Hepatitis B Viral Protein HBx and the Molecular Mechanisms Modulating the Hallmarks of Hepatocellular Carcinoma: A Comprehensive Review

Sivasudhan, Enakshi; Blake, Neil; Lu, Zhi-Liang; Meng, Jiao; Rong, Rong

doi:10.3390/cells11040741

Cited by 60 publications

(36 citation statements)

References 168 publications

(171 reference statements)

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“…This suggests that CLD promotes the integration of HBx-encoding HBV DNA ( Figure 2 ), and sustained high levels of HBx could act as a complete carcinogen [ 61 ]. Thus, HBx promotes the development of cancer hallmarks [ 62 ]. None of these HBx transgenic mice developed HCC on a background of cirrhosis.…”

Section: Role Of Hbx In the Immunopathogenesis Of Cld And Hccmentioning

confidence: 99%

Hepatitis B x (HBx) as a Component of a Functional Cure for Chronic Hepatitis B

Feitelson

Arzumanyan

Spector³

et al. 2022

Biomedicines

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Patients who are carriers of the hepatitis B virus (HBV) are at high risk of chronic liver disease (CLD) which proceeds from hepatitis, to fibrosis, cirrhosis and to hepatocellular carcinoma (HCC). The hepatitis B-encoded X antigen, HBx, promotes virus gene expression and replication, protects infected hepatocytes from immunological destruction, and promotes the development of CLD and HCC. For virus replication, HBx regulates covalently closed circular (ccc) HBV DNA transcription, while for CLD, HBx triggers cellular oxidative stress, in part, by triggering mitochondrial damage that stimulates innate immunity. Constitutive activation of NF-κB by HBx transcriptionally activates pro-inflammatory genes, resulting in hepatocellular destruction, regeneration, and increased integration of the HBx gene into the host genome. NF-κB is also hepatoprotective, which sustains the survival of infected cells. Multiple therapeutic approaches include direct-acting anti-viral compounds and immune-stimulating drugs, but functional cures were not achieved, in part, because none were yet devised to target HBx. In addition, many patients with cirrhosis or HCC have little or no virus replication, but continue to express HBx from integrated templates, suggesting that HBx contributes to the pathogenesis of CLD. Blocking HBx activity will, therefore, impact multiple aspects of the host–virus relationship that are relevant to achieving a functional cure.

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Section: Role Of Hbx In the Immunopathogenesis Of Cld And Hccmentioning

confidence: 99%

Hepatitis B x (HBx) as a Component of a Functional Cure for Chronic Hepatitis B

Feitelson

Arzumanyan

Spector³

et al. 2022

Biomedicines

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“…Moreover, HBx also regulates the cccDNA transcriptional activity by preventing transcriptional repressor recruitment on the cccDNA, including SIRT1 and HDAC1 [ 11 , 12 ]. HBx not only contributes to persistent HBV infection but also modulates several cell-signaling pathways, such as P53, mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), and the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathways, thereby promoting cell proliferation and inducing carcinoma formation [ 13 , 14 , 15 , 16 ]. Anti-HBx could be a potential antivirus strategy for HBV infection, but because HBx is an intracellular protein and most antibodies against HBx are not sensitive enough, the discovery of inhibitors of HBx would be facilitated by the ability to screen large chemical libraries in a short time for molecular compounds against HBx.…”

Section: Introductionmentioning

confidence: 99%

Identification of Estradiol Benzoate as an Inhibitor of HBx Using Inducible Stably Transfected HepG2 Cells Expressing HiBiT Tagged HBx

Chen

et al. 2022

Molecules

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HBx plays a significant role in the cccDNA epigenetic modification regulating the hepatitis B virus (HBV) life cycle and in hepatocyte proliferation and carcinogenesis. By using the sleeping-beauty transposon system, we constructed a tetracycline-induced HBx-expressing stable cell line, SBHX21. HBx with a HiBiT tag can be quickly detected utilizing a NanoLuc-based HiBiT detection system. By screening a drug library using SBHX21 cells, we identified estradiol benzoate as a novel anti-HBx agent. Estradiol benzoate also markedly reduced the production of HBeAg, HBsAg, HBV pgRNA, and HBV DNA in a dose-dependent manner, suggesting that estradiol benzoate could be an anti-HBV agent. Docking model results revealed that estradiol benzoate binds to HBx at TRP87 and TRP107. Collectively, our results suggest that estradiol benzoate inhibits the HBx protein and HBV transcription and replication, which may serve as a novel anti-HBV molecular compound for investigating new treatment strategies for HBV infection.

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“…In this study, we selected HBx as the target of siRNA silencing. HBx plays a critical role in HBV replication by binding with the nuclear cccDNA mini chromosome to initiate and maintain viral transcription [ 12 ]. Furthermore, a previous report demonstrated that inhibiting HBx using an NQO1 inhibitor could block cccDNA transcription [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, IL-12 can promote macrophages to differentiate into the M1 phenotype [29]. However, the detailed mechanism of inhibition of HBV replication by IL- 12 is not yet understood well enough.…”

Section: Introductionmentioning

confidence: 99%

Codelivery of HBx-siRNA and Plasmid Encoding IL-12 for Inhibition of Hepatitis B Virus and Reactivation of Antiviral Immunity

Ren

Han

et al. 2022

Pharmaceutics

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Chronic hepatitis B is a critical cause of many serious liver diseases such as hepatocellular carcinoma (HCC). The main challenges in hepatitis B treatment include the rebound of hepatitis B virus (HBV)-related antigen levels after drug withdrawal and the immunosuppression caused by the virus. Herein, we demonstrate that the HBV-related antigen can be effectively inhibited and antiviral immunity can be successfully reactivated through codelivery of the small interfering RNA (siRNA) targeting HBV X protein (HBx) and the plasmid encoding interleukin 12 (pIL-12) to hepatocytes and immune cells. After being treated by the siRNA/pIL-12 codelivery system, HBx mRNA and hepatitis B surface antigen (HBsAg) are dramatically reduced in HepG2.215 cells. More importantly, the downregulated CD47 and programmed death ligand 1 (PD-L1) and the upregulated interferon-β promoter stimulator-1 (IPS-1), retinoic acid-inducible gene-1 (RIG-1), CD80, and human leukocyte antigen-1 (HLA-1) in treated HepG2.215 cells indicate that the immunosuppression is reversed by the codelivery system. Furthermore, the codelivery system results in inhibition of extracellular regulated protein kinases (ERK) and phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) pathways, as well as downregulation of B-cell lymphoma-2 (Bcl-2) and upregulation of p53, implying its potential in preventing the progression of HBV-induced HCC. In addition, J774A.1 macrophages treated by the codelivery system were successfully differentiated into the M1 phenotype and expressed enhanced cytokines with anti-hepatitis B effects such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α). Therefore, we believe that codelivery of siRNA and pIL-12 can effectively inhibit hepatitis B virus, reverse virus-induced immunosuppression, reactivate antiviral immunity, and hinder the progression of HBV-induced hepatocellular carcinoma. This investigation provides a promising approach for the synergistic treatment of HBV infection.

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Hepatitis B Viral Protein HBx and the Molecular Mechanisms Modulating the Hallmarks of Hepatocellular Carcinoma: A Comprehensive Review

Cited by 60 publications

References 168 publications

Hepatitis B x (HBx) as a Component of a Functional Cure for Chronic Hepatitis B

Hepatitis B x (HBx) as a Component of a Functional Cure for Chronic Hepatitis B

Identification of Estradiol Benzoate as an Inhibitor of HBx Using Inducible Stably Transfected HepG2 Cells Expressing HiBiT Tagged HBx

Codelivery of HBx-siRNA and Plasmid Encoding IL-12 for Inhibition of Hepatitis B Virus and Reactivation of Antiviral Immunity

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