Upregulation of cancer-associated gene expression in activated fibroblasts in a mouse model of non-alcoholic steatohepatitis

Autor:	Yoshihiro Ogawa, Yutaka Inagaki, Takayoshi Suganami, Sayaka Kanai, Tomomi Hatayama, Shinji Tanaka, Masahiro Asakawa, Xunmei Yuan, Takeru Sakai, Shu Shimada, Katsuhito Fujiu, Ichiro Manabe, Ibuki Shirakawa, Shoji Yamaoka, Yoshimitsu Akiyama, Tetsuya Yamada, Michiko Itoh
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	Liver Cirrhosis Male 0301 basic medicine lcsh:Medicine Apoptosis medicine.disease_cause Mice 0302 clinical medicine Cell Movement Non-alcoholic Fatty Liver Disease Fibrosis Neoplasms Gene expression lcsh:Science Non-alcoholic steatohepatitis Mice Knockout Regulation of gene expression Multidisciplinary Liver Neoplasms Metabolic syndrome Up-Regulation Experimental models of disease Gene Expression Regulation Neoplastic Liver 030220 oncology & carcinogenesis Disease Progression Fibroblast Growth Factor 9 Carcinoma Hepatocellular Biology Article 03 medical and health sciences FGF9 Downregulation and upregulation Cell Line Tumor medicine Animals Humans Cell Proliferation Gene Expression Profiling lcsh:R Fibroblasts medicine.disease digestive system diseases Mice Inbred C57BL Gene expression profiling 030104 developmental biology Cancer research lcsh:Q Steatohepatitis Carcinogenesis Neoplasm Transplantation
Zdroj:	Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019) Scientific Reports
ISSN:	2045-2322
DOI:	10.1038/s41598-019-56039-0
Popis:	Non-alcoholic steatohepatitis (NASH), characterized by chronic inflammation and fibrosis, is predicted to be the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the next decade. Although recent evidence suggests the importance of fibrosis as the strongest determinant of HCC development, the molecular mechanisms underlying NASH-induced carcinogenesis still remain unclear. Here we performed RNA sequencing analysis to compare gene expression profiles of activated fibroblasts prepared from two distinct liver fibrosis models: carbon tetrachloride–induced fibrosis as a model without obesity and HCC and genetically obese melanocortin 4 receptor–deficient (MC4R-KO) mice fed Western diet, which develop steatosis, NASH, and eventually HCC. Our data showed that activated fibroblasts exhibited distinct gene expression patterns in each etiology, and that the ‘pathways in cancer’ were selectively upregulated in the activated fibroblasts from MC4R-KO mice. The most upregulated gene in these pathways was fibroblast growth factor 9 (FGF9), which was induced by metabolic stress such as palmitate. FGF9 exerted anti-apoptotic and pro-migratory effects in fibroblasts and hepatoma cells in vitro and accelerated tumor growth in a subcutaneous xenograft model. This study reveals upregulation of cancer-associated gene expression in activated fibroblasts in NASH, which would contribute to the progression from NASH to HCC.
Databáze:	OpenAIRE
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