Repression of Death Receptor–Mediated Apoptosis of Hepatocytes by Hepatitis B Virus e Antigen

Liu, Wei; Guo, Teng-Fei; Jing, Zhen-Tang; Tong, Qiao-Yun

doi:10.1016/j.ajpath.2019.07.014

Cited by 7 publications

(6 citation statements)

References 43 publications

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“…As shown previously, HBeAg and its precursors may function as a significant enhancer of HCC through many mechanisms, including repressing p53 activity through interacting with NUMB [128,148]. A study by Liu and colleagues showed that HBeAg serves to inhibit p53-dependent FasL-and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated hepatic apoptosis by down-regulating both membrane (m) Fas death receptors DR4 and DR5 expression at a transcriptional level and enhancing the expression of soluble (s) Fas by increasing Fas alternative splicing [148]. The results indicate that HBeAg can protect hepatocytes from apoptosis induced by the Fas/FasL and TRAIL/DR systems [148].…”

mentioning

confidence: 69%

“…Secondly, defective expression of HBeAg results in the immune system and inflammatory cytokines being directed towards HBV-infected hepatocytes, which cause an increase in inflammation [74,78]. Thirdly, HBeAg and its precursors interfere with both intrinsic and extrinsic apoptotic pathways to ensure the survival of HBV-infected hepatocytes [122,128,148]. Lastly, HBeAg and its precursors, can initiate an intracellular signalling cascade, which leads to cell growth and division [155,162].…”

Section: Discussionmentioning

confidence: 99%

“…A study by Liu and colleagues showed that HBeAg serves to inhibit p53-dependent FasL-and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated hepatic apoptosis by down-regulating both membrane (m) Fas death receptors DR4 and DR5 expression at a transcriptional level and enhancing the expression of soluble (s) Fas by increasing Fas alternative splicing [148]. The results indicate that HBeAg can protect hepatocytes from apoptosis induced by the Fas/FasL and TRAIL/DR systems [148]. Therefore, HBeAg likely possesses negative immunomodulatory roles [30,31].…”

mentioning

confidence: 99%

“…Although through different mechanisms, the role of HBeAg in these apoptotic pathways helps promote the survival of hepatocytes infected with HBV. [148]. Intrinsic pathways: (a) P53 pathway-p22 interacts with NUMB, which regulates Notch and MDM2 preventing ubiquitination and degradation of p53 and impairing the stability and transcriptional activity of p53 [128]; (b) G1862T mutation-G1862T mutation results in the accumulation of p25 in the ER, decreasing the activity of the PERK and IRE1/XBP1 while increasing the activity of the ATF6 receptor pathways.…”

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confidence: 99%

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The Complex Role of HBeAg and Its Precursors in the Pathway to Hepatocellular Carcinoma

Padarath

Deroubaix

Kramvis

2023

Viruses

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Hepatitis B virus (HBV) is one of the seven known human oncogenic viruses and has adapted to coexist with a single host for prolonged periods, requiring continuous manipulation of immunity and cell fate decisions. The persistence of HBV infection is associated with the pathogenesis of hepatocellular carcinoma, and various HBV proteins have been implicated in promoting this persistence. The precursor of hepatitis e antigen (HBeAg), is translated from the precore/core region and is post-translationally modified to yield HBeAg, which is secreted in the serum. HBeAg is a non-particulate protein of HBV and can act as both a tolerogen and an immunogen. HBeAg can protect hepatocytes from apoptosis by interfering with host signalling pathways and acting as a decoy to the immune response. By evading the immune response and interfering with apoptosis, HBeAg has the potential to contribute to the hepatocarcinogenic potential of HBV. In particular, this review summarises the various signalling pathways through which HBeAg and its precursors can promote hepatocarcinogenesis via the various hallmarks of cancer.

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confidence: 69%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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The Complex Role of HBeAg and Its Precursors in the Pathway to Hepatocellular Carcinoma

Padarath

Deroubaix

Kramvis

2023

Viruses

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“…The purposes of this precise strategy (secreting and retaining) are mainly contributing to HBV survival in hepatocytes. Secreted HBeAg can protect the injury of infected hepatocytes' immune-system responses 72 , and the retained HBeAg can help infected hepatocytes escape from apoptosis by antagonizing the cytotoxicity from p53dependent Fas/FasL and TRAIL 74 . Moreover, the carcinogenic effects of intracellular HBeAg were also found to be the consequence of compromised p53 activity.…”

Section: Hbv-induced Hepatoma Cell Transformationmentioning

confidence: 99%

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

et al. 2020

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Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2-p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2-p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes' transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4 + T cells by disrupting their MDM2-p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2-p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2-p53 axis in HCC, and specifically discuss the impact of MDM2-p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2-p53 axis in HCC.

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TRAIL inhibition by soluble death receptor 5 protects against acute myocardial infarction in rats

et al. 2022

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Repression of Death Receptor–Mediated Apoptosis of Hepatocytes by Hepatitis B Virus e Antigen

Cited by 7 publications

References 43 publications

The Complex Role of HBeAg and Its Precursors in the Pathway to Hepatocellular Carcinoma

The Complex Role of HBeAg and Its Precursors in the Pathway to Hepatocellular Carcinoma

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

TRAIL inhibition by soluble death receptor 5 protects against acute myocardial infarction in rats

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