title: Epigenetic inactivation of the human sprouty2 (hSPRY2) homologue in prostate cancer.
abstract: Abnormal signalling events mediated by receptor tyrosine kinases (RTKs) contribute to human carcinogenesis. Sprouty2 (Spry2) is a key antagonistic regulator of RTK signalling and suppression of its expression or function may facilitate proliferation and angiogenesis. Using prostate cancer (CaP) as a model, we investigated the significance of Spry2 in human malignancy. We observed downregulated Spry2 expression in invasive CaP cell lines and high-grade clinical CaP (compared to benign prostatic hyperplasia (BPH) and well-differentiated tumours, P=0.041). A large CpG island is associated with hSPRY2, and extensive hypermethylation of this CpG island was observed in 76-82% of high-grade CaP, while control BPH tissues were predominantly unmethylated (P=0.0005). Furthermore, suppressed Spry2 expression correlated with methylation of the CpG region in clinical samples (P=0.004) and treatment with 5-aza-2'-deoxycytidine reactivated Spry2 expression in LNCaP and PC-3M cells. hSPRY2 maps to the long arm of chromosome 13 (13q31.1), where loss of heterozygosity (LOH) has been reported. We found no evidence of mutation; however, we demonstrated 27-40% LOH using flanking markers to hSPRY2. Hence, while biallelic epigenetic inactivation of hSPRY2 represents the main genetic event in prostate carcinogenesis, the observed 27-40% LOH presents evidence of hemizygous deletion with the remaining allele hypermethylated. We therefore propose hSPRY2 as a potential tumour suppressor locus in CaP.
authors.affiliation: Urology Research Group, Northern Institute for Cancer Research, The Medical School, University of Newcastle, Newcastle upon Tyne NE2 4AD, UK.
authors.forename: Arthur B
authors.initials: AB
authors.lastname: McKie
authors.forename: David A
authors.initials: DA
authors.lastname: Douglas
authors.forename: Sharon
authors.initials: S
authors.lastname: Olijslagers
authors.forename: Julia
authors.initials: J
authors.lastname: Graham
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Omar
authors.forename: Rakesh
authors.initials: R
authors.lastname: Heer
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Gnanapragasam
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
authors.forename: Hing Y
authors.initials: HY
authors.lastname: Leung
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D002893:Chromosomes, Human, Pair 3; D019175:DNA Methylation; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019656:Loss of Heterozygosity; D008297:Male; D008565:Membrane Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics*; D011506:Proteins / Q000235:genetics*
chemical_list: D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011506:Proteins; C485561:SPRY2 protein, human