Abstract
Chronic Hepatitis B virus (HBV) infection is a major risk of hepatocellular carcinoma (HCC) worldwide. Hepatitis B virus X protein (HBx) is encoded by one of the four open reading frames of HBV, and is well known as an important coactivator for HBV replication and HBV-associated hepatocellular carcinogenesis. However, its role in keeping cells from apoptosis to promote HCC proliferation remains controversial. Here, we used HBx expressing HCC cells as a model, to investigate the mechanism of HBx-mediated cellular response to endoplasmic reticulum (ER) stress. We found that HBx protein was localized in ER lumen and interacted with GRP78 directly. This interaction resulted in suppression of eIF2α phosphorylation, inhibited expression of ATF4/CHOP/Bcl-2, and reduced cleavage of poly ADP-ribose polymerase (PARP) and level of γH2AX, thus preventing HCC cells from cell death and negatively regulating DNA repair. This study reveals a novel mechanism of the HBx-mediated oncogenesis and provides a basis for potential HBx-targeted therapeutic intervention of HCC.
Highlights
Chronic Hepatitis B virus (HBV) infection is closely associated with the development of liver cirrhosis and progression to hepatocellular carcinoma (HCC) [1]
When the level of poly (ADP ribose) polymerase 1 (PARP-1), a key executer of DNA repair and apoptosis, was further assayed, we found that the expression of Hepatitis B virus X protein (HBx) markedly inhibited the level of the cleaved poly ADP-ribose polymerase (PARP)-1 (Figure 5C and 5D), which suggested that HBx inhibited the PERK pathway, avoiding the activation of ATF4-mediated DNA repair
How HBx alters the host gene expression has been the focus of many intensive investigations
Summary
Chronic Hepatitis B virus (HBV) infection is closely associated with the development of liver cirrhosis and progression to hepatocellular carcinoma (HCC) [1]. HBV association with HCC has been well documented, the sophisticated mechanisms of HBVmediated oncogenesis remain to be fully elucidated. HBx is mainly localized in the nucleus and mitochondria, and is a multifunctional transactivator that regulates host cell proliferation, metabolism, autophagy and senescence [2,3,4,5]. How HBx causes hepatocytes transformed or maintains malignancy of HCC remains still elusive. Liver is the largest exocrine gland and detoxification organ in the human body, and the endoplasmic reticulum (ER) in hepatocytes has a complex functionality. Sustained or excessive ER stress induces apoptosis. To counter the HBV-induced ER stress, the virus must have an adaptive mechanism to maintain survival of the infected cells
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