miR-4324-RACGAP1-STAT3-ESR1 feedback loop inhibits proliferation and metastasis of bladder cancer.
Qiangqiang GeMengxin LuLingao JuKaiyu QianGang WangChin-Lee WuXuefeng LiuYu XiaoXing-Huan WangPublished in: International journal of cancer (2019)
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.
Keyphrases
- cell proliferation
- estrogen receptor
- transcription factor
- dna methylation
- cell cycle
- poor prognosis
- long non coding rna
- pi k akt
- gene expression
- high glucose
- long noncoding rna
- binding protein
- diabetic rats
- signaling pathway
- cell cycle arrest
- drug delivery
- drug induced
- cell death
- radiation therapy
- case control
- protein protein