Upregulation of cancer-associated gene expression in activated fibroblasts in a mouse model of non-alcoholic steatohepatitis
Upregulation of cancer-associated gene expression in activated fibroblasts in a mouse model of non-alcoholic steatohepatitis
复制标题
DOI：
10.1038/s41598-019-56039-0
复制
发表时间：
2019-12-20
影响因子：
4.6
通讯作者：
Ogawa, Yoshihiro
中科院分区：
文献类型：
--
作者：
Asakawa, Masahiro;Itoh, Michiko;Ogawa, Yoshihiro
非酒精性脂肪性肝炎(NASH)以慢性炎症和纤维化为特征，预计在未来十年内将成为肝硬变和肝细胞癌(HCC)的主要原因。尽管最近的证据表明，肝纤维化是肝细胞癌发生的最重要的决定因素，但NASH诱导癌变的分子机制仍不清楚。在这里，我们进行了RNA测序分析，以比较两种不同的肝纤维化模型制备的活化成纤维细胞的基因表达谱：四氯化碳诱导的肝纤维化作为无肥胖和肝细胞癌的模型，以及喂养西方饮食的遗传性肥胖的黑素皮质素4受体缺陷(MC4R-KO)小鼠，后者发生脂肪变性、NASH，并最终发展为肝细胞癌。我们的数据显示，激活的成纤维细胞在每种病因中都显示出不同的基因表达模式，并且在MC4R-KO小鼠的激活的成纤维细胞中，“癌症通路”被选择性地上调。在这些途径中上调最多的基因是成纤维细胞生长因子9(FGF9)，它是由棕榈酸酯等代谢应激诱导的。FGF9在体外对成纤维细胞和肝癌细胞具有抗凋亡和促迁移作用，并在皮下移植瘤模型中促进肿瘤生长。这项研究揭示了NASH中活化的成纤维细胞中癌症相关基因的表达上调，这可能有助于NASH向肝细胞癌的进展。
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.