Nucleotide changes related to hepatocellular carcinoma in the enhancer 1/x-promoter of hepatitis B virus subgenotype C2 in cirrhotic patients.
Hepatocellular carcinoma (HCC) is widely known to develop more frequently in cirrhotic patients with a high expression of Hepatitis B virus X protein (HBx), which is controlled by the enhancer 1 (Enh1)/X-promoter. To examine the effect of the mutations in the Enh1/X-promoter region in hepatitis B virus (HBV) genomes on the development of HCC, we investigated the differences in HBV isolated from cirrhotic patients with or without HCC along with the promoter activities of certain specific mutations within the Enh1/X-promoter. We examined 160 hepatitis B surface antigen (HBsAg)-positive cirrhotic patients (80 HCC patients, 80 non-HCC patients) by evaluating the biochemical, virological, and molecular characteristics. We evaluated the functional differences in certain specific mutations within the Enh1/X-promoter. The isolated sequences included all of the subgenotypes C2. The sites that showed higher mutation rates in the HCC group were G1053A and G1229A, which were found to be independent risk factors through multiple logistic analysis (P < 0.05). Their promoter activities were elevated 2.38- and 4.68-fold, respectively, over that of the wild type in the HepG2 cells. Similarly, both the mRNA and protein levels of HBx in these two mutants were much higher than that in wild type-transfected HepG2 cells. Mutated nucleotides of the Enh1/X-promoter, especially G1053A and G1229A mutations in the HBV subgenotype C2 of patients with cirrhosis, can be risk factors for hepatocarcinogenesis, and this might be due to an increase in the HBx levels through the transactivation of the Enh1/X-promoter.
Cho
Eun-Young
EY
Departments of Internal Medicine, Wonkwang University, Iksan, Korea.
Kim
Haak-Cheoul
HC
Choi
Chang-Soo
CS
Shin
Sae Ron
SR
Park
Channy
C
So
Hong-Seob
HS
Kim
Hyung Jin
HJ
Park
Raekil
R
Cho
Ji Hyun
JH
Moon
Hyung Bae
HB
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D004742:Enhancer Elements, Genetic; D005260:Female; D005838:Genotype; D006801:Humans; D008103:Liver Cirrhosis / Q000821:virology*; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins
D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein