ERα-mediated alterations in circ_0023642 and miR-490-5p signaling suppress bladder cancer invasion

Epidemiological studies show obvious gender differences in the incidence and the prognosis of bladder cancer (BCa). Estrogen receptor alpha (ER alpha) was recently shown to play a protective role in BCa. However, the mechanisms by which ER alpha mediates BCa progression need to be further elucidated. In the present study, we explored the mechanisms by which ERa inhibits BCa invasion by modulating circRNA levels. ER alpha suppressed BCa invasion by decreasing circ_0023642 expression. Chromatin immunoprecipitation (ChIP) and luciferase assays revealed that ER alpha reduced circ_0023642 expression by regulating the expression of its host gene, UVRAG, at the transcriptional level. ER alpha decreased circ_0023642 levels and subsequently increased miR-490-5p expression, resulting in decreased EGFR expression to suppress BCa cell invasion. Circ_0023642 was demonstrated to directly bind to miR-490-5p. Notably, miR-490-5p regulated EGFR expression by binding to the miR-490-5p-binding site located in the 3'-untranslated region (UTR) of the EGFR mRNA. Preclinical studies using an in vivo mouse model also confirmed that this ER alpha/circ_0023642/miR-490-5p/EGFR signaling pathway suppressed BCa progression. Altogether, this newly identified pathway may serve as the basis for developing novel therapeutic strategies to treat BCa.