McKie Arthur B, Douglas David A, Olijslagers Sharon, Graham Julia, Omar Mahmoud M, Heer Rakesh, Gnanapragasam Vincent J, Robson Craig N, Leung Hing Y
Urology Research Group, Northern Institute for Cancer Research, The Medical School, University of Newcastle, Newcastle upon Tyne NE2 4AD, UK.
Oncogene. 2005 Mar 24;24(13):2166-74. doi: 10.1038/sj.onc.1208371.
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.
受体酪氨酸激酶（RTK）介导的异常信号转导事件与人类癌症发生相关。Sprouty2（Spry2）是RTK信号转导的关键拮抗调节因子，抑制其表达或功能可能会促进细胞增殖和血管生成。我们以前列腺癌（CaP）为模型，研究了Spry2在人类恶性肿瘤中的意义。我们观察到侵袭性CaP细胞系和高级别临床CaP中Spry2表达下调（与良性前列腺增生（BPH）和高分化肿瘤相比，P = 0.041）。一个大的CpG岛与hSPRY2相关，在76 - 82%的高级别CaP中观察到该CpG岛广泛高甲基化，而对照BPH组织主要为未甲基化（P = 0.0005）。此外，临床样本中Spry2表达受抑制与CpG区域甲基化相关（P = 0.004），用5 - 氮杂 - 2'-脱氧胞苷处理可使LNCaP和PC - 3M细胞中Spry2表达重新激活。hSPRY2定位于13号染色体长臂（13q31.1），该区域已有杂合性缺失（LOH）的报道。我们未发现突变证据；然而，我们使用hSPRY2侧翼标记证明存在27 - 40%的LOH。因此，虽然hSPRY2的双等位基因表观遗传失活是前列腺癌发生中的主要遗传事件，但观察到的27 - 40%的LOH表明存在半合子缺失，其余等位基因发生高甲基化。我们因此提出hSPRY2是CaP中一个潜在的肿瘤抑制基因座。
