MicroRNA deregulation in nonalcoholic steatohepatitis-associated liver carcinogenesis.
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abstract
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-, Wnt/-catenin, ERK1/2, mTOR, and EGF signaling. In addition, the over-expression of the miR-221-3p and miR-222-3p and oncogenic miR-106b25 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.
de Conti, A., Ortega, J. F., Tryndyak, V., Dreval, K., Moreno, F. S., Rusyn, I., Beland, F. A., & Pogribny, I. P.
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de Conti, Aline||Ortega, Juliana Festa||Tryndyak, Volodymyr||Dreval, Kostiantyn||Moreno, Fernando Salvador||Rusyn, Ivan||Beland, Frederick A||Pogribny, Igor P
