RESUMO
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.
Assuntos
Cromossomos Humanos Par 3 , Genes Supressores de Tumor , Perda de Heterozigosidade , Neoplasias da Próstata/genética , Proteínas/genética , Sequência de Bases , Linhagem Celular Tumoral , Metilação de DNA , Primers do DNA , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana , Regiões Promotoras Genéticas/genéticaRESUMO
Prostate cancer is the most common cancer amongst men in the USA and the second most common malignant cause of male death worldwide after lung cancer. The life time risk of having microscopic evidence of prostate cancer for a 50 year old man is 42%. Prostate cancer is thus becoming an increasingly significant global health problem in terms of mortality, morbidity, as well as economically. This review, discusses current medical therapeutic options for prostate cancer including traditional treatments using luteinising hormone releasing analogues (LHRH), anti-androgens and estrogen treatments, and the use of novel drugs directed against molecular targets considered important in oncogenesis and metastasis. Prostate cancer chemoprevention using 5alpha-reductase inhibitors and the role of gene therapy are also considered.