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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.

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Abbreviations

RTK:

receptor tyrosine kinase

FGF:

fibroblast growth factor

Spry2:

Sprouty 2

CaP:

cancer of the prostate

BPH:

benign prostatic hyperplasia

5-Aza-dCR:

5-aza-2′-deoxycytidine

RT–PCR:

reverse transcriptase–polymerase chain reaction

MSP:

methylation-specific PCR

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Acknowledgements

We are grateful to Mark Houseman for technical assistance. Dr Wei Ding and Dr D Warburton for the Sprouty2-luciferase promoter constructs. The work was funded by grants from DOH, CRUK and MRC (Grant no. G0100100/64424) and the Newcastle-Upon-Tyne Hospitals NHS charity (grant no. TRC108).

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Correspondence to Hing Y Leung.

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McKie, A., Douglas, D., Olijslagers, S. et al. Epigenetic inactivation of the human sprouty2 (hSPRY2) homologue in prostate cancer. Oncogene 24, 2166–2174 (2005). https://doi.org/10.1038/sj.onc.1208371

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