title: Prognostic value of opioid binding protein/cell adhesion molecule-like promoter methylation in bladder carcinoma.
abstract: The OPCML gene (opioid binding protein/cell adhesion molecule-like), a putative tumour suppressor gene, is frequently inactivated in carcinomas, namely through aberrant promoter methylation. Herein, we aimed to determine whether OPCML altered expression mediated by epigenetic mechanisms was implicated in bladder carcinogenesis and to assess its potential as a bladder cancer epi-marker. OPCML promoter methylation levels from 91 samples of bladder urothelial carcinoma, 25 normal bladder tissues and bladder cancer cell lines were assessed by quantitative methylation-specific polymerase chain reaction, and correlated with OPCML mRNA expression, determined by quantitative reverse-transcription polymerase chain reaction. To prove the epigenetic regulation of OPCML, five bladder cancer cell lines were exposed to 5-aza-2'deoxycytidine (5-aza-dC), a specific DNA methyltransferase inhibitor and trichostatin A (TSA), a histone deacetylase inhibitor. In bladder tumours, the overall frequency of methylation was 60% and methylation levels were significantly higher when compared with normal mucosa (P=0.0001). No correlation was found between methylation levels and clinicopathological parameters. Interestingly, OPCML promoter methylation was associated with worse disease-specific survival (P=0.022) in univariate analysis. Furthermore, a significant inverse correlation between OPCML promoter methylation and mRNA expression levels was found, although a significant re-expression was only achieved when 5-aza-dC and TSA were used simultaneously. The high frequency of OPCML promoter methylation in urothelial carcinomas suggests an important role for this epigenetic alteration in bladder carcinogenesis, highlighting its potential as an epigenetic biomarker for bladder urothelial carcinoma with prognostic significance.
authors.affiliation: Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Duarte-Pereira
authors.forename: Filipa
authors.initials: F
authors.lastname: Paiva
authors.forename: Vera Lúcia
authors.initials: VL
authors.lastname: Costa
authors.forename: João
authors.initials: J
authors.lastname: Ramalho-Carvalho
authors.forename: Joana
authors.initials: J
authors.lastname: Savva-Bordalo
authors.forename: Angelo
authors.initials: A
authors.lastname: Rodrigues
authors.forename: Franclim Ricardo
authors.initials: FR
authors.lastname: Ribeiro
authors.forename: Vitor M
authors.initials: VM
authors.lastname: Silva
authors.forename: Jorge
authors.initials: J
authors.lastname: Oliveira
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C059785:OPCML protein, human