Hepatitis B virus promotes β-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion

Abstract

Hepatitis B virus (HBV) infection is a prominent cause of hepatocellular carcinoma (HCC) but the underlying molecular mechanisms are complex and multiple pathways have been proposed such as the activation of the Wnt−/β-catenin-signalling and dysregulation of E-cadherin/β-catenin adherens junctions. This study aimed to identify mechanisms of how HBV infection and replication as well as HBV X protein (HBx) gene expression in the context of an HBV genome influence Wnt−/β-catenin-signalling and formation of adherens junctions and to which extent HBx contributes to this.Regulation of E-cadherin/β-catenin junctions and β-catenin-signalling as well as the role of HBx were investigated using constructs transiently or stably inducing replication of HBV+/−HBx in hepatoma cell lines. In addition, HCC and adjacent non-tumorous tissue samples from HBV-infected HCC patients and drug interference in HBV-infected cells were studied.Although HBV did not alter overall expression levels of E-cadherin or β-catenin, it diminished their cell surface localization resulting in nuclear translocation of β-catenin and activation of its target genes. In addition, HBV gene expression increased the amount of phosphorylated c-Src kinase. Treatment with Src kinase inhibitor Dasatinib reduced HBV replication, prevented adherens junction disassembly and reduced β-catenin-signalling, while Sorafenib only did so in cells with mutated β-catenin. Interestingly, none of the HBV induced alterations required HBx.Thus, HBV stimulated β-catenin-signalling and induced disassembly of adherens junctions independently of HBx through Src kinase activation. These pathways may contribute to hepatocellular carcinogenesis and seem to be more efficiently inhibited by Dasatinib than by Sorafenib.

Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review

“…Numerous studies reported an association between the HBx protein and hepatocarcinogenesis [159,160,161,162,163,164,165,166,167,168,169,170]. Integrated HBV DNA harbors the conserved sequences for genes encoding the core protein, surface antigens, and HBx along with their respective promoter sequences [159,160], suggesting that HBx is important for hepatocarcinogenesis.…”

“…HBx represents a transactivating factor [161], and transgenic mice expressing HBx develop HCC [162]. HBx transactivates binding sites for the transcription factors AP-1 and NF-κB [163], activates the p53-RB [164,165] and β-catenin [164,165,166,167,168,169,170] pathways, and is involved in chromatin remodeling [171,172,173] and transcriptional modulation in hepatocarcinogenesis [174].…”

The Interaction of Viruses with the Cellular Senescence Response

“…Thus, CML patients treated with these drugs present more predisposition for infection with or reactivation of different viruses such as cytomegalovirus, human herpesvirus 6, VZV or SARS-CoV-2 [ 82 , 83 , 84 , 85 , 86 , 87 ]. Additionally, although dasatinib treatment has been reported to inhibit the replication of HBV [ 88 ], enhanced HBV replication and reactivation has been reported in CML patients [ 89 , 90 ].…”

Gut-liver axis signaling in portal hypertension

“…The bacterium Salmonella typhimurium , for example, can penetrate the vascular barrier by interfering with Wnt/β-catenin signaling that regulates AJ functionality via E-cadherin/β-catenin[74,75]. Importantly, hepatitis B virus also interferes with Wnt/β-catenin signaling[76].…”