Aberrant methylation of the 8p22 tumor suppressor gene DLC1 in renal cell carcinoma
Aberrant methylation of the 8p22 tumor suppressor gene DLC1 in renal cell carcinoma
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肾细胞癌中 8p22 抑癌基因 DLC1 的异常甲基化
DOI：
10.1016/j.canlet.2006.08.019
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发表时间：
2007-05-08
期刊：
影响因子：
9.7
通讯作者：
Jin, Jie
中科院分区：
文献类型：
--
作者：
Zhang, Qlan;Ying, Jianming;Jin, Jie
包括DNA甲基化和染色质重塑在内的表观遗传机制在包括肾细胞癌（RCC）在内的各种恶性肿瘤中沉默肿瘤抑制基因（TSG）是重要的。DLC1（在肝癌1中缺失）/ARHGAP7是最近发现的8p22候选TSG。DLC1启动子频繁甲基化导致基因沉默已在几种肿瘤中报道，但尚未在RCC中报道。我们检测了34例原发性RCC及相应的非恶性组织中DLC1启动子的甲基化，以及dcl1甲基化与RCC患者临床病理特征的相关性。尽管使用甲基化特异性PCR （MSP）和半定量反转录PCR技术仅在7株RCC细胞系中检测到dcl1甲基化和下调，但我们发现dcl1启动子在35%（12/34）的原发性RCC肿瘤中被甲基化，这一发现通过MSP产物的直接测序和高分辨率亚硫酸盐基因组测序得到了进一步证实。相比之下，34例非恶性肾组织中只有1例（3%）存在弱甲基化。异常dcl1甲基化似乎是肾脏肿瘤发生过程中相对早期的事件，因为33%的pT1 （TNM分期）的RCC肿瘤显示甲基化，这与其他晚期肿瘤相似。因此，我们的研究结果表明，dcl1甲基化发生在RCC肿瘤的一个子集中，并可能在肾癌发生中发挥作用。2006爱思唯尔爱尔兰有限公司版权所有。
Epigenetic mechanisms involving DNA methylation and chromatin remodeling are important in silencing tumor suppressor genes (TSG) in various malignancies, including renal cell carcinoma (RCC). DLC1 (deleted in liver cancer 1)/ARHGAP7 is a recently identified 8p22 candidate TSG. Frequent methylation of the DLC1 promoter with resultant gene silencing has been reported in several tumors, but not in RCC yet. We examined DLC1 promoter methylation in 34 primary RCCs and the corresponding non-malignant tissues, and the correlation of DLC1 methylation with the clinicopathological characteristics of RCC patients. Although DLC1 methylation and downregulation were only detected in one of seven RCC cell lines using methylation-specific PCR (MSP) and semi-quantitative reverse-transcription PCR, we found that the DLC1 promoter was methylated in 35% (12/34) of primary RCC tumors, which was further confirmed by direct sequencing of MSP products and high-resolution bisulfite genomic sequencing. In contrast, only one of the 34 (3%) non-malignant renal tissues had weak methylation. Aberrant DLC1 methylation appeared to be a relatively early event during renal tumorigenesis since 33% of the RCC tumors with pT1 (TNM staging) showed methylation, which is similar to other late stage tumors. Thus, our results demonstrated that DLC1 methylation occurs in a subset of RCC tumors and may play a role in renal carcinogenesis. (c) 2006 Elsevier Ireland Ltd. All rights reserved.