Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma.
Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma.
复制标题
DOI：
10.18632/oncotarget.14492
复制
发表时间：
2017-02-14
期刊：
影响因子：
--
通讯作者：
Fazio VM
中科院分区：
文献类型：
--
作者：
Fabrizio FP;Costantini M;Copetti M;la Torre A;Sparaneo A;Fontana A;Poeta L;Gallucci M;Sentinelli S;Graziano P;Parente P;Pompeo V;De Salvo L;Simone G;Papalia R;Picardo F;Balsamo T;Flammia GP;Trombetta D;Pantalone A;Kok K;Paranita F;Muscarella LA;Fazio VM
Keap 1/Nrf 2通路是细胞氧化还原状态的主要调节因子，通过诱导与肿瘤细胞的化疗药物抗性有关的几种抗氧化防御基因。越来越多的证据支持Keap 1/Nrf 2通路在肾脏疾病和肾细胞癌（RCC）中的关键作用，但关于其失调的分子基础和临床效应的数据仍然不完整。在这里，我们通过分析89个肿瘤/正常配对组织（肾透明细胞癌，ccRCC;嗜酸细胞瘤; 1型乳头状肾细胞癌，PRCC 1; 2型乳头状肾细胞癌，PRCC 2;和嫌色细胞癌），提出了5种不同肾细胞癌组织型中KEAP 1和NFE 2L 2基因的分子谱。KEAP 1基因启动子区的肿瘤特异性DNA甲基化被发现是ccRCC亚型的特异性特征（18/37，48.6%），并通过体外5-氮杂胞苷治疗证实与mRNA水平直接相关。对481例ccRCC和265例PRCC肿瘤的独立数据集的分析证实了我们的结果，多变量分析揭示了ccRCC表观遗传KEAP 1沉默与分期、分级和总生存率之间的显著相关性。我们的分子结果首次显示KEAP 1启动子的表观遗传沉默是调控ccRCC中KEAP 1表达的主要机制，并证实了Keap 1/Nrf 2轴失调的驱动作用，其具有作为肾细胞癌中独立表观遗传预后标志物的潜在新功能。
The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defence genes implicated in chemotherapeutic drugs resistance of tumor cells. An increasing body of evidence supports a key role for Keap1/Nrf2 pathway in kidney diseases and renal cell carcinoma (RCC), but data concerning the molecular basis and the clinical effect of its deregulation remain incomplete. Here we present a molecular profiling of the KEAP1 and NFE2L2 genes in five different Renal Cell Carcinoma histotypes by analysing 89 tumor/normal paired tissues (clear cell Renal Carcinoma, ccRCCs; Oncocytomas; Papillary Renal Cell Carcinoma Type 1, PRCC1; Papillary Renal Cell Carcinoma Type 2, PRCC2; and Chromophobe Cell Carcinoma). A tumor-specific DNA methylation of the KEAP1 gene promoter region was found as a specific feature of the ccRCC subtype (18/37, 48.6%) and a direct correlation with mRNA levels was confirmed by in vitro 5-azacytidine treatment. Analysis of an independent data set of 481 ccRCC and 265 PRCC tumors corroborates our results and multivariate analysis reveals a significant correlation among ccRCCs epigenetic KEAP1 silencing and staging, grading and overall survival. Our molecular results show for the the first time the epigenetic silencing of KEAP1 promoter as the leading mechanism for modulation of KEAP1 expression in ccRCCs and corroborate the driver role of Keap1/Nrf2 axis deregulation with potential new function as independent epigenetic prognostic marker in renal cell carcinoma.