Abstract
Published studies have identified genetic variants, somatic mutations, and changes in gene expression profiles that are associated with hepatocellular carcinoma (HCC), particularly involving genes that encode drug metabolizing enzymes (DMEs). CYP2C9, one of the most abundant and important DMEs, is involved in the metabolism of many carcinogens and drugs and is down-regulated in HCC. To investigate the molecular mechanisms that control CYP2C9 expression, we applied integrative approaches including in silico, in vitro, and in vivo analyses to elucidate the role of microRNA hsa-miR-128-3p in the regulation of CYP2C9 expression and translation. RNA electrophoresis mobility shift assays demonstrated a direct interaction between hsa-miR-128-3p and its cognate target, the CYP2C9 transcript. Furthermore, the expression of a luciferase reporter gene containing the 3′-UTR of CYP2C9 and the endogenous expression of CYP2C9 were suppressed by transfection of hsa-miR-128-3p. Importantly, chemically-induced up- or down-regulation of hsa-miR-128-3p correlated inversely with the expression of CYP2C9. Finally, an association analysis revealed that the expression of hsa-miR-128-3p is inversely correlated with the expression of CYP2C9 in HCC tumor tissues. Altogether, the study helped to elucidate the mechanism of CYP2C9 regulation by hsa-miR-128-3p, and the inverse association in HCC.
Highlights
Published studies have identified genetic variants, somatic mutations, and changes in gene expression profiles that are associated with hepatocellular carcinoma (HCC), involving genes that encode drug metabolizing enzymes (DMEs)
Suppression of CYP2C9 expression has been reported as a biomarker of HCC14–17; the mechanism of CYP2C9 dysregulation through microRNA modulation has not been investigated in HCC
We demonstrated that hsa-miR-128-3p plays an important role in the suppression of CYP2C9 expression and translation in human liver cells by a series of in silico analyses and in vitro and in vivo experiments
Summary
Published studies have identified genetic variants, somatic mutations, and changes in gene expression profiles that are associated with hepatocellular carcinoma (HCC), involving genes that encode drug metabolizing enzymes (DMEs). It is well documented that hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, dietary aflatoxin B1 contamination, chronic alcohol abuse and tobacco consumption, lack of dietary antioxidants, environmental arsenic exposure, obesity, and non-alcoholic fatty liver disease are major risk factors for HCC2 These findings indicate that chronic xenobiotic stress plays a pivotal role in the development of HCC, the precise molecular mechanisms are poorly understood. Studies have shown that dysregulation of DMEs, including several cytochrome P450 (CYP) family genes such as CYP2A6, CYP2C9, CYP2E1, CYP3A58–10, might play important roles in the development of HCC. The high level of CYP1B1 may decrease the estrogen activity by CYP1B1-mediated 4hydroxylation, the increased metabolite 4-hydroxyestadiol level may contribute more significantly to breast carcinogenesis[19]
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