ER{beta}-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 (ERβ) can influence the progression of clear cell renal cell carcinoma (ccRCC). Here we report the mechanistic details of ERβ-mediated progression of ccRCC. ERβ increased ccRCC cell invasion via suppression of circular RNA ATP2B1 (circATP2B1) expression by binding directly to the 5' promoter region of its host gene ATPase plasma membrane Ca2+ transporting 1 (ATP2B1). ERβ-suppressed circATP2B1 then led to reduced miR-204-3p, which increased fibronectin 1 (FN1) expression and enhanced ccRCC cell invasion. Targeting ERβ 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 TCGA indicated that higher ERβ and FN1 expression had worse overall survival and higher miR-204-3p expression had significantly better overall survival. Together, these results suggest that ERβ promotes ccRCC cell invasion by altering the ERβ/circATP2B1/miR-204-3p/FN1 axis, and that therapeutic targeting of this newly identified pathway may better prevent ccRCC progression.

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