Epigenetic inactivation of the human sprouty2 (hSPRY2) homologue in prostate cancer.
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.
McKie
Arthur B
AB
Urology Research Group, Northern Institute for Cancer Research, The Medical School, University of Newcastle, Newcastle upon Tyne NE2 4AD, UK.
Douglas
David A
DA
Olijslagers
Sharon
S
Graham
Julia
J
Omar
Mahmoud M
MM
Heer
Rakesh
R
Gnanapragasam
Vincent J
VJ
Robson
Craig N
CN
Leung
Hing Y
HY
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*
D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011506:Proteins; C485561:SPRY2 protein, human