title: Epigenetic regulation of Wnt signaling pathway in urological cancer.
abstract: Constitutive activation of the Wnt signaling pathway is a common feature of solid tumors and contributes to uncontrolled cell-growth and impaired differentiation. We hypothesized that gene silencing mediated through aberrant promoter methylation of upstream Wnt antagonist genes might result in beta-catenin accumulation, resulting in constitutive Wnt activation. Wnt antagonist genes (SFRP1, WIF1, APC and CDH1) and CTNNB1 promoter methylation was examined in genomic DNA extracted from 12 urological cancer cell lines and correlated with CTNNB1 mRNA expression. Promoter methylation status was then assessed in 36 BCa, 30 PCa, 31 RCT, and normal bladder mucosa (15), prostate (10) and renal (5) tissue samples. Finally, CTNNB1 mRNA relative expression levels were correlated with Wnt antagonist gene methylation status in RCT. Methylation was found in at least one Wnt antagonist gene and the CTNNB1 promoter was unmethylated in all cancer cell lines tested. When gene methylation levels were compared between cancer cell lines with high and low CTNNB1 mRNA expression, a trend was found for increased CDH1 promoter methylation levels in the former. BCa and PC a tumors demonstrated high frequency of promoter methylation at all tested genes. In RCT, CTNNB1 was unmethylated in all cases and the overall frequency of promoter methylation at the remainder genes was lower. Interestingly, median CTNNB1 mRNA expression levels were significantly higher in RCTs methylated in at least one Wnt antagonist gene promoter. We concluded that epigenetic deregulation of Wnt pathway inhibitors may contribute to aberrant activation of Wnt signaling pathway in bladder, prostate and renal tumors.
authors.affiliation: Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute at Porto, Porto, Portugal.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Costa
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.forename: Franclim R
authors.initials: FR
authors.lastname: Ribeiro
authors.forename: João R
authors.initials: JR
authors.lastname: Carvalho
authors.forename: Jorge
authors.initials: J
authors.lastname: Oliveira
authors.forename: Francisco
authors.initials: F
authors.lastname: Lobo
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014571:Urologic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin