The Silencing of CCND2 by Promoter Aberrant Methylation in Renal Cell Cancer and Analysis of the Correlation between CCND2 Methylation Status and Clinical Features.
The Silencing of CCND2 by Promoter Aberrant Methylation in Renal Cell Cancer and Analysis of the Correlation between CCND2 Methylation Status and Clinical Features.
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肾细胞癌中CCND2启动子异常甲基化沉默及CCND2甲基化状态与临床特征的相关性分析
DOI：
10.1371/journal.pone.0161859
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Wang L;Cui Y;Zhang L;Sheng J;Yang Y;Kuang G;Fan Y;Zhang Q;Jin J
细胞周期蛋白D2（Cyclin D2，CCND 2）是D型细胞周期蛋白家族的一员，在细胞周期调控、分化和恶性转化中发挥重要作用。然而，其在肾细胞癌（RCC）中的表达状况及相关调控机制尚不清楚。在我们的研究中，22/23对RCC组织中CCND 2 mRNA表达水平下调（p<0.05）。43例肾细胞癌组织中有43例其蛋白表达水平低于相应的非恶性组织（p<0.001）。我们进一步检测到CCND 2在6/7个RCC细胞系中下调或沉默，但在“正常”人近端肾小管（HK-2）细胞系中表达。MSP和BGS结果显示，CCND 2启动子区甲基化状态与其在RCC细胞系中的表达水平密切相关。用5-Aza与或不与TSA处理恢复了几种甲基化RCC细胞系中的CCND 2表达。在102例RCC肿瘤中，29/102（28%）例检测到CCND 2甲基化。只有2/23（8.7%）的邻近非恶性组织显示甲基化。然后分析临床特征与其启动子甲基化的相关性。总的来说，我们的数据表明CCND 2表达的缺失与启动子异常甲基化密切相关。
Cyclin D2 (CCND2) is a member of the D-type cyclins, which plays a pivotal role in cell cycle regulation, differentiation and malignant transformation. However, its expression status and relative regulation mechanism remains unclear in renal cell cancer (RCC). In our study, the mRNA expression level of CCND2 is down-regulated in 22/23 paired RCC tissues (p<0.05). In addition, its protein expression level is also decreased in 43/43 RCC tumor tissues compared with its corresponding non-malignant tissues (p<0.001). We further detected that CCND2 was down-regulated or silenced in 6/7 RCC cell lines, but expressed in “normal” human proximal tubular (HK-2) cell line. Subsequently, MSP and BGS results showed that the methylation status in CCND2 promoter region is closely associated with its expression level in RCC cell lines. Treatment with 5-Aza with or without TSA restored CCND2 expression in several methylated RCC cell lines. Among the 102 RCC tumors, methylation of CCND2 was detected in 29/102 (28%) cases. Only 2/23 (8.7%) adjacent non-malignant tissues showed methylation. We then analyzed the correlation of clinical features and its promoter methylation. Collectively, our data suggested that loss of CCND2 expression is closely associated with the promoter aberrant methylation.
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