Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma
Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma
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DOI：
10.1038/sj.onc.1209200
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发表时间：
2006-03-01
期刊：
影响因子：
8
通讯作者：
Shuin, T
中科院分区：
文献类型：
--
作者：
Okuda, H;Toyota, M;Shuin, T
表观遗传学改变如DNA甲基化和由此导致的癌症相关基因的失活通常有助于各种癌症的发展。为了鉴定肾细胞癌（RCC）中异常甲基化沉默的基因，我们对两个RCC系进行甲基化CpG岛扩增/代表性差异分析。这鉴定了27个CpG岛。联合亚硫酸氢盐限制性分析显示，这些CpG岛在原发性肾细胞癌的情况下，四个甲基化的肿瘤特异性的方式。其中一个被鉴定为人类同源盒基因B13（HOXB 13）基因，但其余三个CpG岛与已知基因无关。原发性RCC样品和细胞系中HOXB 13的甲基化频率分别为30%和73%。HOXB 13的甲基化状态与其在RCC系和原发肿瘤中表达的丧失相关，甲基转移酶抑制剂治疗诱导其表达的恢复。在缺乏内源性HOXB 13表达的RCC细胞中外源性表达HOXB 13抑制集落形成并诱导凋亡特征。HOXB 13甲基化与肿瘤分级和微血管浸润呈正相关。这些结果表明HOXB 13是一个新的候选肿瘤抑制基因，其失活可能在RCC肿瘤的发生和发展中起重要作用。
Epigenetic alterations like DNA methylation and the resulting inactivation of cancer-related genes often contribute to the development of various cancers. To identify the genes that are silenced by aberrant methylation in renal cell carcinoma (RCC), we subjected two RCC lines to methylated CpG island amplification/representational difference analysis. This identified 27 CpG islands. Combined bisulfite restriction analysis of these CpG islands in primary RCC cases revealed that four were methylated in a tumor-specific manner. One of these was identified as the human homeo-box gene B13 (HOXB13) gene, but the remaining three CpG islands were not associated with known genes. The methylation frequencies of HOXB13 in primary RCC samples and lines were 30 and 73%, respectively. The methylation status of HOXB13 correlated with the loss of its expression both in RCC lines and primary tumors, and methyltransferase inhibitor treatment induced the recovery of its expression. Exogenous expression of HOXB13 in RCC cells that lacked endogenous HOXB13 expression suppressed colony formation and induced apoptotic features. Furthermore, HOXB13 methylation correlated positively with tumor grade and microvessel invasion. These results suggest that HOXB13 is a novel candidate tumor suppressor gene in RCC and that its inactivation may play an important role in both RCC tumorigenesis and progression.