Abstract 472: Role of miRNAome deregulation in the pathogenesis of non-alcoholic steatohepatitis (NASH)-derived hepatocellular carcinoma

Abstract

Abstract Recent epidemiological studies have attributed the growing incidence of liver cancer, including hepatocellular carcinoma (HCC), in the United States to NASH, an advanced form of non-alcoholic fatty liver disease. Elucidating the molecular pathways that lead to the development of NASH-derived HCC is critical not only for identifying early diagnostic biomarkers of the disease, but also for treatment and prevention. We have investigated the role of microRNAs (miRNAs) in the development of NASH-derived HCC by using a Stelic Animal Model (STAM) of liver carcinogenesis. Using Liver miFinder PCR arrays, we examined the miRNA profiles in the livers of STAM mice and identified 25 and 35 miRNAs that were differentially expressed at a NASH-fibrotic stage (12 weeks) and in full-fledged HCC (20 weeks), respectively. Among these differentially expressed miRNAs, 18 miRNAs were in common. Multi-algorithm target prediction analysis of the common differentially expressed miRNAs revealed the involvement of these miRNAs in the deregulation of major molecular processes associated with the development of HCC, including epithelial-mesenchymal transition, HCC stem cell activation, and the induction of the β-catenin/Wnt and Hippo signaling pathways. These findings were confirmed by a marked up-regulation of Yes-associated protein 1 (YAP1), the main effector of the Hippo-pathway, the activation of epithelial-mesenchymal transition, and an increased-expression of hepatic progenitor cell markers. In addition to the common differentially expressed miRNAs, 10 miRNAs, including 5 members of the polycistronic oncomir miR-17-92 cluster, were found to be over-expressed in only HCC. These results indicate the fundamental role of miRNAs in the development of NASH-associated HCC. This is evidenced by the early occurrence of miRNA alterations at the preneoplastic stage of liver carcinogenesis, the persistence of these changes in HCC, and the accumulation of additional miRNA alterations in HCC, and by the existence of a mechanistic link between miRNA alterations and deregulation key cancer-related pathways. Citation Format: Juliana F. Ortega, Aline DeConti, Kostiantyn Dreval, Fernando S. Moreno, Frederick A. Beland, Igor P. Pogribny. Role of miRNAome deregulation in the pathogenesis of non-alcoholic steatohepatitis (NASH)-derived hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 472. doi:10.1158/1538-7445.AM2017-472