ることで効果を発揮する薬剤の探索を、私どもが見つけた歯周炎原因細胞を含む培養モデルを用いて行った。しかし、上皮に作用させるだけで歯と骨を繋ぐコラーゲンが溶けるのを止められる物質は見つけられなかった。 そこで、歯周炎原因細胞を調べ直したところ、肝細胞増殖因子（HGF）という物質が大量に出て来てコラーゲンを壊していることがわかった。このＨＧＦの働きを止める抗体を使ったところ、モデルではコラーゲンの分解を阻害し、歯周炎を自然発症したサルでは臨床的な指標を改善させることがわかった。


• トランスクリプトーム・シストローム統合解析による肺小細胞癌転写ネットワークの解明

  堀江 真史

  日本学術振興会, 科学研究費助成事業, 若手研究(B), 東京大学, 2016年04月, 研究代表者

  Cancer Cell Line Encyclopedia (CCLE)から51細胞株の小細胞癌(SCLC)のトランスクリプトームのデータを入手しクラスタリング解析・主成分分析等を行ったところ、1. ASCL1 high、2. NeuroD1 high、3. YAP/TAZ highの3つのクラスターに分類された。E-MTAB-2706に登録されている30種類のSCLCのRNA-seqのデータを用いても同様の結果が得られた。YAP/TAZ, ASCL1. NeuroD1の高発現はそれぞれexclusiveである傾向が観察された。それぞれのクラスターにおける細胞の形態学的特徴を観察したところ、YAP/TAZ highのsubgroupでは接着系のphenotypeが多く、ASCL1 highのsubgroupでは浮遊系のphenotypeが多かった。In vitroでは、H209, Lu134A, Lu134B, Lu139, SBC3, SBC5の6つのSCLC細胞株を用いてYAP・TAZの発現を確認したところ、SBC3ではYAP/TAZの高発現、SBC5ではYAPの高発現が確認された。これらの細胞においてsiRNAを用いてYAPのノックダウンを行ったところ、細胞形態が小型・円形に変化した。YAPの下流の遺伝子をmicroarrayにより探索したところ、AJUBAやAMOTL2などの遺伝子が同定された。さらにsiRNAによりAJUBAのノックダウンを行ったところ、YAPのノックダウンと同様に細胞形態の小型・円形化が認められ、YAP-AJUBAのシグナルが細胞形態の維持に関与している可能性が示唆された。最後にYAP/TAZのdrug sensitivityへの影響を検討した。公開されているSCLC細胞株のIC50のデータを用いてYAP/TAZ highとlowのsubgroupにおける薬剤感受性の比較したところ、YAP/TAZ high群では、SCLCの治療でよく使われるEtoposideやTopotecanなどの薬剤へのIC50が有意に低くこれらの薬剤への治療反応性が高いと考えられた。またYAP/TAZ high群ではあらたにPLK inhibitorやmTOR inhibitorのIC50が明らかに低いことが判明し、これらの新規薬剤がYAP/TAZ high群で有効となる可能性が示唆された。


• 肺上皮細胞における Rab27 関連分子の機能の解明

  齋藤 朗

  群馬大学 生体調節研究所, 内分泌・代謝学共同研究拠点共同研究, 2016年04月, 研究分担者

  競争的資金


• CAGE法を活用した非小細胞肺癌の新規バイオマーカーの探求

  堀江 真史

  公益信託癌臨床研究助成基金, 2015年, 研究代表者


• 歯周炎診断システムの研究開発・事業化

  堀江 真史, 岩本 久美

  ふくしま医療福祉機器開発助成事業, 2015年, 研究分担者

  競争的資金


• 肺線維芽細胞におけるIL-13-STAT6シグナリングの網羅的解析

  堀江 真史

  GSKジャパン, 研究助成, 2015年, 研究代表者

  競争的資金


• CAGE法を活用した非小細胞肺癌の新規バイオマーカーの探求

  堀江 真史

  日本学術振興会, 科学研究費助成事業, 研究活動スタート支援, 東京大学, 2014年08月, 研究代表者

  FANTOM5プロジェクトにより公開された17種のNSCLC細胞株と16種の正常肺上皮肺胞のCAGEデータを比較し、NSCLCに極めて特異的に発現するMYEOVを同定した。siRNAによるノックダウンにより、MYEOVがNSCLCの増殖・上皮間葉転換・浸潤に寄与していることが明らかとなった。またMYEOVの発現はDNAメチル化に大きく依存していた。予後解析ではMYEOV高発現群では有意に予後不良であった。MYEOVは治療ターゲットや予後予測のバイオマーカーとして極めて有望であり、今後の臨床への応用が期待される。


• 肺上皮細胞のリプログラミング法の開発

  齋藤 朗, 長瀬 隆英, 大島 光宏, 山口 洋子, 鈴木 洋, 堀江 真史, 野口 智史, 奥西 勝秀, 小野 直亮

  日本学術振興会, 科学研究費助成事業, 基盤研究(C), 東京大学, 2014年04月, 連携研究者

  ヒトiPS細胞・皮膚線維芽細胞でエレクトロポレーションの条件検討を行い、低い細胞毒性と高い遺伝子導入効率が得られた。TTF-1・YAP/TAZ・FOXA2の発現ベクターを作成し、これらの強制発現により細胞分化誘導を試みた。TGF-beta・BMP-4・FGF-2のリガンドおよび阻害剤、脱メチル化剤やHDAC阻害剤の効果も検証した。肺上皮細胞培養に適した無血清培地を活用し、さらにコラーゲンゲルに包埋した肺線維芽細胞との共培養、三次元培養、air-liquid interfaceの培養法も組合せた。肺上皮細胞マーカー（SPC、CC10、FoxJ1）の発現上昇を定量的PCRで確認できた。

• miRNAをマーカーとする歯周炎検査キット、及び検査方法

  大島 光宏, 山口 洋子, 堀江 真史, 齋藤 朗, 長瀬 隆英, 岩本 久美

  特願2018-516243, 2016年05月10日, 株式会社アイシーエレクトロニクス, 学校法人日本大学, 国立大学法人 東京大学, 特許第6800470号, 2020年11月27日

  特許権

  外部リンク


• 歯周炎原因細胞の特定方法、歯周炎治療薬のスクリーニング方法、歯周炎の検査方法、検査キット

  大島 光宏, 山口 洋子, 堀江 真史, 齋藤 朗, 長瀬 隆英, 岩本 久美

  特願2015-060644, 2015年03月24日, 株式会社アイシーエレクトロニクス, 学校法人日本大学, 国立大学法人 東京大学, 特開2016-178889, 2016年10月13日, 特許第6009023号, 2016年09月23日

  特許権

  外部リンク