Naturally Occurring Hepatitis B Virus Mutations Leading to Endoplasmic Reticulum Stress and Their Contribution to the Progression of Hepatocellular Carcinoma

Choi, Yu Min; Lee, So Young; Kim, Bum Joon

doi:10.3390/ijms20030597

Cited by 62 publications

(55 citation statements)

References 84 publications

(106 reference statements)

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“…HBV mutations might affect the success rates of diagnostic/vaccination protocols, leading to the development of drug-resistant strains [33][34][35][36][37][38][39]. The expression, distribution, and secretion of HBV proteins could be affected by amino acid mutations that are also correlated with HCC [40][41][42][43]. Here, we identified an HBV strain from an acute clinically infected patient and performed full genome sequencing, characterization, mutational analysis, cloning, and expression analysis of the major viral proteins.…”

Section: Discussionmentioning

confidence: 99%

PreS1 Mutations Alter the Large HBsAg Antigenicity of a Hepatitis B Virus Strain Isolated in Bangladesh

Hossain

Mahmud

Nazir

et al. 2020

IJMS

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Mutations in the hepatitis B virus (HBV) genome can potentially lead to vaccination failure, diagnostic escape, and disease progression. However, there are no reports on viral gene expression and large hepatitis B surface antigen (HBsAg) antigenicity alterations due to mutations in HBV isolated from a Bangladeshi population. Here, we sequenced the full genome of the HBV isolated from a clinically infected patient in Bangladesh. The open reading frames (ORFs) (P, S, C, and X) of the isolated HBV strain were successfully amplified and cloned into a mammalian expression vector. The HBV isolate was identified as genotype C (sub-genotype C2), serotype adr, and evolutionarily related to strains isolated in Indonesia, Malaysia, and China. Clinically significant mutations, such as preS1 C2964A, reverse transcriptase domain I91L, and small HBsAg N3S, were identified. The viral P, S, C, and X genes were expressed in HEK-293T and HepG2 cells by transient transfection with a native subcellular distribution pattern analyzed by immunofluorescence assay. Western blotting of large HBsAg using preS1 antibody showed no staining, and preS1 ELISA showed a significant reduction in reactivity due to amino acid mutations. This mutated preS1 sequence has been identified in several Asian countries. To our knowledge, this is the first report investigating changes in large HBsAg antigenicity due to preS1 mutations.

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Section: Discussionmentioning

confidence: 99%

PreS1 Mutations Alter the Large HBsAg Antigenicity of a Hepatitis B Virus Strain Isolated in Bangladesh

Hossain

Mahmud

Nazir

et al. 2020

IJMS

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“…The genes involved in the organelle membrane are all existed on the endoplasmic membrane. The relationship between the endoplasmic membrane and carcinogenesis of HCC may be involved in the ER stress (49), and more studies with high credibility are in need to validate this relationship.…”

Section: Discussionmentioning

confidence: 99%

Revelation of critical genes and pathways involved in hepatocellular carcinoma (HCC) and phylogenetic tree construction of CDK1 protein family An integrated multi-omics bioinformatics analysis

Zhou

Chen

Cao

et al. 2020

Preprint

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Background Hepatocellular carcinoma (HCC) is one of the leading and fastest increasing causes of death in the world. It primarily happens in the people who have been exposed to high-risk factors for a long time, such as the hepatitis B virus, hepatitis C virus, etc. Some similar analysis on HCC were published years ago, and results need updating. Methods In this study. We analyzed the gene expression pattern obtained from the GEO database in healthy tissue and tumor tissue and identified differentially expressed genes (DEGs), then GO and KEGG pathway analyses were performed subsequently on DEGs. We also used the protein-protein interaction (PPI) network drawn from STRING to find hub genes and analyzed their effects on prognosis and expression level in different stages of HCC from GEPIA. Furthermore, we analyzed the CDK1 in different species and established the phylogenetic tree of the CDK1 family by the MEGA-X (version 5) according to the amino acid sequence of CDK1 in different species. Results Among all DEGs identified in this study, the CDK1 is the most statically significant hub gene in the perspective of prognosis and differential ex pression. The expression level of CDK1 varies in different stages of HCC. The expression level reaches the highest in stage two and three and reaches the lowest in Stage four. And the human CDK1 gene and ape-like CDK1 gene subtype 5 may be homologous genes. However, human CDK1 gene and the gene encoding human CDK1 protein A chain may be heterozygous genes. Conclusion CDK1 is a gene with great significance in the diagnosis and prognosis of HCC, more studies that investigate deeply about the CDK1 is needed in the future.

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“…Host cell-mediated N-glycosylation on L, but not on M or SHBs proteins is vital for viral morphogenesis [ 40 ]. Moreover, recent studies have shown that the N-glycans on LHBs are associated with ER stress-mediated cell cycle dysregulation and cell proliferation, triggering carcinogenic processes [ 41 , 42 ]. These findings clearly demonstrate that posttranslational modifications of LHBs play significant roles in regulating HBV carcinogenesis.…”

Section: Glycosylations Of the Lhbs Pre-s Regions That Regulate Prmentioning

confidence: 99%

Association of the Hepatitis B Virus Large Surface Protein with Viral Infectivity and Endoplasmic Reticulum Stress-mediated Liver Carcinogenesis

Lin

Hung

Huang

2020

Cells

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Hepatitis B is the most prevalent viral hepatitis worldwide, affecting approximately one-third of the world’s population. Among HBV factors, the surface protein is the most sensitive biomarker for viral infection, given that it is expressed at high levels in all viral infection phases. The large HBV surface protein (LHBs) contains the integral pre-S1 domain, which binds to the HBV receptor sodium taurocholate co transporting polypeptide on the hepatocyte to facilitate viral entry. The accumulation of viral LHBs and its prevalent pre-S mutants in chronic HBV carriers triggers a sustained endoplasmic reticulum (ER) overload response, leading to ER stress-mediated cell proliferation, metabolic switching and genomic instability, which are associated with pro-oncogenic effects. Ground glass hepatocytes identified in HBV-related hepatocellular carcinoma (HCC) patients harbor pre-S deletion variants that largely accumulate in the ER lumen due to mutation-induced protein misfolding and are associated with increased risks of cancer recurrence and metastasis. Moreover, in contrast to the major HBs, which is decreased in tumors to a greater extent than it is in peritumorous regions, LHBs is continuously expressed during tumorigenesis, indicating that LHBs serves as a promising biomarker for HCC in people with CHB. Continuing efforts to delineate the molecular mechanisms by which LHBs regulates pathological changes in CHB patients are important for establishing a correlation between LHBs biomarkers and HCC development.

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Naturally Occurring Hepatitis B Virus Mutations Leading to Endoplasmic Reticulum Stress and Their Contribution to the Progression of Hepatocellular Carcinoma

Cited by 62 publications

References 84 publications

PreS1 Mutations Alter the Large HBsAg Antigenicity of a Hepatitis B Virus Strain Isolated in Bangladesh

PreS1 Mutations Alter the Large HBsAg Antigenicity of a Hepatitis B Virus Strain Isolated in Bangladesh

Revelation of critical genes and pathways involved in hepatocellular carcinoma (HCC) and phylogenetic tree construction of CDK1 protein family An integrated multi-omics bioinformatics analysis

Association of the Hepatitis B Virus Large Surface Protein with Viral Infectivity and Endoplasmic Reticulum Stress-mediated Liver Carcinogenesis

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