title: Methylation of Tip30 promoter is associated with poor prognosis in human hepatocellular carcinoma.
abstract: 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.
authors.affiliation: International Cancer Institute and Eastern Hospital of Hepatobiliary Surgery, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.forename: Yunchao
authors.initials: Y
authors.lastname: Ma
authors.forename: Guobin
authors.initials: G
authors.lastname: Wu
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.forename: Huaizu
authors.initials: H
authors.lastname: Guo
authors.forename: Anmin
authors.initials: A
authors.lastname: Liang
authors.forename: Wenming
authors.initials: W
authors.lastname: Cong
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: 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*
chemical_list: D014157:Transcription Factors; D000123:Acetyltransferases; C111246:HTATIP2 protein, human