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Lookup NU author(s): Dr Arthur Mckie,
Dr Sharon Olijslagers,
Professor Rakesh Heer,
Professor Craig Robson,
Professor Hing Leung
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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.
Author(s): McKie AB, Douglas DA, Olijslagers S, Graham J, Omar MM, Heer R, Gnanapragasam VJ, Robson CN, Leung HY
Publication type: Article
Publication status: Published
ISSN (print): 0950-9232
ISSN (electronic): 1476-5594
Publisher: Nature Publishing Group
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