Methylation of Tip30 promoter is associated with poor prognosis in human hepatocellular carcinoma.
OBJECTIVE
To investigate Tip30 promoter methylation status in human hepatocellular carcinoma (HCC) and the correlation with clinicopathologic features and prognosis.


METHODS
The methylation status of CpG islands in Tip30 promoter was examined in 15 HCC cell lines as well as 59 paired HCC and adjacent nontumor tissues. The associations between Tip30 methylation status and the survival of patients were analyzed.


RESULTS
Tip30 promoter was hypermethylated in 6 of 10 HCC cell lines with reduced Tip30 mRNA. DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, greatly enhanced TIP30 expression and sensitized HCC cells to cytotoxic drug-induced cell death. The promoter region of Tip30 was identified and the main promoter activity was located in the -135 to -45 region sited within a CpG island. The minimal promoter element contained four Sp1 binding sites, which were hypermethylated in HCC cell-derived promoters. Moreover, analyses of Tip30 promoter methylation status in 59 paired HCC tissues showed that 47% of the cases were hypermethylated. Recurrence rate (95% versus 67%; P = 0.011) and mortality (82% versus 53%; P = 0.033) were significantly higher in patients with methylated Tip30. Disease-free survival was significantly higher in patients with unmethylated Tip30 (33.3% versus 4.5%; P = 0.036).


CONCLUSIONS
Our results show that epigenetic silencing of Tip30 gene expression by CpG island DNA hypermethylation is associated with poor prognosis in patients with HCC.
Lu
Bin
B
International Cancer Institute and Eastern Hospital of Hepatobiliary Surgery, Second Military Medical University, Shanghai, People's Republic of China.
Ma
Yunchao
Y
Wu
Guobin
G
Tong
Xin
X
Guo
Huaizu
H
Liang
Anmin
A
Cong
Wenming
W
Liu
Chang
C
Wang
Hao
H
Wu
Mengchao
M
Zhao
Jian
J
Guo
Yajun
Y
D000123:Acetyltransferases / Q000235:genetics*; D000368:Aged; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*
D014157:Transcription Factors; D000123:Acetyltransferases; C111246:HTATIP2 protein, human