The microRNA profile is altered in fibrosis-associated hepatocarcinogenesis in mice
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AbstractHepatocellular carcinoma (HCC) is one of the most common cancers and its incidence is rising worldwide. The molecular mechanisms associated with the development of HCC are complex and include multiple interconnected alterations driven by both genetic and epigenetic events. Mounting evidence indicates an important role of microRNAs (miRNAs), post-transcriptional negative regulators of gene expression, in the pathogenesis of HCC. In humans, the development of HCC is commonly associated with liver cirrhosis. To mimic the molecular pathogenesis of human HCC, we used a mouse model of fibrosis-associated liver cancer, which was designed to emulate cirrhotic liver. Tumor and non-tumor liver samples from B6C3F1 mice treated with N-nitrosodiethylamine (DEN; a single ip injection of 1 mg/kg at 14 days of age) and carbon tetrachloride (CCl4; 200 l/kg, 2 times/week ip for 14 weeks starting at 8 weeks of age) were analyzed. Using TaqMan array miRNA cards, we identified a total of 52 and 45 miRNAs that were differentially expressed in tumor and non-tumor liver tissue, respectively, from DEN/CCl4-treated mice as compared to those in livers of vehicle-treated control B6C3F1 mice. Importantly, 27 differentially expressed miRNAs were common for both tumor and non-tumor samples from DEN/CCl4-treated mice. These miRNAs are involved in the major cancer pathways including apoptosis, cell proliferation, angiogenesis, and epithelial-to-mesenchymal transition. These results suggest that changes in miRNA expression during hepatocarcinogenesis may occur at very early stages of the carcinogenic process, preceding the formation of detectable neoplastic lesions. Most notably, our results showing 27 miRNAs common for tumor and non-tumor tissue suggest that a miRNA profile associated with the development of HCC could potentially be used to decipher the precise molecular mechanisms of disease progression and/or be used as early markers for detecting neoplastic lesions in the liver.Citation Format: April K. Marrone, Volodymyr Tryndyak, Grace Chappell, Frederick A. Beland, Ivan Rusyn, Igor P. Pogribny. The microRNA profile is altered in fibrosis-associated hepatocarcinogenesis in mice. [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 5227. doi:10.1158/1538-7445.AM2014-5227
