Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling

Abstract

Hepatitis C virus (HCV) infection usually induces chronic hepatic inflammation, which favors the initiation and progression of hepatocellular carcinoma (HCC). Moreover, microRNA-155 (miR-155) plays an important role in regulating both inflammation and tumorigenesis. However, little is known about whether and how miR-155 provides the link between inflammation and cancer. In this study we found that miR-155 levels were markedly increased in patients infected with HCV. MiR-155 transcription was regulated by nuclear factor kappa B (NF-jB), and p300 increased NF-jB-dependent miR-155 expression. The overexpression of miR-155 significantly inhibited hepatocyte apoptosis and promoted cell proliferation, whereas miR-155 inhibition induced G 0 /G 1 arrest. Upregulated miR-155 resulted in nuclear accumulation of b-catenin and a concomitant increase in cyclin D1, c-myc, and survivin. Gain-of-function and loss-of-function studies demonstrated that miR-155 promoted hepatocyte proliferation and tumorigenesis by increasing Wnt signaling in vitro and in vivo, and DKK1 (Wnt pathway inhibitor) overexpression inhibited the biological role of miR-155 in hepatocytes. Finally, adenomatous polyposis coli (APC), which negatively regulates Wnt signaling, was identified as the direct and functional target of miR-155. Conclusion: HCV-induced miR-155 expression promotes hepatocyte proliferation and tumorigenesis by activating Wnt signaling. The present study provides a better understanding of the relationship between inflammation and tumorigenesis, and thus may be helpful in the development of effective diagnosis and treatment strategies against HCV-HCC. (HEPATOLOGY 2012;56:1631-1640

MicroRNA-155 enhances the activation of Wnt/β-catenin signaling in colorectal carcinoma by suppressing HMG-box transcription factor 1

“…Subsequent experiments demonstrated that miR-155-induced suppression of HBP1 accounted for its effects on activation of the Wnt/β-catenin signaling pathway. Previous studies have revealed that overexpression of miR-155 promotes activation of the Wnt/β-catenin signaling pathway (16,17). However, these findings were attributed to miR-155-induced activation of Wnt/β-catenin signaling to suppression of adenomatous polyposis coli, a Wnt/β-catenin inhibitor.…”

Alterations of Wnt/β-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus

“…Zhang et al demonstrated that also the up-regulated microRNA-155 (miR-155), markedly increased in HCV-infected patients, activates the Wnt signaling pathway with nuclear accumulation of β-catenin and the accompanying increase in cyclin D1, c-Myc, and survivin. It was also determined that a direct and functional target of miR-155 involved APC [89]. However, it was not until in vitro studies were conducted that interactions between HCV proteins and the Wnt/β-catenin signaling pathway were clarified.…”

Role of biomarkers in the prediction and diagnosis of hepatocellular carcinoma

“…Furthermore, multiple mutations at the chromosomales, genetics and epigenetics levels have been implicated as pathogenetic mechanisms in the development of HCC [26,27] . MicroRNA has been shown to aid in the transcription of HCC oncogenes and (Wnt) signaling, and it plays important roles in the development of HCC through the activation of β catenin, the overexpression of Wnt receptors and the inactivation of Ecadherin [28] .…”