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

Autor: Ferronika Paranita, Massimiliano Copetti, Paola Parente, Teresa Balsamo, Rocco Papalia, Vincenzo Pompeo, Klaas Kok, Paolo Graziano, Annamaria la Torre, Vito Michele Fazio, Federico Pio Fabrizio, Andrea Fontana, Michele Gallucci, Steno Sentinelli, Angela Pantalone, Laura De Salvo, Lucia Anna Muscarella, Luana Poeta, Angelo Sparaneo, Gerardo Flammia, Giuseppe Simone, Domenico Trombetta, Francesco Picardo, Manuela Costantini
Přispěvatelé: Guided Treatment in Optimal Selected Cancer Patients (GUTS)
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Pathology
Chromophobe cell
Epigenesis
Genetic
ACTIVATION
0302 clinical medicine
Renal cell carcinoma
Enzyme Inhibitors
EPIGENETIC REGULATION
Promoter Regions
Genetic
Aged
80 and over
Kidney
Kelch-Like ECH-Associated Protein 1
Papillary renal cell carcinomas
Reverse Transcriptase Polymerase Chain Reaction
ASSOCIATION
Middle Aged
Immunohistochemistry
Kidney Neoplasms
Gene Expression Regulation
Neoplastic
medicine.anatomical_structure
Oncology
IKK-BETA
030220 oncology & carcinogenesis
DNA methylation
Azacitidine
outcome
Female
Signal Transduction
Research Paper
Adult
medicine.medical_specialty
NF-E2-Related Factor 2
Biology
Papillary renal cell carcinoma type 2
NRF2
03 medical and health sciences
LUNG-CANCER
medicine
Carcinoma
Humans
RNA
Messenger
Carcinoma
Renal Cell
Aged
MUTATIONS
ccRCC
epigenetic biomarker
DNA Methylation
medicine.disease
Survival Analysis
KEAP1
030104 developmental biology
Cancer research
methylation
Kidney cancer
GENOMICS
Zdroj: Oncotarget, 8(7), 11187-11198. Impact Journals LLC
Oncotarget
ISSN: 1949-2553
Popis: 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.
Databáze: OpenAIRE
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