Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas
Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas
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DOI：
10.1158/0008-5472.can-06-0157
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Ushijima, Toshikazu
中科院分区：
文献类型：
--
作者：
Furuta, Junichi;Nobeyama, Yoshimasa;Ushijima, Toshikazu
启动子CpG岛（CGI）的异常甲基化与肿瘤抑制基因的沉默有关，也是一种潜在的癌症生物标志物。在这里，为了识别在人类黑色素瘤中异常甲基化的cgi，我们使用甲基化敏感的代表性差异分析进行了全基因组搜索。34个基因（ABHD9、BARHL1、CLIC5、CNNM1、COL2A1、CPT1C、DDIT4L、DERL3、DHRS3、DPYS、EFEMP2、FAM62C、FAM78A、FLJ33790、GBX2、GPR10、GPRASP1、HOXA9、HOXD11、HOXD12、HOXD13、p14ARF、PAX6、PRDX2、PTPBG、RASD1、RAX、REC8L1、SLC27A3、TGFB2、TLX2、TMEM22、dm - em30b和UNC5C）的启动子区域的CGIs在13个黑色素瘤细胞系中至少1个中被甲基化，但在2个培养的正常黑色素细胞中未被甲基化。在这些基因中，过氧化氧还蛋白2 （PRDX2）在正常黑素细胞中表达，在甲基化的黑素瘤中表达缺失。用去甲基化剂5-aza-2 '-脱氧胞苷治疗黑色素瘤后，这种表达的丧失得以恢复。在手术黑色素瘤标本中，36例中有3例（8%）检测到PRDX2甲基化。此外，PRDX2的免疫组织化学分析显示，免疫反应性的消失往往与其甲基化有关。最近有报道称PRDX2是血小板衍生生长因子信号传导的负调控因子，其沉默可能与黑色素瘤有关。另一方面，在13个黑色素瘤细胞系中，有12个cgi在>= 9中被甲基化，被认为是候选的黑色素瘤生物标志物。
Aberrant methylation of promoter CpG islands (CGI) is involved in silencing of tumor suppressor genes and is also a potential cancer biomarker. Here, to identify CGIs aberrantly methylated in human melanomas, we did a genome-wide search using methylation-sensitive representational difference analysis. CGIs in putative promoter regions of 34 genes (ABHD9, BARHL1, CLIC5, CNNM1, COL2A1, CPT1C, DDIT4L DERL3 DHRS3 DPYS EFEMP2 FAM62C FAM78A, FLJ33790, GBX2, GPR10, GPRASP1, HOXA9, HOXD11, HOXD12, HOXD13, p14ARF, PAX6, PRDX2, PTPBG, RASD1, RAX, REC8L1, SLC27A3, TGFB2, TLX2, TMEM22, TM-EM30B, and UNC5C) were found to be methylated in at least 1 of 13 melanoma cell lines but not in two cultured normal melanocytes. Among these genes, Peroxiredoxin 2 (PRDX2) was expressed in normal melanocytes, and its expression was lost in melanomas with methylation. The loss of expression was restored by treatment of melanomas with a demethylating agent 5-aza-2 '-deoxycytidine. In surgical melanoma specimens, methylation of PRDX2 was detected in 3 of 36 (8%). Furthermore, immunohistochemical analysis of PRDX2 showed that disappearance of immunoreactivity tends to associate with its methylation. PRDX2 was recently reported to be a negative regulator of platelet-derived growth factor signaling, and its silencing was suggested to be involved in melanomas. On the other hand, 12 CGIs were methylated in >= 9 of the 13 melanoma cell lines and are considered as candidate melanoma biomarkers.