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

Abstract

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.

• Authors: Guosong Jiang, Chao Huang, Jingxia Li, Haishan Huang, Honglei Jin, Junlan Zhu, Xue-Ru Wu, Chuanshu Huang
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 16 Issue 5 Pg. 924-935 (05 2017) ISSN: 1538-8514 [Electronic] United States
• PMID: 28223425 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

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

Topics

• 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, genetics, pathology)