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Oncotarget. 2017 Aug 1;8(51):88517-88528. doi: 10.18632/oncotarget.19774. eCollection 2017 Oct 24.

MicroRNA deregulation in nonalcoholic steatohepatitis-associated liver carcinogenesis.

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Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas, USA.
Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA.


Hepatocellular carcinoma (HCC) is the fastest-rising cause of cancer-related death in the United States. Recent epidemiological studies have identified nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease (NAFLD), as a major risk factor for HCC. Elucidating the underlying mechanisms associated with the development of NASH-derived HCC is critical for identifying early biomarkers for the progression of the disease and for treatment and prevention. In the present study, using liver samples from C57BL/6J mice submitted to the Stelic Animal Model (STAM) of NASH-associated liver carcinogenesis, we investigated the role of microRNA (miRNA) alterations in the pathogenesis of NASH-derived HCC. We found substantial alterations in the expression of miRNAs, with the greatest number occurring in full-fledged HCC. Mechanistically, altered miRNA expression was associated with activation of major hepatocarcinogenesis-related pathways, including the TGF-β, Wnt/β-catenin, ERK1/2, mTOR, and EGF signaling. In addition, the over-expression of the miR-221-3p and miR-222-3p and oncogenic miR-106b∼25 cluster was accompanied by the reduced protein levels of their targets, including E2F transcription factor 1 (E2F1), phosphatase and tensin homolog (PTEN), and cyclin-dependent kinase inhibitor 1 (CDKN1A). Importantly, miR-93-5p, miR-221-3p, and miR-222-3p were also significantly over-expressed in human HCC. These findings suggest that aberrant expression of miRNAs may have mechanistic significance in NASH-associated liver carcinogenesis and may serve as an indicator for the development of NASH-derived HCC.


epigenetics; hepatocarcinogenesis; miR-93-5p; microRNAs; non-alcoholic steatohepatitis

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