Erb-mediated alteration of circatp2b1 and mir-204-3p signaling promotes invasion of clear cell renal cell carcinoma

Abstract

Early studies have indicated that estrogen receptor beta (ERb) can influence the progression of clear cell renal cell carcinoma (ccRCC). Here, we report the mechanistic details of ERb-medi-ated progression of ccRCC. ERb increased ccRCC cell invasion via suppression of circular RNA ATP2B1 (circATP2B1) expression by binding directly to the 50 promoter region of its host gene ATPase plasma membrane Ca2þ transporting 1 (ATP2B1). ERb-suppressed circATP2B1 then led to reduced miR-204-3p, which increased fibronectin 1 (FN1) expression and enhanced ccRCC cell invasion. Targeting ERb with shRNA suppressed ccRCC metastasis in a murine model of RCC; adding cir-cATP2B1 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 ERb and FN1 expression had worse overall survival and a patient with higher miR-204-3p expression had significantly better overall survival. Together, these results suggest that ERb promotes ccRCC cell invasion by altering the ERb/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 ERb/circATP2B1/miR-204-3p/FN1 signaling axis in RCC, suggesting ERb and circular RNA ATP2B1 as prognostic biomarkers for this disease.