Elucidation Of The Role Of Microrna-155 In A Murine Model Of Non-Alcoholic Steatohepatitis

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide with increasing incidence and mortality. Risk factors for this deadly disease include acquisition of the Hepatitis B or C virus, alcohol use, and non-alcoholic steatohepatitis (NASH). Due to their ability to regulate multiple genes and their therapeutic potential, miRNAs (miRs) have received considerable attention for their role as tumor suppressors or oncogenes. In our previous study to identify miRs involved in the pathogenesis of HCC, we have demonstrated consistent upregulation of miR-155, a pro-inflammatory microRNA, in a CDAA diet-induced mouse model of HCC that mimics the progression of steatohepatitis to HCC in humans (B.Wang et.al, Hepatology. 2009). Importantly, increased miR-155 level in humans is an independent predictor of poor prognosis and survival and also correlates with invasion in HCC patients. Upregulation of miR-155 at very early stages of HCC suggested that it plays a causal role in NASH and HCC and that its absence will result in decreased inflammation, fibrosis, and eventually, development of HCC. The overall goal of this study is to establish the role of miR-155 in the pathogenesis of HCC for future development of anti-miR therapy. For this purpose, male C57BL6 mice and miR-155KO mice were fed the chow diet (control) or the CDAA diet for 4 or 8 weeks. Blood and liver were then harvested for serologic, pathologic, and biochemical studies. Additionally, body and liver weight were also measured at the time of sacrifice. Analysis of the ratio of liver weight to body weight demonstrated a small but significant increase of this ratio (in the absence of any increase in body weight) in the miR-155KO mice compared to the control mice. As expected, reduced inflammation was seen in the miR-155KO mice that correlated with decreased NF-κB activity. Histopathological analysis also revealed increased steatosis in the KO mice suggesting that miR-155 plays a role in hepatic lipid metabolism. Global gene expression analysis performed on RNA isolated from livers was consistent with reduced inflammation and enhanced steatosis in the miR-155KO mice. Importantly, changes in expression of genes associated with hepatic necrosis, fibrosis and cancer indicated reduced liver damage in miR-155KO mice suggesting that these mice will be less prone to tumorigenesis. Reduced expression of the p65 subunit of NF-κB in the miR-155KO mice was identified as one of the mechanisms of decreased NF-κB activity. Currently studies are underway to explore further the mechanism of regulation of p65 expression/NF-κB activity and lipid metabolism in HCC by miR-155. Citation Format: Tasneem Motiwala, Mufaddal Mustafa, Huban Kutay, Rachael C. Sullivan, Kun-Yu Teng, Vivek Chowdhary, Lianbo Yu, Kalpana Ghoshal, Samson T. Jacob. Elucidation of the role of microRNA-155 in a murine model of non-alcoholic steatohepatitis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4359. doi:10.1158/1538-7445.AM2014-4359