Androgen receptor-regulated miRNA-193a-3p targets AJUBA to promote prostate cancer cell migration

Li Jia, Bin Gui, Dali Zheng, Keith F. Decker, Ilker Tinay, Mingyue Tan, Xiaowei Wang, Adam S. Kibel

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Background Dysregulation of microRNA (miRNA) expression is implicated in cancer development and progression by modulating oncogenes or tumor suppressors at the post-transcriptional level. Methods To investigate the role of miRNAs in prostate cancer (PCa) progression, we performed small RNA-sequencing (RNA-seq) analysis in androgen-dependent LNCaP cells and LNCaP-derived castration-resistant prostate cancer (CRPC) C4-2B cells. For functional validation, we specifically investigated miR-193a-3p, which is highly upregulated in C4-2B cells and modulated by the androgen receptor (AR). We elucidated the role of miR-193a-3p and its downstream target gene in PCa cell migration using biochemical approaches. Results We identified a subset of differentially expressed miRNAs in C4-2B cells compared to LNCaP cells. Computational analysis shows that the targets of upregulated miRNAs are significantly associated with downregulated protein-coding mRNAs in C4-2B cells. Gene Ontology analysis further reveals that these downregulated mRNAs are significantly enriched in cell-cell adhesion functions. Downregulation of these miRNA-targeted genes may change PCa cell motility resulting in the acquisition of metastatic potential. We then focus on miR-193a-3p and demonstrate overexpression of miR-193a-3p increases cell migration through downregulating its target AJUBA. AJUBA is a LIM domain protein and contributes to the formation and stability of cadherin-mediated cell-cell adhesion. Loss of AJUBA enhances PCa migration and downregulation of AJUBA expression is observed in metastatic PCa tumors. Conclusions Our results suggest a novel AR/miR-193a-3p/AJUBA pathway implicated in PCa progression. MiR-193a-3p is a potential therapeutic target for metastatic PCa.

Original languageEnglish
Pages (from-to)1000-1011
Number of pages12
JournalProstate
Volume77
Issue number9
DOIs
StatePublished - Jun 15 2017

Keywords

  • AJUBA
  • androgen receptor
  • microRNA
  • migration
  • prostate cancer

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