miR‐4324‐RACGAP1‐STAT3‐ESR1 feedback loop inhibits proliferation and metastasis of bladder cancer

摘要

Considering the importance of microRNAs (miRNAs) in regulating cellular processes, we performed microarray analysis and revealed miR‐4324 as one of the most differentially expressed miRNAs in bladder cancer (BCa). Then, we discovered that miR‐4324 was a negative regulator of Rac GTPase activating protein 1 (RACGAP1) and that RACGAP1 functioned as an oncogenic protein in BCa. Our studies indicated that ectopic overexpression of miR‐4324 in BCa cells significantly suppressed cell proliferation and metastasis and enhanced chemotherapy sensitivity to doxorubicin by repressing RACGAP1 expression. Further studies showed that estrogen receptor 1 (ESR1) increased the expression of miR‐4324 by binding to its promoter, while the downregulation of ESR1 in BCa was caused by hypermethylation of its promoter. p‐STAT3 induced the enrichment of DNMT3B by binding to the ESR1 promoter and then induced methylation of the ESR1 promoter. In turn, RACGAP1 induced STAT3 phosphorylation, increasing p‐STAT3 expression and promoting its translocation to the nucleus. Therefore, the miR‐4324‐RACGAP1‐STAT3‐ESR1 feedback loop could be a critical regulator of BCa progression.