The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner

Abstract

Chronic hepatitis B virus infection is strongly associated with the development of hepatocellular carcinoma (HCC). Epithelial tumors are frequently characterized by loss of cadherin expression or function. Cadherindependent adhesion prevents the acquisition of a migratory and invasive phenotype, and loss of its function is itself enough for the progression from adenoma to carcinoma. The HBx protein of hepatitis B virus is thought to contribute to the development of the carcinoma, however, its role in the oncogenic and metastatic processes is far from being fully understood. We report herein the ability of HBx to disrupt intercellular adhesion in three di erent cell lines stably transfected with an inducible HBx expression vector. The linkage between the actin cytoskeleton and cadherin complex, which is essential for its function, is disrupted in the presence of HBx, as indicated by detergent solubility and immunoprecipitation experiments. In addition, b-catenin was tyrosine phosphorylated in HBx-expressing cells. Inhibition of the src family of tyrosine kinases resulted in the prevention of the disruption of adherens junctions. These results suggest that HBx is able to disrupt intercellular adhesion in a src-dependent manner, and provide a novel mechanism by which HBx may contribute to the development of HCC. Oncogene (2001) 20, 3323 ± 3331.

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

“…Alternatively, or in addition, the finding that activated bcatenin turns on the expression of genes that upregulate the expression of Slug, may provide another pathway whereby E-cadherin is suppressed in HBxAg-positive cells (Nelson and Nusse, 2004). The finding that HBxAg stimulates src signaling, which disrupts E-cadherin/ b-catenin complexes (Lara-Pezzi et al, 2001c), is yet another way that HBxAg may disrupt E-cadherin function. Whatever the mechanism(s), it is clear that HBxAg mutants that fail to suppress E-cadherin, stimulate b-catenin (Figure 6), but fail to stimulate the mobility of HepG2 cells ( Figure 5).…”

Up-regulation of Cyclin D1 by HBx Is Mediated by NF-κB2/BCL3 Complex through κB Site of Cyclin D1 Promoter

“…In vitro analyses using HBx-overexpressing cell lines have shown that the overexpression of HBx increases its mobility associated with HCC progression. HBx down-regulates E-cadherin (33,34) and up-regulates MMPs (35,36), thereby enhancing the cell mobility and eventually increasing the malignant phenotype of HCC.…”

Angiogenesis in chronic inflammatory liver disease

“…62 HGF effects include a decrease and redistribution of VE-cadherin (which participates in intercellular contacts), ␤-catenin, and plakoglobin (linking molecules between VE-cadherin and the actin cytoskeleton) in ECs. Additionally, viral proteins may also play a role in inducing a disruption of interendothelial junctions 81 through mechanisms involving Src kinases, molecules required for vascular permeability during angiogenesis. 82 Binding between ECs and the ECM may be altered in the livers of chronic viral hepatitis patients.…”