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.
Conflict of interest statement
Michiko Itoh and Ibuki Shirakawa are assigned to the Joint Research Department of Tokyo Medical and Dental University and Shionogi & Co. Ltd.
Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects.Sci Rep. 2020 Jan 22;10(1):983. doi: 10.1038/s41598-020-57935-6. Sci Rep. 2020. PMID: 31969650 Free PMC article.
Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis.Am J Pathol. 2011 Nov;179(5):2454-63. doi: 10.1016/j.ajpath.2011.07.014. Epub 2011 Sep 7. Am J Pathol. 2011. PMID: 21906580 Free PMC article.
A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer.J Hepatol. 2018 Aug;69(2):385-395. doi: 10.1016/j.jhep.2018.03.011. Epub 2018 Mar 21. J Hepatol. 2018. PMID: 29572095 Free PMC article.
Pathogenesis of Non-alcoholic Steatohepatitis and Its Potential Therapeutic Strategies.In: Nakao K, Minato N, Uemoto S, editors. Innovative Medicine: Basic Research and Development [Internet]. Tokyo: Springer; 2015. Innovative Medicine: Basic Research and Development. 2015. PMID: 29787166 Free Books & Documents. Review.
Nonalcoholic fatty liver disease and hepatocellular carcinoma.Metabolism. 2016 Aug;65(8):1151-60. doi: 10.1016/j.metabol.2016.01.010. Epub 2016 Jan 23. Metabolism. 2016. PMID: 26907206 Review.