Inactivation of VHL, deregulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, and altered redox homeostasis, together with changes in glutathione transferase (GST) profile, are considered as important contributing factors in RCC development and progression.
In 50 patients who had metastatic RCC and received cytoreductive nephrectomy, we performed Nrf2 gene mutation analysis using targeted next-generation sequencing, as well as investigating a specific single nucleotide polymorphism (SNP; rs6721961) in the Nrf2 promoter region and Nrf2 protein expression.
In conclusion, Nrf2-ARE signaling is important for RCC progression, and its inhibition may increase sensitivity to targeted drugs to provide novel developments for RCC 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.