Downregulation of E-cadherin by hepatitis B virus X antigen in hepatocellullar carcinoma

Abstract

Hepatitis B virus (HBV)-encoded X antigen (HBxAg) contributes to the development of hepatocellular carcinoma (HCC). A frequent characteristic of HCC is reduced or absent expression of the cell adhesion protein, Ecadherin, although it is not known whether HBxAg plays a role. To address this, the levels of E-cadherin were determined in HBxAg-positive and -negative HepG2 cells in culture, and in tumor and surrounding nontumor liver from a panel of HBV carriers. The results showed an inverse relationship between HBxAg and E-cadherin expression both in tissue culture and in vivo. In HBxAgpositive cells, E-cadherin was suppressed at both the mRNA and protein levels. This was associated with hypermethylation of the E-cadherin promoter. Depressed E-cadherin correlated with HBxAg trans-activation function, as did the migration of HepG2 cells in vitro. Decreased expression of E-cadherin was also associated with the accumulation of b-catenin in the cytoplasm and/ or nuclei in tissues and cell lines, which is characteristic of activated b-catenin. Additional work showed that HBxAg-activated b-catenin. Together, these results suggest that the HBxAg is associated with decreased expression of E-cadherin, accumulation of b-catenin in the cytoplasm and nucleus, and increased cell migration, which may contribute importantly to hepatocarcinogenesis.

Hepatitis B virus X protein induces epithelial–mesenchymal transition by repressing E-cadherin expression via upregulation of E12/E47

“…Immunohistochemical studies of E-cadherin expression in HBV-related HCC have demonstrated significant downregulation of E-cadherin in the tumour tissue compared with adjacent non-tumour tissues (Yoshiura et al, 1995). Also, both in vitro and in vivo studies have suggested that HBx is implicated in the downregulation of E-cadherin (Arzumanyan et al, 2012;Lee et al, 2005;Liu et al, 2006). Consistently, the present study showed that HBx could induce EMT by downregulating levels of E-cadherin in hepatoma cells.…”

“…In addition, several reports have provided direct evidence for a role of HBx in the downregulation of E-cadherin (Arzumanyan et al, 2012;Lee et al, 2005;Liu et al, 2006). Two different mechanisms can be considered for the repression of E-cadherin expression by HBx in HCC.…”

The regulation of proteins associated with the cytoskeleton by hepatitis B virus X protein during hepatocarcinogenesis

“…HBx may be able to induce an EMT phenotype in hepatoma cells, with decreased E-cadherin expression levels as well as an upregulation of vimentin and N-cadherin (29). In addition, β-catenin is primarily observed in the cytoplasm and nuclei of HBx-transfected cells (30). Furthermore, HBx has been demonstrated to induce EMT in human hepatoma cells by activating proto-oncogene tyrosine-protein kinase (c-Src) (29), or by modulating the signal transducer and activator of transcription (STAT) 3 signaling pathway in order to activate Twist (31).…”

Mechanisms of HBx Mediated Liver Cancer: Multiple Pathways and Opportunities

“…The latter is of particular importance because suppression of the cell adhesion protein, E-cadherin, is a hallmark of EMT, which is important to the pathogenesis of CLD and HCC. The importance of suppressed E-cadherin expression is further underscored by the findings that this occurs by DNA methylation of the E-cadherin promoter (Lee et al, 2005;Liu et al, 2006), by the inhibition miR-373 expression by HBx, and by HBx mediated stimulation of histone deacetylase (HDAC) at the E-cadherin promoter (Arzumanyan et al, 2011). Independent of the mechanism involved, suppression of E-cadherin has important ramifications upon -catenin.…”

“…The finding that the activation of wild type -catenin was associated with URG11 and URG7 (Pan et al, 2007), underscores the importance of this activation in hepatocarcinogenesis. Moreover, -catenin appears to be stabilized by a number of mechanisms, including trans-activation of the -catenin promoter Pan et al, 2007), inhibition of proteasomal degradation (Cui et al, 2006;Zhang et al, 2000), and suppression of E-cadherin expression (Arzumanyan et al, 2011;Lee et al, 2005;Liu et al, 2006) (Figure 2). The latter is of particular importance because suppression of the cell adhesion protein, E-cadherin, is a hallmark of EMT, which is important to the pathogenesis of CLD and HCC.…”