Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145

Mol Cancer Ther. 2017 May;16(5):924-935. doi: 10.1158/1535-7163.MCT-16-0631. Epub 2017 Feb 21.


Although miR-145 is the most frequently downregulated miRNA in bladder cancer, its exact stage association and downstream effector have not been defined. Here, we found that miR-145 was upregulated in human patients with bladder cancer with lymph node metastasis and in metastatic T24T cell line. Forced expression of miR-145 promoted anchorage-independent growth of T24T cells accompanied by the downregulation of forkhead box class O1 (FOXO1). In contrast, in non-metastatic T24 cells, miR-145 overexpression inhibited cell growth with upregulation of FOXO1, and the knockdown of FOXO1 abolished the miR-145-mediated inhibition of cell growth. Mechanistic studies revealed that miR-145 directly bound to and attenuated 3'-untranslated region (UTR) activity of foxo1 mRNA in both T24 and T24T cells. Interestingly, miR-145 suppressed STAT3 phosphorylation at Tyr705 and increased foxo1 promoter transcriptional activity in T24 cells, but not in T24T cells, suggesting a role of STAT3 in the divergent responses to miR-145. Supporting this was our finding that STAT3 knockdown mimicked miR-145-mediated upregulation of FOXO1 in T24T cells and inhibition of anchorage-independent growth. Consistently, ectopic expression of miR-145 promoted tumor formation of xenograft T24T cells, whereas such promoting effect became inhibitory due to specific knockdown of STAT3. Together, our findings demonstrate the stage-specific association and function of miR-145 in bladder cancers and provide novel insights into the therapeutic targeting of miR-145. Mol Cancer Ther; 16(5); 924-35. ©2017 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Forkhead Box Protein O1 / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Humans
  • MicroRNAs / genetics*
  • Neoplasm Metastasis
  • STAT3 Transcription Factor / genetics*
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / pathology


  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • MIRN145 microRNA, human
  • MicroRNAs
  • STAT3 Transcription Factor
  • STAT3 protein, human