Interference of Apoptosis by Hepatitis B Virus

Lin, Shaoli; Zhang, Yan Jin

doi:10.3390/v9080230

Cited by 39 publications

(21 citation statements)

References 176 publications

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“…Secondly, immune response is affected by alcohol [ 21 ] that may also promote apoptosis in HCV infected hepatocytes [ 22 ]. There are conflicting reports on the interference of HBV infection with the apoptosis, most studies showing inhibition and a minority induction, the HBV-mediated alteration of apoptosis being prevalently achieved via interference with cellular signaling pathways and regulation of epigenetics HBV X protein (HBX) [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Sex difference in the interaction of alcohol intake, hepatitis B virus, and hepatitis C virus on the risk of cirrhosis

et al. 2017

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BackgroundThe joint effect of the interaction of alcohol intake, hepatitis B virus (HBV) and hepatitis C virus (HCV) on the risk of cirrhosis is still unexplored because a large sample size is required for this investigation.ObjectiveEvaluation of interaction of HBV, HCV and alcohol abuse on the risk of cirrhosis.DesignWe analysed 12,262 consecutive patients with chronic liver disease of various aetiologies referring to 95 Italian liver units in 2001 or 2014. To evaluate the interaction between alcohol abuse, HBV infection, and HCV infection, patients unexposed to either factors were used as reference category. Adjustment for BMI and age was done by multiple logistic regression analysis.ResultsFemales were older than males (p<0.01) and less frequently showed HBV and alcoholic aetiology (p<0.01). In both sexes, an overtime increasing age and an increasing proportion of subjects with liver cirrhosis was observed, reflecting a better survival (0.01).An additive interaction is observed in females: the O.R. generated by the simultaneous presence of HBV, HCV, and alcohol (5.09; 95% C.I. 1.06–24.56) exceeds the sum (4.14) of the O.R. generated by a single exposure (O.R. = 0.72 for HBsAg positivity, OR = 1.34 for anti-HCV positivity, and O.R. = 2.08 for alcohol intake). No interaction is observed in male sex.ConclusionsThe observed gender difference suggests that the simultaneous presence of HBV/HCV coinfection and risky alcohol intake enhances the mechanism of liver damage to a greater extent in females than in males.

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Section: Discussionmentioning

confidence: 99%

Sex difference in the interaction of alcohol intake, hepatitis B virus, and hepatitis C virus on the risk of cirrhosis

et al. 2017

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“…Over 1 million people die from chronic HBV infection-related cirrhosis and liver cancer each year (46). Hepatocyte apoptosis is frequently altered in liver cancer development and correlated with HCC progression (12). A large body of studies have been performed by the investigators in the field trying to determine the relationship of HBV infection and apoptosis; however, the results are still in controversy.…”

Section: Discussionmentioning

confidence: 99%

“…A large body of studies have been performed by the investigators in the field trying to determine the relationship of HBV infection and apoptosis; however, the results are still in controversy. HBV or HBx is generally believed to inhibit cellular apoptosis, thereby facilitating virus proliferation and promoting HCC progression (12,(47)(48)(49). However, the fact that HBV infection could induce apoptosis has also been reported in several studies (17,20,50).…”

Section: Discussionmentioning

confidence: 99%

“…It has been well established that HBV infection could interfere with the apoptosis signaling to promote viral proliferation and HCC progression. The HBV-mediated alteration of apoptosis is accomplished mainly through interference with cellular signaling pathways and/or regulation of epigenetics (12). External stimuli such as Fas ligand (FasL), tumor necrosis factor alpha (TNF-␣), and TRAIL (TNF-related apoptosisinducing ligand) trigger the extrinsic pathway by binding to their respective receptors on the cell surface, resulting in the recruitment of adaptor proteins to transmit the intracellular signals via the caspase cascades (13).…”

mentioning

confidence: 99%

“…While the induction of apoptosis is a hallmark of many viruses infecting humans, studies that aim to determine the relationship of HBV infection and apoptosis have shown contradictory results. The majority of the studies documented that HBV or, more specifically, hepatitis B virus X protein (HBx) could inhibit cellular apoptosis to facilitate virus proliferation and promote HCC progression (12). However, it has also been reported that HBx was able to activate apoptosis or sensitize hepatocytes to apoptotic inducers in vitro (17)(18)(19)(20).…”

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confidence: 99%

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Hepatitis B Spliced Protein (HBSP) Suppresses Fas-Mediated Hepatocyte Apoptosis via Activation of PI3K/Akt Signaling

Chen

Jing

et al. 2018

J Virol

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Hepatitis B spliced protein (HBSP) is known to associate with viral persistence and pathogenesis; however, its biological and clinical significance remains poorly defined. Acquired resistance to Fas-mediated apoptosis is thought to be one of the major promotors for hepatitis B virus (HBV) chronicity and malignancy. The purpose of this study was to investigate whether HBSP could protect hepatocytes against Fas-initiated apoptosis. We showed here that HBSP mediated resistance of hepatoma cells or primary human hepatocytes (PHH) to agonistic anti-Fas antibody (CH11)- or FasL-induced apoptosis. Under Fas signaling stimulation, expression of HBSP inhibited Fas aggregation and prevented recruitment of the adaptor molecule Fas-associated death domain (FADD) and procaspase-8 (or FADD-like interleukin-1β-converting enzyme [FLICE]) into the death-inducing signaling complex (DISC) while increasing recruitment of cellular FLICE-inhibitory protein L (FLIP) into the DISC. Those effects may be mediated through activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway as evidenced by increased cellular phosphatidylinositol (3,4,5)-trisphosphate (PIP3) content and PI3K activity and enhanced phosphorylation of mTORC2 and PDPK1 as well as Akt itself. Confirmedly, inhibition of PI3K by LY294002 reversed the effect of HBSP on Fas aggregation, FLIP expression, and cellular apoptosis. These results indicate that HBSP functions to prevent hepatocytes from Fas-induced apoptosis by enhancing PI3K/Akt activity, which may contribute to the survival and persistence of infected hepatocytes during chronic infection. Our study revealed a previously unappreciated role of HBSP in Fas-mediated apoptosis. The antiapoptotic activity of HBSP is important for understanding hepatitis B virus pathogenesis. In particular, HBV variants associated with hepatoma carcinoma may downregulate apoptosis of hepatocytes through enhanced HBSP expression. Our study also found that Akt is centrally involved in Fas-induced hepatocyte apoptosis and revealed that interventions directed at inhibiting the activation or functional activity of Akt may be of therapeutic value in this process.

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HBV suppresses ZHX2 expression to promote proliferation of HCC through miR‐155 activation

Song

Tan

et al. 2018

Intl Journal of Cancer

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Initiation of hepatocellular carcinoma (HCC) by chronic hepatitis B virus (HBV) infection is a complex process that includes both oncogene activation and tumor suppressor inhibition. The HBV X (HBx) protein has an important and complex role in processes leading to HCC. We previously identified the mammalian Zinc fingers and homeoboxes 2 (ZHX2) gene as an HCC-associated tumor suppressor gene. In the present study, we investigated whether the oncogenic properties of HBV and, more specifically, HBx, involved ZHX2 silencing. Our data indicates that ZHX2 expression is significantly decreased in tumor tissues from HBV-positive HCC patients and livers from HBV transgenic mice. In vitro and in vivo studies confirmed that HBV-encoded proteins, particularly HBx, inhibits both the expression and tumor suppression properties of ZHX2. Further analyses identified miR-155, a well-known oncomiR in various cancers, as an important link between HBx and ZHX2 inhibition. Increased miR-155 levels were found in HBV-positive tumors, livers of HBV transgenic mice and HBx-overexpressing hepatoma cell lines. MiR-155 overexpression reduced ZHX2 levels via miR-155 seed sites in the ZHX2 3'UTR, whereas blocking miR-155 levels led to increased ZHX2 levels. Taken together, our data indicate that HCC-promoting properties of HBV may include ZHX2 silencing via a miR-155 dependent pathway and suggests a novel therapy for HBV-related HCC.

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Interference of Apoptosis by Hepatitis B Virus

Cited by 39 publications

References 176 publications

Sex difference in the interaction of alcohol intake, hepatitis B virus, and hepatitis C virus on the risk of cirrhosis

Sex difference in the interaction of alcohol intake, hepatitis B virus, and hepatitis C virus on the risk of cirrhosis

Hepatitis B Spliced Protein (HBSP) Suppresses Fas-Mediated Hepatocyte Apoptosis via Activation of PI3K/Akt Signaling

HBV suppresses ZHX2 expression to promote proliferation of HCC through miR‐155 activation

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