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

Masahiro Asakawa, Michiko Itoh, Takayoshi Suganami, Takeru Sakai, Sayaka Kanai, Ibuki Shirakawa, Xunmei Yuan, Tomomi Hatayama, Shu Shimada, Yoshimitsu Akiyama, Katsuhito Fujiu, Yutaka Inagaki, Ichiro Manabe, Shoji Yamaoka, Tetsuya Yamada, Shinji Tanaka, Yoshihiro Ogawa

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Abstract

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.

Original languageEnglish
Article number19601
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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