Compartmentalisation of Hepatitis B virus X gene evolution in hepatocellular carcinoma microenvironment and the genotype-phenotype correlation of tumorigenicity in HBV-related patients with hepatocellular carcinoma

  • Emerg Microbes Infect. 2022 Sep 14;1-48. doi: 10.1080/22221751.2022.2125344.
Ya Fu  1  2  3  4 ,  Fengling Fang  1  2  3  4 ,  Hongyan Guo  1  2  3  4 ,  Xialin Xiao  1  2  3  4 ,  Yuhai Hu  5 ,  Yongbin Zeng  1  2  3  4 ,  Tianbin Chen  1  2  3  4 ,  Songhang Wu  1  2  3  4 ,  Ni Lin  1  2  3  4 ,  Jinlan Huang  1  2  3  4 ,  Ling Jiang  1  2  3  4 ,  Qishui Ou  1  2  3  4 ,  Can Liu  1  2  3  4
Affiliations
  • 1. Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
  • 2. Clinical Laboratory Diagnostics, The First Clinical College, Fujian Medical University, Fuzhou, China.
  • 3. Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
  • 4. Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China.
  • 5. Department of Hepatobiliary Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
PMID: 36102940 DOI: 10.1080/22221751.2022.2125344
Abstract

Hepatitis B virus (HBV) exists as quasispecies (QS). However, the evolutionary characteristics of haplotypes of HBV X gene in the hepatocellular carcinoma (HCC) microenvironment remain unclear. Mutations across X gene are essential for the tumorigenicity of HBV X protein (HBx). However, the functional phenotypes of many mutant HBx remain unknown. This study aims to compare the characteristics of X gene evolution between tumour and non-tumour tissues in patients with HCC and investigate the tumorigenic phenotype of HBx harbouring mutation T81P/S101P/L123S. This study included 24 patients with HCC. Molecular cloning of X gene was performed to analyse characteristics of haplotypes in liver tissues. HCC cell lines stably expressing wild-type or mutant HBx and subcutaneous tumour xenograft mouse model were used to assess HBx-T81P/S101P/L123S tumorigenicity. The mean heterogeneity of HBV QS across X gene in tumour tissues was lower than that in non-tumour tissues. A location bias was observed in X gene clones with genotype C or D in tumour tissues compared to those with genotype B. Mutations in genotype-C or -D clones were mainly clustered in the dimerization region and aa110-aa140 within the transactivation region. A novel mutation combination at residues 81, 101 and 123 was identified in tumour tissues. Further, HBx-T81P/S101P/L123S promotes cell proliferation and increases genomic instability, which was mediated by MYC. This study elucidates the compartmentalised evolution patterns of HBV X gene between intra tumour and non-tumour tissues in patients with HCC and provides a new mechanism underlying HBV-driven hepatocarcinogenesis, suggesting a potential viral marker for monitoring HCC.

Keywords
Hepatitis B virus; hepatocellular carcinoma; mutation; quasispecies; tumorigenicity.
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