ERβ-Mediated Alteration of circATP2B1 and miR-204-3p Signaling Promotes Invasion of Clear Cell Renal Cell Carcinoma

Early studies have indicated that estrogen receptor beta (ER beta) can influence the progression of clear cell renal cell carcinoma (ccRCC). Here, we report the mechanistic details of ER beta-mediated progression of ccRCC. ER beta increased ccRCC cell invasion via suppression of circular RNA ATP2B1 (circATP2B1) expression by binding directly to the 5' promoter region of its host gene All case plasma membrane Ca2+ transporting 1 (ATP2B1). ERP-suppressed circATP2B1 then led to reduced milt-204-3p, which increased fibronectin 1 (FN1) expression and enhanced ccRCC cell invasion. Targeting ER beta with shRNA suppressed ccRCC metastasis in a murine model of RCC; adding circATP2B1 shRNA partly reversed this effect. Consistent with these experimental results, ccRCC patient survival data from The Cancer Genome Atlas indicated that a patient with higher IV and FM expression had worse overall survival and a patient with higher miR-204-3p expression had significantly better overall survival. Together, these results suggest that ER beta promotes ccRCC cell invasion by altering the ER beta/circATP2B1/miR-204-3p/FN1 axis and that therapeutic targeting of this newly identified pathway may better prevent ccRCC progression. Significance: These results identify an ER beta/circATP2B1/miR204-3p/FN1 signaling axis in RCC, suggesting ER beta and circular RNA ATP2B1 as prognostic hiontarkers for this disease. (C) 2018 AACR.