Title |
Core promoter mutation of nucleotides A1762T and G1764A of hepatitis B virus increases core promoter transactivation by hepatocyte nuclear factor 1 |
Author |
Mi So Seong1, Hyeon Jeong Hwang1, Eun Ah Jang1, Jeong Ah Jang1, Wah Wah Aung2, Yi Yi Kyaw2, and JaeHun Cheong1* |
Address |
1Department of Molecular Biology, Pusan National University, Busan 46241, Republic of Korea, 2Advanced Molecular Research Centre, Department of Medical Research, Yangon 11191, Republic of Union of Myanmar |
Bibliography |
Journal of Microbiology, 60(10),1039-1047, 2022,
|
DOI |
10.1007/s12275-022-1675-1
|
Key Words |
HBV, HBV core promoter, HBx, virus mutation,
HNF1 |
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. |