Dissection of cell context-dependent interactions between HBx and p53 family members in regulation of apoptosis: A role for HBV-induced HCC

Abstract

Chronic hepatitis B virus (HBV) infection is the major risk for hepatocellular carcinomas (HCC). HBV X protein (HBx) and p53 tumor suppressor family interactions may be crucial for HCC induction. We compared p53 and p73 interactions with HBx in normal and HCC tumor cell lines differing in their p53 status. In the latter, HBx was pro-apoptotic but exhibited opposite effects in non-tumor cells. In these normal cells, p53 and p73 were retained in the cytoplasm. In hepatoma cells, however, HBx led to nuclear translocation of p53 and p73, followed by enhanced transactivation of p53-dependent promoters. The nuclear transfer of p53, but not of p73, was abrogated by protein kinase C inhibitor Gö6976. HBx overexpression in HCC cells led to strong p53 phosphorylation at Ser15, but not in non-tumor cells. Our results define ATM kinase as mediator for HBx-induced p53 phosphorylation. While HBx promotes cell death in p53/p73-positive hepatoma cells also in presence of increased levels of the oncogenic ΔTAp73 isoform, it significantly potentiates ΔTAp73-mediated proliferation and malignant transformation of fibroblasts. Our data suggest that prevention of apoptosis in normal cells by HBx through inhibition of pro-apoptotic p53 family members via direct interaction and coaction with anti-apoptotic ΔTAp73 seems to be the key element in the decision in favor of cell survival. The complex cell context-dependent interactions between p53 family members and HBx in the regulation of apoptosis may be essential in HBV-induced HCC and anticancer therapy.

Tissue-specific expression of p73 C-terminal isoforms in mice

“…p73 is a p53-related transcription factor with fundamental roles in development, 1 - 4 tumor suppression 5 - 11 and senescence 12 - 23 . Transcription from two different promoters on the TRp73 gene results in generation of TAp73 and ΔNp73 isoforms with opposing pro- and anti-apoptotic functions 24 - 28 .…”

Lobaplatin Inhibits the Proliferation of Hepatollular Carcinoma Through P53 Apoptosis Axis

“…A common truth was that chronic hepatitis B virus(HBV) infection contributed dominantly to HCC, and HBx suppressed the p53 induced apoptosis to promote HCC progression (14). HBx-p53 reciprocal transcription repression was so important that p53 related pathways were key targets in HCC drugs development (15). furthermore Wu et al assessed the regulation of p53 expression in lobaplatin signaling pathway.They demonstrated that p53 upregulation was related to E2F1/Rb in lobaplatin treated HCC cells by RT-PCR and western blotting methods.…”

Therapeutic targeting of liver cancer with a recombinant DNA vaccine containing the hemagglutinin-neuraminidase gene of Newcastle disease virus via apoptotic-dependent pathways

“…Apoptosis in mammals engages the interplay of intricate mechanisms that are affected by multiple factors. There are three genes, consisting of p53 , Bcl-2 and c-myc , that are considered the major apoptosis-associated genes (23–25). The occurrence and progression of tumors may be controlled when the tumor cells are induced to undergo apoptosis.…”