HBx-induced reactive oxygen species activates hepatocellular carcinogenesis<i>via</i>dysregulation of PTEN/Akt pathway

Ha, Hojin

doi:10.3748/wjg.v16.i39.4932

Cited by 60 publications

(47 citation statements)

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“…A large body of literature has documented that HBx localizes to the mitochondrial membrane and disturbs mitochondrial function (10,16,31,51,54), and the observation that HBx increases cellular ROS levels has been reported by many research groups (5,13,15,31,33,51,61). Additionally, recent work showed that cisplatin also triggers oxidative stress (21,46).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1

Chen

Liang

et al. 2011

J Virol

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Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1

Chen

Liang

et al. 2011

J Virol

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“…Recent work has revealed that ROS may play an important role in JNK-dependent autophagy regulation (46)(47)(48)(49), while HBx treatment has been reported to cause ROS generation in hepatoma cells (50,51). We thus investigated the role of ROS in HBx-induced JNK activation and the ensuing autophagosome formation.…”

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confidence: 99%

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Zhong

Shu

Dai

et al. 2017

J Virol

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Autophagy is closely associated with the regulation of hepatitis B virus (HBV) replication. HBV X protein (HBx), a multifunctional regulator in HBV-associated biological processes, has been demonstrated to be crucial for autophagy induction by HBV. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we demonstrated that HBx induced autophagosome formation independently of the class I phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway. In contrast, the class III PI3K(VPS34)/beclin-1 pathway was revealed to be critical for HBx-induced autophagosome formation. Further study showed that HBx did not affect the level of VPS34 and beclin-1 expression but inhibited beclin-1/Bcl-2 association, and c-Jun NH2-terminal kinase (JNK) signaling was found to be important for this process. Moreover, it was found that HBx treatment led to the generation of reactive oxygen species (ROS), and inhibition of ROS activity abrogated both JNK activation and autophagosome formation. Of importance, ROS-JNK signaling was also revealed to play an important role in HBV-induced autophagosome formation and subsequent HBV replication. These data may provide deeper insight into the mechanisms of autophagy induction by HBx and help in the design of new therapeutic strategies against HBV infection.IMPORTANCE HBx plays a key role in diverse HBV-associated biological processes, including autophagy induction. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we found that HBx induced autophagy independently of the class I PI3K/AKT/mTOR signaling pathway, while the class III PI3K(VPS34)/beclin-1 pathway was revealed to be crucial for this process. Further data showed that ROS-JNK activation by HBx resulted in the release of beclin-1 from its association with Bcl-2 to form a complex with VPS34, thus enhancing autophagosome formation. Of importance, ROS-JNK signaling was also demonstrated to be critical for HBV replication via regulation of autophagy induction. These data help to elucidate the molecular mechanisms of autophagy induction by HBx/HBV and might be useful for designing novel therapeutic approaches to HBV infection.KEYWORDS HBV X protein, autophagy, signaling pathway, viral replication H epatitis B virus (HBV) is an important human pathogen that can cause a wide spectrum of liver diseases, including hepatitis, liver cirrhosis, and hepatocellular carcinoma (1, 2). The HBV genome is about 3.2 kb in length, carrying four genes named

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“…HBx of genotype D HBV causes hypermethylation of the gene promoter of glutathione Stransferase GSTP1, which is a candidate enzyme for protecting cells against ROS with www.intechopen.com related toxic products (Niu et al, 2009). In turn, ROS stimulate HBx expression (Ha et al, 2010), suggesting that ROS may be an autocrine transducer of HBx-mediated carcinogenesis. Very recently, HBX was shown to activate the transcriptional activity of Forkhead box class O 4 (Foxo4) via JNK, leading to enhancement of the resistance to oxidative stress-induced cell death (Srisuttee et al, 2011).…”

Section: Hbv and Rosmentioning

confidence: 99%

Molecular Mechanism of DNA Damage Response Pathway During Hepatic Carcinogenesis

Matsuda¹,

Wakai²

2012

Hepatocellular Carcinoma - Basic Research

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HBx-induced reactive oxygen species activates hepatocellular carcinogenesisviadysregulation of PTEN/Akt pathway

Abstract: HBx induced ROS promoted Akt pathways via oxidized inactive PTEN. HBx and ROS maintained a positive regulatory loop, which aggravated carcinogenesis.

Cited by 60 publications

References 22 publications

Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1

Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Molecular Mechanism of DNA Damage Response Pathway During Hepatic Carcinogenesis

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HBx-induced reactive oxygen species activates hepatocellular carcinogenesisviadysregulation of PTEN/Akt pathway

Abstract: HBx induced ROS promoted Akt pathways via oxidized inactive PTEN. HBx and ROS maintained a positive regulatory loop, which aggravated carcinogenesis.

Cited by 60 publications

References 22 publications

Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1

Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1

Reactive Oxygen Species-Mediated c-Jun NH 2 -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Molecular Mechanism of DNA Damage Response Pathway During Hepatic Carcinogenesis

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Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction