Hepatitis C virus core protein induces epithelial-mesenchymal transition in human hepatocytes by upregulating E12/E47 levels.

Downregulation of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT), an essential component of cancer progression to more aggressive phenotypes characterized by tumor dedifferentiation, infiltration, and metastasis. However, the underlying mechanism for E-cadherin downregulation in hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) is still unclear. In this study, we found that ectopic expression of HCV core protein or infection with HCV in human hepatocytes upregulated the levels of the transcriptional repressors, E12 and E47, resulting in inactivation of the E-cadherin promoter, containing E-box motifs, and subsequent repression of its expression. E12/E47 knock-down almost completely abolished the potential of HCV core protein to repress E-cadherin expression. HCV core protein inhibited ubiquitin-dependent proteasomal degradation of E12/E47 without affecting their expression at the transcriptional level. E12/E47 upregulation ultimately led to EMT in human hepatocytes, as demonstrated by morphological changes, altered expression levels of EMT markers, including E-cadherin, plakoglobin, and fibronectin, and increased capacity for cell detachment and migration. In conclusion, HCV core protein represses E-cadherin expression by upregulating E12/E47 levels to induce EMT in HCV-associated HCC.