Silencing of Hint1, a novel tumor suppressor gene, by promoter hypermethylation in hepatocellular carcinoma.
The Hint1 protein, a member of the histidine triad (HIT) family, is highly conserved in diverse species and ubiquitously expressed in mammalian tissues. Previous studies in mice provided evidence that Hint1 may be haploinsufficient with respect to its function as a tumor suppressor. In the present study, we investigated the aberrant methylation of Hint1 and explored possible relationships between aberrant methylation and clinicopathological features in hepatocellular carcinoma (HCC). Hypermethylation of Hint1 was evaluated by the methylation specific PCR (MSP) method in 40 patients with HCC (tumor and paired adjacent non-tumor tissues) from Taiwan, 22 cases of normal liver tissue (14 from Taiwan and 8 from the US). HINT1 expression in tissues was detected by immunohistochemistry. The frequencies of hypermethylation of Hint1 in tumor, paired adjacent non-tumor and normal liver tissue were 55.0%, 37.5% and 9.1%, respectively. A statistically significant inverse association was found between Hint1 methylation status and expression of the HINT1 protein in tumor tissues (p=0.003). The relationship between Hint1 methylation status and clinical features and other, previously measured biomarkers was also analyzed. p16 hypermethylation was statistically significantly associated with Hint1 methylation status (p=0.035). There were no correlations between Hint1 methylation and hepatitis B (HBV) or hepatitis C (HCV) infection status or aflatoxin B(1) (AFB(1)-) and polycyclic aromatic hydrocarbons (PAHs)-DNA adduct levels. These results suggest that promoter hypermethylation of Hint1 may play a role in hepatocarcinogenesis.
Zhang
Yu-Jing
YJ
Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, 630 W. 168th St., New York, NY 10032, USA. yz6@columbia.edu
Li
Haiyang
H
Wu
Hui-Chen
HC
Shen
Jing
J
Wang
Lin
L
Yu
Ming-Whei
MW
Lee
Po-Huang
PH
Bernard Weinstein
I
I
Santella
Regina M
RM
D000328:Adult; D000368:Aged; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D019175:DNA Methylation; D017931:DNA Primers; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
D017931:DNA Primers; C063306:HINT1 protein, human; D009419:Nerve Tissue Proteins