Epigenetic Regulation of MicroRNA Expression by Hepatitis B Virus Pre-S2 Mutant Promotes Hepatocellular Carcinoma Tumorigenesis

  • Liver Int. 2026 Apr;46(4):e70582. doi: 10.1111/liv.70582.
Yueh-Te Lin  1 ,  Long-Bin Jeng  2  3  4  5 ,  Fu-Ying Shih  6 ,  Chiao-Fang Teng  2  7  8  9
Affiliations
  • 1. Cancer Genome Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
  • 2. Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan.
  • 3. Department of Surgery, China Medical University Hospital, Taichung, Taiwan.
  • 4. Cell Therapy Center, China Medical University Hospital, Taichung, Taiwan.
  • 5. School of Medicine, China Medical University, Taichung, Taiwan.
  • 6. Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, Taichung, Taiwan.
  • 7. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
  • 8. Master Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan.
  • 9. Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan.
PMID: 41797438 DOI: 10.1111/liv.70582
Abstract

Background & aims: Discovery of therapeutic targets for hepatocellular carcinoma (HCC) is urgently needed. As an important hepatitis B virus (HBV) oncoprotein, pre-S2 mutant activates multiple signalling pathways to induce HCC development.

Methods: This study investigated the effect of pre-S2 mutant on regulating MicroRNA (miRNA) expression and the role of miRNAs in mediating pre-S2 mutant's oncogenic functions.

Results: The results showed that 9 miRNAs were downregulated in both tumour tissues of pre-S2 mutant-positive HCC patients and pre-S2 mutant-expressed human HCC cell lines, contributing to pre-S2 mutant-promoted cell proliferation, anchorage-independent cell growth, cell cycle progression, and tumour growth and malignancy. Moreover, pre-S2 mutant downregulated miRNA expression at the epigenetic levels through suppression of lysine acetyltransferase 3B (KAT3B)- and KAT5-mediated histone H3 lysine 9 acetylation (H3K9ac) and H4K5ac modifications. The decreased levels of pre-S2 mutant-dysregulated miRNAs could also be detected in blood exosomes of patients.

Conclusions: Collectively, this study provided new mechanistic insights and therapeutic perspectives for pre-S2 mutant-associated HCC tumorigenesis.

Keywords
epigenetic modification; hepatitis B virus; hepatocellular carcinoma; microRNA; pre‐S2 mutant.
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