Differentially expressed MicroRNAs provide mechanistic insight into fibrosis-associated liver carcinogenesis in mice

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers, with a rising incidence worldwide. The molecular mechanisms associated with the development of HCC are complex and include multiple interconnected molecular alterations with mounting evidence indicating an important role of microRNAs (miRNAs) in the pathogenesis of HCC. In humans, the development of HCC is commonly associated with liver cirrhosis. To study fibrosis-associated liver carcinogenesis, we used a mouse model designed to emulate the development of HCC in cirrhotic liver. Specifically, we were interested in evaluating the role of miRNAs in the molecular pathogenesis of liver carcinogenesis in male B6C3F1/J mice treated with N-nitrosodiethylamine (DEN) or carbon tetrachloride (CCl4 ) alone or a combination of DEN and CCl4 and characterized by a differential tumor incidence that increased in the following order: DEN<CCl4 <DEN+CCl4 . Treatment with DEN alone had negligible effect on hepatic miRNA expression. In contrast, treatment with either CCl4 alone or a combination of DEN and CCl4 resulted in major changes in miRNA expression. The analysis of miRNA profiles demonstrated an involvement of dysregulated miRNAs in major processes associated with the development of liver tumors, including inflammation, fibrosis, and stem cell activation. Importantly, the greatest incidence of liver tumors in mice treated with DEN+CCl4 was accompanied by a distinct over-expression of miRNAs suggesting that miRNA alterations may be responsible, at least in part, for the high tumor incidence.

Keywords: hepatocellular carcinoma; liver carcinogenesis; microRNAs; mouse.