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Publications

Journal Article Epublish

PubMed: 40405227 DOI: 10.1186/s13046-025-03413-8

HBV sequence integrated to enhancer acting as oncogenic driver epigenetically promotes hepatocellular carcinoma development.

J Exp Clin Cancer Res 44(1):155

Authors: Lu Chen, Wenxuan Li, Wenjing Zai, Xiangyi Zheng, Xianlong Meng, Qunyan Yao, Wei Li, Ying Liang, Mu Ye, Kaicheng Zhou, Mengxing Liu, Zhicong Yang, Zhanrui Mao, Hongyan Wei, Shuai Yang, Guoming Shi, Zhenghong Yuan, Wenqiang Yu

Affiliations

  • Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China.
  • Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. Liver Cancer Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
  • Department of Liver Surgery and Transplantation, Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • Precision Pharmacy and Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
  • Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China. Research and Development Department, Shanghai Epicurer Biotechnology Co. Ltd. Shanghai, China.
  • Department of Liver Surgery and Transplantation, Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
  • Shanghai Public Health Clinical Center & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, China.

Abstract

BACKGROUND

HBV integration is considered as the main contributor to hepatocellular carcinoma (HCC). However, whether HBV integrated sequences determine genotype pathogenicity and how to block their function during HCC progression remains unclear.

METHODS

An in vitro HBV-infected PHH model and liver cancer cell lines were established to confirm the pathogenic potential of HBV-SITEs. The roles of HBV-SITE-1 in HCC development were analyzed using cellular phenotypic assays and molecular biology techniques, including the combined analysis of RNA-seq and ChIP-seq. Animal models were also used to evaluate the therapeutic effect of HBV-miR-2 inhibitors.

RESULTS

We identified nine fragments of HBV Sequences Integrated To Enhancer, termed as "HBV-SITEs". Particularly, a single nucleotide variation (T > G) was embedded at seed sequence of HBV-miR-2 in the highest integrated HBV-SITE-1 between genotypes B and H. Unexpectedly, B-HBV-SITE-1, not H-HBV-SITE-1, could abnormally activate oncogenic genes including TERT and accelerate HCC cell proliferation and migration. Meanwhile, HBV-miR-2 was gradually increased in HBV-infected cells and patient plasma with different HCC stages. Importantly, 227 genes upregulated by HBV, were also activated by HBV-miR-2 through triggering HBV-SITE-1 enhancer. Conversely, enhancer activities were particularly decreased by HBV-miR-2 inhibitors, and further downregulated activated oncogenic genes. Finally, HCC growth was dramatically restrained and HBV-induced transcripts were systematically reduced via injection of HBV-miR-2 inhibitors in animal models.

CONCLUSION

HBV-SITEs were identified as novel oncogenic elements for HCC, which provides an insightful perspective for the other cancers caused by oncogenic DNA viruses. We demonstrated that the integrated HBV sequence itself acted as oncogenic enhancers and nucleotide variations of HBV genotypes account for particular pathogenic progression, supporting that the viral nucleotide sequences are vital pathogenic substances beyond viral proteins. And modulation of their enhancer activities could be clinically achievable strategy for blocking DNA viruses-related cancer progression in the future.

MeSH

Cells, Genes, Carcinoma, Hepatocellular, Neoplasms, Viruses, Genotype, Medical Oncology, Enhancer Elements, Genetic