Genetic Polymorphisms of Aldehyde Dehydrogenase 2, Cytochrome p450 2E1 for Liver Cancer Risk in HCV Antibody-Positive Japanese Patients and the Variations of CYP2E1 mRNA Expression Levels in the Liver due to its Polymorphism
Hepatocellular carcinoma (HCC) in persons with liver cirrhosis (LC) arises following hepatitis virus infection. Alcohol may accelerate the risk of development of LC and HCC. Cytochrome p450 2E1 (CYP2E1) oxidizes ethanol to form acetaldehyde and aldehyde dehydrogenase 2 (ALDH2) detoxifies acetaldehyde, which is carcinogenic in humans, and both alcohol-metabolizing enzymes show the genetic polymorphisms in a Japanese population.
Using polymorphism analysis, we studied the frequency of ALDH2 functional deletion due to the G to A single-bp mutation in exon 12 and CYP2E1 polymorphism in the transcriptional region, both associated with higher levels of acetaldehyde, in 135 patients with LC and/or HCC, including 99 with HCC, and 135 non-cancer controls. The mRNA expression levels of CYP2E1 in the liver were also examined in 55 surgical specimens.
The allelic frequency of the homozygous ALDH2 2-2 genotype, coding for the enzyme deletion, was significantly higher compared to that of the homozygous or heterozygous ALDH2 1-1 genotypes in cases with HCC (OR = 5.4, 95% CI 2.1-14.0). There were no differences in the frequencies of specific genotypes of CYP2E1 in cases of HCC, but combined analysis of ALDH2 and CYP2E1 revealed that the odds ratio of occurrence of the C1/C1 homozygosity of CYP2E1 and the ALDH2 2-2 homozygosity was as high as 23.0 (2.9-182). The mRNA levels of CYP2E1 were higher in the liver of patients with the C1/C1 homozygosity of CYP2E1 than in those with other genotypes (P < 0.05).
ALDH2 and CYP2E1 polymorphisms may modify the risk of development of HCC against the background of LC in the Japanese. Polymorphism analysis of alcohol-metabolizing enzymes using molecular techniques may be useful in the risk assessment of liver cancer in patients with hepatitis C virus infection.
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) and hepatoblastoma (HB) are malignancies of the liver with different etiologies, but the HB
cell line HepG2 has been frequently used in various studies of HCC. In this study, we compare the protein expression patterns
between HepG2 cells and three HCC cell lines, HKCI-2, HKCI-3, and HKCI-4, respectively. The cell lysates of individual cell
lines were separated by two-dimensional polyacrylamide gel electrophoresis. The protein spots in the gel images were quantified
and compared by image analysis software. The differentially expressing proteins were then identified by tryptic peptide, mass
fingerprinting. Compared with the HepG2 cells, the normalized quantities of 49 and 58 protein spots were found to be at least
twofold higher and twofold lower, respectively, in all three HCC cell lines. The differentially expressed proteins can be
grouped into structural proteins (annexins, transgelin, laminin receptor), stress-induced proteins (HSP27, 60, and 70), enzymes
(aldehyde dehydrogenase, pyruvate kinase, α-enolase, ect.), and transcription factors (far upstream element binding protein
2, GTP-binding nuclear protein RAN). Some of these proteins play important roles in regulating homeostasis, drug resistance,
apoptosis, cell differentiation, cell growth, and metastasis. In conclusion, our proteomic data indicate that there are considerable
differences in the protein expression patterns between HepG2 cells and the HCC cells, suggesting differences in cellular properties.
Hence, HepG2 may not be a good cell line model for studying HCC.
[Show abstract][Hide abstract] ABSTRACT: More than 18 million adults in the United States abuse alcohol, a prevalence 5 times higher than that of hepatitis C. Chronic alcohol use of greater than 80 g/day for more than 10 years increases the risk for hepatocellular carcinoma (HCC) approximately 5-fold; alcohol use of less than 80 g/day is associated with a nonsignificant increased risk for HCC. The risk for HCC in decompensated alcohol induced cirrhosis approaches 1% per year. The risk does not decrease with abstinence, and HCC can occur in a noncirrhotic liver. Alcohol use in chronic hepatitis C doubles the risk for HCC as compared with the risk in hepatitis C alone. Furthermore, there may be synergism between alcohol and hepatitis C in the development of HCC, and in these patients HCC may occur at an earlier age and the HCC may be histologically more advanced. Studies in the United States and Italy suggest that alcohol is the most common cause of HCC (accounting for 32%-45% of HCC). The mechanisms by which alcohol causes HCC are incompletely understood, but may include chromosomal loss, oxidative stress, a decreased retinoic acid level in the liver, altered DNA methylation, and genetic susceptibility. Alcohol use is increasing in many countries, suggesting that alcohol will continue to be a common cause of HCC throughout the world.
[Show abstract][Hide abstract] ABSTRACT: Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC). The host genetic factors that are involved in the development of HCC in patients with HCV infection remain to be investigated. To search for single nucleotide polymorphisms (SNPs) in HCC susceptibility genes, 393 SNPs in 171 candidate genes were examined in 188 Japanese patients with chronic HCV infection, including 77 patients with HCC. HCC-related SNPs were then examined in another 188 patients (including 93 patients with HCC) with chronic HCV infection. Haplotype analyses of HCC-related genes were performed in a total of 376 patients. Of the 393 SNPs, 31 SNPs in 29 genes were significantly associated with HCC based on an initial screening (P < .05). Of these 31 SNPs, 3 SNPs of 3 genes (SCYB14, GFRA1, and CRHR2) were significantly associated with HCC in a secondary screening. Haplotype analyses of these 3 genes identified 2 haplotype blocks associated with HCC. In conclusion, these SNPs and haplotypes located in the SCBY14, CRHR2, and GFRA1 genes will be used as markers to identify a subgroup of Japanese patients with chronic HCV infection who are at high risk of developing HCC.
Kali Zhou, Fengyu Hu, Charles Wang, Min Xu, Yun Lan, Jamie P. Morano, Stanley M. Lemon, Joseph D. Tucker, Weiping Cai
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