The Effects and Underlying Mechanisms of Hepatitis B Virus X Gene Mutants on the Development of Hepatocellular Carcinoma

Pu, Rui; Liu, Wenbin; Zhou, Xinyu; Chen, Xi; Hou, Xiaomei; Cai, Shiliang; Chen, Liping; Wu, Jianfeng; Yang, Fan; Tan, Xiaojie; Yin, Jianhua; Wang, Xin; Cao, Guangwen

doi:10.3389/fonc.2022.836517

Cited by 7 publications

(9 citation statements)

References 49 publications

(64 reference statements)

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“…Liver cirrhosis is the result of an immune response to hepatic injury caused by chronic inflammation (30). HBV, especially its integrated forms in the human genome and its evolved forms generated in the long-term process of chronic infection, directly promotes the development of HCC (31)(32)(33)(34). HBV replication, integration, and evolution also improve the recurrence and metastasis of HCC while long-term treatment of chronic HBV infection can reduce the development and postoperative recurrence of HBV-HCC (15,(35)(36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Epidemiological Characteristics of Primary Liver Cancer in Mainland China From 2003 to 2020: A Representative Multicenter Study

Lin

Zhang

et al. 2022

Front. Oncol.

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BackgroundThe contribution of hepatitis B virus (HBV) and hepatitis C virus (HCV) to primary liver cancer (PLC) and their association with cancer aggressiveness remains uncertain in China, a country with half of global PLC. We aimed to characterize this using data from four representative medical centers.MethodsIn total, 15,801 PLC patients were enrolled from the centers distributed in Easter5n, Southern, Northern, and Western China from 2003 to 2020. Of those, 7585 with curative surgery were involved in survival analysis. A nomogram was constructed using preoperative parameters to predict postoperative survival.ResultsHepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma accounted for 93.0%, 4.3%, and 1.6% in PLC, respectively. The seropositivities of HBV and HCV were 84.4% and 3.2% in HCC, respectively. The seropositivity of anti-HCV antibody was significantly higher in HBV-negative than in HBV-positive HCC patients (13.2% vs. 1.1%). Compared to HCV-positive HCC (HCV-HCC), HBV-positive HCC (HBV-HCC) was associated with 12-year earlier onset, higher proportions of males, high α-fetoprotein, large tumor size, advanced Barcelona Clinic Liver Cancer (BCLC) stage, and vascular tumor thrombus. The proportions of HCC and HBV seropositivity increased, whereas that of anti-HCV decreased, from 2003 to 2020. Postoperative five-year survival rate was 73.5%, 64.1%, 34.9%, and 19.7% in HCC at BCLC stage 0, A, B, and C, respectively. The multivariate Cox regression analysis showed that HBV seropositivity, incomplete tumor capsule, vascular tumor thrombus, tumor diameter (≥3 cm), advanced BCLC stage (B+C), α-fetoprotein (≥20ng/ml), and direct bilirubin (>8µmol/L) contributed independently to shorter overall survival (OS); whereas post-operative radiofrequency ablation and second resection independently improved OS in HCC. HCV-HCC had a more favorable prognosis than did HBV-HCC (Log-rank test, P<0.001). A nomogram composed of age, gender, and the preoperative independent risk factors was accurate in predicting postoperative survival in HCC (C-index: 0.735; 95% confidence interval: 0.727–0.743).ConclusionHBV contributes to 84.4% of HCC in China, and actively promotes hepatocarcinogenesis and HCC progression. A favorable postoperative survival obtained in patients at the early BCLC stage highlights the importance of screening for early HCC in high-risk populations. Our preoperative prognosis prediction model is important in clinical decision-making.

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Section: Discussionmentioning

confidence: 99%

Epidemiological Characteristics of Primary Liver Cancer in Mainland China From 2003 to 2020: A Representative Multicenter Study

Lin

Zhang

et al. 2022

Front. Oncol.

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“…Hepatitis B virus X (HBx) mutations also increase HCC. Among them, HBx combination mutants and the carboxylic-acid-terminal-truncated HBV X protein (Ct-HBx) are considered to have a higher carcinogenic risk [83,84]. HBV integration into the host genome often results in the truncation of the HBV genome, especially at the C-terminus of hepatitis B virus X (HBx), resulting in the production of Ct-HBx.…”

Section: Hbv Gene Mutationmentioning

confidence: 99%

Hepatitis Virus and Hepatocellular Carcinoma: Recent Advances

Shen¹,

Jiang²,

Li³

et al. 2023

Cancers

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Hepatocellular carcinoma (HCC) remains a global health challenge, causing 600,000 deaths each year. Infectious factors, including hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV), have long been considered the major risk factors for the development and progression of HCC. These pathogens induce hepatocyte transformation through a variety of mechanisms, including insertional mutations caused by viral gene integration, epigenetic changes, and the induction of long-term immune dysfunction. The discovery of these mechanisms, while advancing our understanding of the disease, also provides targets for new diagnostic and therapeutic approaches. In addition, the discovery and research of chronic HEV infection over the past decade indicate that this common hepatitis virus also seems to have the potential to induce HCC. In this review, we provide an overview of recent studies on the link between hepatitis virus and HCC, as well as new diagnostic and therapeutic approaches to HCC based on these findings. Finally, we also discuss the potential relationship between HEV and HCC. In conclusion, these associations will further optimize the diagnosis and treatment of infection-associated HCC and call for better management policies.

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“…From HBV-infected patients in this cohort study, we amplified the fragments of wild-type preS1/preS2/S ORF (WT) and the mutant preS1/preS2/S ORFs carrying G2950A/G2951A/A2962G/C2964A (M1), C3116T/T31C (M2), and preS2 deletion (nt.15-nt.56, M3). The fragments of WT, M1, M2, and M3 were inserted into EcoRI restriction sites of a SB transposon vector, pKT2-FAH-Caggs-SB, which contained the cDNA of Fah gene (Figure S1) [19]. For the production of lentiviruses expressing preS1/preS2/S variants, the fragments of WT, M1, M2, and M3 were linked with a flag tag at the 3 end and were inserted into the plteni-CMV-GFP-puro lentiviral vector.…”

Section: Plasmid Constructionmentioning

confidence: 99%

“…The Fah-deficient mouse was applied to construct the model of the preS1/preS2/Sinduced HCC [19]. Fah −/− mice suffered lethal liver injury caused by the accumulation of intracellular fumarylacetoacetate.…”

Section: Mouse Modelsmentioning

confidence: 99%

HBV preS Mutations Promote Hepatocarcinogenesis by Inducing Endoplasmic Reticulum Stress and Upregulating Inflammatory Signaling

Liu

Cai

et al. 2022

Cancers

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This study aimed to elucidate the effects and underlying mechanisms of hepatitis B virus (HBV) preS mutations on hepatocarcinogenesis. The effect of the preS mutations on hepatocellular carcinoma (HCC) occurrence was evaluated using a prospective cohort study with 2114 HBV-infected patients, of whom 612 received antiviral treatments. The oncogenic functions of HBV preS mutations were investigated using cancer cell lines and Sleeping Beauty (SB) mouse models. RNA-sequencing and microarray were applied to identify key molecules involved in the mutant-induced carcinogenesis. Combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C significantly increased HCC risk in patients without antiviral treatment, whereas the preS2 deletion significantly increased HCC risk in patients with antiviral treatment. In SB mice, the preS1/preS2/S mutants induced a higher rate of tumor and higher serum levels of inflammatory cytokines than did wild-type counterpart. The preS1/preS2/S mutants induced altered gene expression profiles in the inflammation- and metabolism-related pathways, activated pathways of endoplasmic reticulum (ER) stress, affected the response to hypoxia, and upregulated the protein level of STAT3. Inhibiting the STAT3 pathway attenuated the effects of the preS1/preS2/S mutants on cell proliferation. G2950A/G2951A/A2962G/C2964A, C3116T/T31C, and preS2 deletion promote hepatocarcinogenesis via inducing ER stress, metabolism alteration, and STAT3 pathways, which might be translated into HCC prophylaxis.

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The Effects and Underlying Mechanisms of Hepatitis B Virus X Gene Mutants on the Development of Hepatocellular Carcinoma

Cited by 7 publications

References 49 publications

Epidemiological Characteristics of Primary Liver Cancer in Mainland China From 2003 to 2020: A Representative Multicenter Study

Epidemiological Characteristics of Primary Liver Cancer in Mainland China From 2003 to 2020: A Representative Multicenter Study

Hepatitis Virus and Hepatocellular Carcinoma: Recent Advances

HBV preS Mutations Promote Hepatocarcinogenesis by Inducing Endoplasmic Reticulum Stress and Upregulating Inflammatory Signaling

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