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2017 ; 8
(7
): 11187-11198
Nephropedia Template TP
gab.com Text
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English Wikipedia
Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter
in clear renal cell carcinoma
#MMPMID28061437
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
Oncotarget
2017[Feb]; 8
(7
): 11187-11198
PMID28061437
show ga
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.
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