Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma

被引：73

作者：

Fabrizio, Federico Pio ^{[1
]}

Costantini, Manuela ^{[2
,4
,5
]}

Copetti, Massimiliano ^{[3
]}

la Torre, Annamaria ^{[1
]}

Sparaneo, Angelo ^{[1
]}

Fontana, Andrea ^{[3
]}

Poeta, Luana ^{[4
]}

Gallucci, Michele ^{[5
]}

Sentinelli, Steno ^{[6
]}

Graziano, Paolo ^{[7
]}

Parente, Paola ^{[7
]}

Pompeo, Vincenzo ^{[5
]}

De Salvo, Laura ^{[6
]}

Simone, Giuseppe ^{[5
]}

Papalia, Rocco ^{[5
]}

Picardo, Francesco ^{[2
]}

Balsamo, Teresa ^{[1
]}

Flammia, Gerardo Paolo ^{[8
]}

Trombetta, Domenico ^{[1
]}

Pantalone, Angela ^{[2
]}

Kok, Klaas ^{[9
]}

Paranita, Ferronika ^{[9
]}

La, Muscarella ^{[1
]}

Fazio, Vito Michele ^{[1
,2
]}

机构：

[1] IRCCS Casa Sollievo Sofferenza, Lab Oncol, San Giovanni Rotondo, Italy

[2] Univ Campus Biomed Rome, Genet & Clin Pathol Unit, Rome, Italy

[3] IRCCS Casa Sollievo Sofferenza, Unit Biostat, San Giovanni Rotondo, Italy

[4] Univ Bari, Dept Biosci Biotechnol & Biopharmaceut, Bari, Italy

[5] Regina Elena Inst Canc Res, Dept Urol, Rome, Italy

[6] Regina Elena Inst Canc Res, Dept Pathol, Rome, Italy

[7] IRCCS Casa Sollievo Sofferenza, Unit Pathol, San Giovanni Rotondo, Italy

[8] Campus Biomed Univ Hosp, UOC Urol, Rome, Italy

[9] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

来源：

ONCOTARGET | 2017年 / 8卷 / 07期

关键词：

LUNG-CANCER; EPIGENETIC REGULATION; IKK-BETA; NRF2; ACTIVATION; MUTATIONS; ASSOCIATION; GENOMICS;

D O I：

10.18632/oncotarget.14492

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：11187 / 11198

页数：12

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