Abstract
Hepatitis B virus (HBV) infection highly increases the risk for liver cirrhosis and hepatocellular carcinoma (HCC). The clinical manifestation of HBV infection is determined by the mutual interplay of the viral genotype, host genetic factors, mode of transmission, adaptive mutations, and environmental factors. Core promoter activation plays a critical role in the pre-genomic RNA transcription of HBV for HBV replication. The mutations of core promoter have been implicated in HCC development. We had obtained HBV genes from Myanmar HBV infectants and identified gene variations at the core promoter region. For measuring the relative transactivation activity on core promoter, we prepared the core-promoter reporter construct. Both of A1762T and G1764A mutation were consistently found in the HBV genes with hepatocellular carcinoma. The A1762T/G1764A mutation was corresponding to K130M/V131I of HBx protein. We prepared the core promoter-luciferase reporter construct containing the double A1762T/G1764A mutation and the K130M/V131I HBx protein expression construct. The A1762T/G1764A mutation highly was responsive to core promoter transactivation by HBx, regardless of HBx mutation. The A1762T/G1764A mutation newly created hepatocyte nuclear factor 1 (HNF1) responsive element. Ectopic expression of HNF1 largely increased the HBV core promoter containing A1762T/G1764A mutation. In addition, hepatic rich fatty acid, palmitic acid and oleic acid, increased K130M/V131I HBx level by core promoter activation. These results provide biological properties and clinical significance of specific HBV core promoter mutants related with HCC development.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Alonso, S., Guerra, A.R., Carreira, L., Ferrer, J.Á., Gutiérrez, M.L., and Fernandez-Rodriguez, C.M. 2017. Upcoming pharmacological developments in chronic hepatitis B: can we glimpse a cure on the horizon?. BMC Gastroenterol., 17, 168.
Bouchard, M.J. and Schneider, R.J. 2004. The enigmatic X gene of hepatitis B virus. J. Virol., 78, 12725–12734.
Cho, H.K., Kim, S.Y., Yoo, S.K., Choi, Y.H., and Cheong, J. 2014. Fatty acids increase hepatitis B virus X protein stabilization and HBxinduced inflammatory gene expression. FEBS J., 281, 2228–2239.
Choi, J.W., Ahn, S.H., Park, J.Y., Chang, H.Y., Kim, J.K., Baatarkhuu, O., Kim, D.Y., Han, K.H., and Chon, C.Y. 2009. Hepatitis B e antigen-negative mutations in the precore and core promoter regions in Korean patients. J. Med. Virol., 81, 594–601.
Faguer, S., Mayeur, N., Casemayou, A., Pageaud, A.L., Courtellemont, C., Cartery, C., Fournie, G.J., Schanstra, J.P., Tack, I., Bascands, J.L., et al. 2013. Hnf-1β transcription factor is an early Hif-1±-independent marker of epithelial hypoxia and controls renal repair. PLoS ONE, 8, e63585.
Gustafsson, M.V., Zheng, X., Pereira, T., Gradin, K., Jin, S., Lundkvist, J., Ruas, J.L., Poellinger, L., Lendahl, U., and Bondesson, M. 2005. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev. Cell, 9, 617–628.
Hadziyannis, E. and Laras, A. 2018. Viral biomarkers in chronic HBeAg negative HBV infection. Genes, 9, 469.
Jiang, Z.H., Chen, Q.Y., Harrison, T.J., Li, G.J., Wang, X.Y., Li, H., Hu, L.P., Li, K.W., Yang, Q.L., Tan, C., et al. 2016. Hepatitis B virus core promoter double mutations (A1762T, G1764A) are associated with lower levels of serum dihydrolipoyl dehydrogenase. Intervirology, 59, 1–7.
Kao, J.H. and Chen, D.S. 2002. Global control of hepatitis B virus infection. Lancet Infect. Dis., 2, 395–403.
Karayiannis, P. 2017. Hepatitis B virus: virology, molecular biology, life cycle and intrahepatic spread. Hepatol. Int., 11, 500–508.
Kim, D.H., Kang, H.S., and Kim, K.H. 2016. Roles of hepatocyte nuclear factors in hepatitis B virus infection. World J. Gastroenterol., 22, 7017–7029.
Lamontagne, R.J., Bagga, S., and Bouchard, M.J. 2016. Hepatitis B virus molecular biology and pathogenesis. Hepatoma Res., 2, 163–186.
Lau, K.C.K., Joshi, S.S., Mahoney, D.J., Mason, A.L., van Marle, G., Osiowy, C., and Coffin, C.S. 2020. Differences in HBV replication, APOBEC3 family expression, and inflammatory cytokine levels between wild-type HBV and pre-core (G1896A) or basal core promoter (A1762T/G1764A) mutants. Front. Microbiol., 11, 1653.
Li, J., Xu, Z., Zheng, Y., Johnson, D.L., and Ou, J.H. 2002. Regulation of hepatocyte nuclear factor 1 activity by wild-type and mutant hepatitis B virus X proteins. J. Virol., 76, 5875–5881.
Madden, C.R., Finegold, M.J., and Slagle, B.L. 2001. Hepatitis B virus X protein acts as a tumor promoter in development of diethylnitrosamine induced preneoplastic lesions. J. Virol., 75, 3851–3858.
MacLachlan, J.H. and Cowie, B.C. 2015. Hepatitis B virus epidemiology. Cold Spring Harb. Perspect. Med., 5, a021410.
Marignol, L., Coffey, M., Lawler, M., and Hollywood, D. 2008. Hypoxia in prostate cancer: a powerful shield against tumour destruction?. Cancer Treat. Rev., 34, 313–327.
Marusawa, H., Matsuzawa, S., Welsh, K., Zou, H., Armstrong, R., Tamm, I., and Reed, J.C. 2003. HBXIP functions as a cofactor of survivin in apoptosis suppression. EMBO J., 22, 2729–2740.
Mirandola, S., Sebastiani, G., Rossi, C., Velo, E., Erne, E.M., Vario, A., Tempesta, D., Romualdi, C., Campagnolo, D., and Alberti, A. 2012. Genotype-specific mutations in the polymerase gene of hepatitis B virus potentially associated with resistance to oral antiviral therapy. Antiviral Res., 96, 422–429.
Ohsaki, E., Suwanmanee, Y., and Ueda, D. 2021. Chronic hepatitis B treatment strategies using polymerase inhibitor-based combination therapy. Viruses, 13, 1691.
Quarleri, J. 2014. Core promoter: a critical region where the hepatitis B virus makes decisions. World J. Gastroenterol., 20, 425–435.
Reese, V.C., Ondracek, C.R., Rushing, C.N., Li, L., Oropeza, C.E., and McLachlan, A. 2011. Multiple nuclear receptors may regulate hepatitis B virus biosynthesis during development. Int. J. Biochem. Cell Biol., 43, 230–237.
Schweitzer, A., Horn, J., Mikolajczyk, R.T., Krause, G., and Ott, J.J. 2015. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet, 386, 1546–1555.
Tang, H. and McLachlan, A. 2001. Transcriptional regulation of hepatitis B virus by nuclear hormone receptors is a critical determinant of viral tropism. Proc. Natl. Acad. Sci. USA, 98, 1841–1846.
Tong, S., Li, J., Wands, J.R., and Wen, Y.M. 2013. Hepatitis B virus genetic variants: biological properties and clinical implications. Emerg. Microbes Infect., 2, e10.
Zheng, Y., Li, J., and Ou, J.H. 2004. Regulation of hepatitis B virus core promoter by transcription factors HNF1 and HNF4 and the viral X protein. J. Virol., 78, 6908–6914.
Zhong, H., De Marzo, A.M., Laughner, E., Lim, M., Hilton, D.A., Zagzag, D., Buechler, P., Isaacs, W.B., Semenza, G.L., and Simons, J.W. 1999. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res., 59, 5830–5835.
Zhou, Z., Xu, M.J., and Gao, B. 2016. Hepatocytes: a key cell type for innate immunity. Cell. Mol. Immunol., 13, 301–315.
Acknowledgements
This research was supported by PNU-RENovation (2020–2021).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
This study was approved by Ethics Review Committee of Department of Medical Research. The approval number is 22/ Ethics 2015, dated 25.3.2015. Informed consent was obtained from the study participants who were at or more than 16 years and from the parents/guardians of the study participants who were under 16 years.
Additional information
Conflict of Interest
The authors declare no conflicts of interest.
Rights and permissions
About this article
Cite this article
Seong, M.S., Hwang, H.J., Jang, E.A. et al. Core promoter mutation of nucleotides A1762T and G1764A of hepatitis B virus increases core promoter transactivation by hepatocyte nuclear factor 1. J Microbiol. 60, 1039–1047 (2022). https://doi.org/10.1007/s12275-022-1675-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12275-022-1675-1