Lou W, Krill D, Dhir R, Becich M J, Dong J T, Frierson H F, Isaacs W B, Isaacs J T, Gao A C
Department of Pathology and Cancer Institute, University of Pittsburgh Medical Center, Pennsylvania 15213, USA.
Cancer Res. 1999 May 15;59(10):2329-31.
Previous studies demonstrated that CD44 is a metastasis suppressor gene for prostate cancer and that the expression of CD44 both at mRNA and protein levels is down-regulated during prostate cancer progression, with down-regulation being correlated with higher tumor grade, aneuploidy, and distant metastasis. In this study, we evaluated DNA hypermethylation as a potential mechanism accompanying this decreased CD44 expression in human prostate cancer. Nucleotide sequence analysis revealed a CpG island in the CD44 transcriptional regulatory region. We found that cytosine methylation of CD44 promoter occurs in CD44-negative prostate cancer cell line (i.e., LNCaP) but not in prostate cancer cell lines (i.e., TSU, PC3, and DU145) expressing this gene. In addition, we examined methylation status of CD44 in 84 matched normal and cancer prostate specimens. Hypermethylation of the 5' CpG island of CD44 gene was observed in 31 of 40 primary prostate cancer specimens, 3 of 4 distant organ site metastases obtained at autopsy from men who died of prostate cancer, and 4 of the 40 matched normal tissues. These results demonstrated that methylation of the 5' CpG island of CD44 gene is closely associated with transcriptional inactivation, resulting in a decreased expression of CD44 in human prostate cancer.
先前的研究表明，CD44是前列腺癌的转移抑制基因，在前列腺癌进展过程中，CD44在mRNA和蛋白质水平的表达均下调，这种下调与更高的肿瘤分级、非整倍体和远处转移相关。在本研究中，我们评估了DNA高甲基化作为人类前列腺癌中CD44表达降低的潜在机制。核苷酸序列分析揭示了CD44转录调控区域存在一个CpG岛。我们发现，CD44启动子的胞嘧啶甲基化发生在CD44阴性的前列腺癌细胞系（即LNCaP）中，而在表达该基因的前列腺癌细胞系（即TSU、PC3和DU145）中未发生。此外，我们检测了84对匹配的正常和癌性前列腺标本中CD44的甲基化状态。在40例原发性前列腺癌标本中的31例、4例死于前列腺癌的男性尸检获得的远处器官转移灶中的3例以及40例匹配的正常组织中的4例中，观察到CD44基因5' CpG岛的高甲基化。这些结果表明，CD44基因5' CpG岛的甲基化与转录失活密切相关，导致人类前列腺癌中CD44表达降低。
