Abstract
Hepatitis B virus (HBV) is a major risk factor for development and progression of hepatocellular carcinoma (HCC). It has been reported that viral infection can interfere with cellular microRNA (miRNA) expression and participate in the pathogenesis of oncogenicity. Our miRNAs array data indicated that miR-331-3p expression in HCC cell lines increased, but the relationship between miR-331-3p expression and HBV activity is unclear. Here, we observed elevated expression of miR-331-3p in different HCC cell lines expressing HBV. HBV, especially HBx, promotes miR-331-3p expression by enhancing its promoter activity. Using a miRNA target prediction database miRBase, we identified ING5 to be a novel target gene of miR-331-3p. miR-331-3p could inhibit ING5 expression by directly targeting its 3'-untranslated region (3'-UTR). As predicted, HBV was confirmed to repress ING5 at both mRNA and protein levels by promoting miR-331-3p expression. Our result indicated that miR-331-3p expression promotes proliferation of SMMC7721 cells by inhibiting ING5. ING5 overexpression promoted cell apoptosis in HCC cell lines. We also found ING5 expression was decreased in tumor tissue of HCC patient with HBV infection compared to its expression in para-carcinoma tissues. These results showed that miR-331-3p is upregulated by HBV and promotes proliferation of HCC cells though repression of ING5 expression. These data provide new insights for understanding the mechanisms of HBV-related HCC pathogenesis.
Highlights
Hepatocellular carcinoma (HCC) is among the top three causes of cancer death in the Asian Pacific region [1]
MicroRNAs are small single-stranded noncoding RNAs that regulate gene expression by interacting preferentially with the 3′untranslated regions (3′-UTRs) of target mRNAs, which may result in either inhibition of the target protein translation or degradation of the target mRNA [3, 4]. miRNAs and their target corresponding mRNAs form complex regulatory networks that are involved in cell proliferation, apoptosis, differentiation stress responses and other biological processes [5, 6]. miRNAs aberrant expression contributes to a range of human pathologies, including cancer [7]
To investigate the mechanism of miR-331-3p upregulation by Hepatitis B virus (HBV), we constructed pGL3-Basic-miR331-3p vector which contains the miR-331-3p promoter for the luciferase reporter according to luciferase reporter assay. miR-331-3p promoter activity was higher in the pCH9/3091 and pGL3-Basic-miR-331-3p co-transfected group compared to pCH9 and pGL3-Basic-miR-331-3p co-transfected group (Figure 1E)
Summary
Hepatocellular carcinoma (HCC) is among the top three causes of cancer death in the Asian Pacific region [1]. Hepatitis B virus (HBV) of the hepadnavirus family confers major risk for HCC. How HBV contributes to development of HCC is unclear. MiRNAs aberrant expression contributes to a range of human pathologies, including cancer [7]. More and more reports have shown deregulation of miRNAs in human HCCs in recently years. Discovery of the critical role of miRNAs in modulating gene expression has changed our concept of gene expression regulation, but has offered a new opportunity www.impactjournals.com/oncotarget for designing anticancer strategies and therapies in HCC [8, 9]
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