Frequent epigenetic suppression of tumor suppressor gene glutathione peroxidase 3 by promoter hypermethylation and its clinical implication in clear cell renal cell carcinoma.
Frequent epigenetic suppression of tumor suppressor gene glutathione peroxidase 3 by promoter hypermethylation and its clinical implication in clear cell renal cell carcinoma.
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DOI：
10.3390/ijms160510636
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发表时间：
2015-05-11
影响因子：
5.6
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Liu Q;Jin J;Ying J;Sun M;Cui Y;Zhang L;Xu B;Fan Y;Zhang Q
本研究的目的是在肾透明细胞癌(CcRCC)中发现新的由启动子甲基化沉默的抑癌基因，并发现新的表观遗传学生物标志物用于癌症的早期检测。活性氧簇(ROS)是DNA损伤的主要原因，与癌症的发生和发展相关。谷胱甘肽过氧化物酶3(GPX3)是目前已知的唯一的GPXs胞外糖基化酶，是ROS的主要清除剂。GPX3已被确定为许多癌症的肿瘤抑制因子。然而，GPX3在ccRCC中的作用仍不清楚。本研究旨在探讨其在肾细胞癌中的表观遗传学改变及其可能的临床病理联系。在我们的研究中，在6个肾细胞癌细胞系中有5个细胞系检测到GPX3甲基化和下调，并且肾细胞癌组织中GPX3mRNA和蛋白的表达水平显著低于癌旁非恶性肾组织(p<；0.0001)。5-氮杂-2‘-脱氧胞苷可恢复肾癌细胞GPX3的表达。肾细胞癌组织中有77.1%(162/210)发生甲基化，而癌旁非恶性肾组织中仅有14.6%(7/48)发生甲基化。GPX3甲基化状态与较高的肿瘤核分级显著相关(p=0.014)。因此，我们的结果显示肾细胞癌中GPX3经常被启动子超甲基化失活，这可能揭示了肾细胞癌中细胞抗氧化系统的失败，并可能与肾肿瘤的发生有关。GPX3肿瘤特异性甲基化可作为早期发现和预测肾细胞癌预后的生物标志物。
The goal of this study is to identify novel tumor suppressor genes silenced by promoter methylation in clear cell renal cell carcinoma (ccRCC) and discover new epigenetic biomarkers for early cancer detection. Reactive oxygen species (ROS) is a major cause of DNA damage that correlates with cancer initiation and progression. Glutathione peroxidase 3 (GPX3), the only known extracellular glycosylated enzyme of GPXs, is a major scavenger of ROS. GPX3 has been identified as a tumor suppressor in many cancers. However, the role of GPX3 in ccRCC remains unclear. This study aimed to investigate its epigenetic alteration in ccRCC and possible clinicopathological association. In our study, GPX3 methylation and down-regulation were detected in 5 out of 6 ccRCC cell lines and the GPX3 mRNA and protein expression level in ccRCC tumors was significantly lower than in adjacent non-malignant renal tissues (p < 0.0001). Treatment with 5-Aza-2'-deoxycytidine restored GPX3 expression in ccRCC cells. Aberrant methylation was further detected in 77.1% (162/210) of RCC primary tumors, but only 14.6% (7/48) in adjacent non-malignant renal tissues. GPX3 methylation status was significantly associated with higher tumor nuclear grade (p = 0.014). Thus, our results showing frequent GPX3 inactivation by promoter hypermethylation in ccRCC may reveal the failure in the cellular antioxidant system in ccRCC and may be associated with renal tumorigenesis. GPX3 tumor specific methylation may serve as a biomarker for early detection and prognosis prediction of ccRCC.
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