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miR-140-5p inhibits the proliferation and enhances the efficacy of doxorubicin to breast cancer stem cells by targeting Wnt1

Cancer Gene Therapy volume 26, pages 74–82 (2019)Cite this article

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Abstract

MicroRNAs (miRNAs) are a group of small non-coding single-stranded RNAs molecules, the dysregulation of which plays a critical role in the initiation and biological progression of malignancies. The current study demonstrated that miR-140-5p was frequently downregulated in breast cancer stem cells (BCSCs), and miR-140-5p mimics could inhibit the proliferation of BCSCs. Moreover, Wnt1 was a direct target of miR-140-5p, as was proved by luciferase reporter assays. miR-140-5p mimics could downregulate the wnt1 mRNA and protein levels in MCF-7 and MDA-MB-231 cells. Furthermore, miR-140 mimics could enhance the sensitivity of BCSCs to doxorubicin (Dox) through the Wnt1/ABCB1 pathway both in vitro and vivo. Our findings have presented a novel miRNA-mediated regulatory network for BCSCs, which may provide a potential therapeutic target for breast cancer.

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References

  1. Wang X, Wang X, Gu J, Zhou M, He Z, Wang X, et al. Overexpression of miR-489 enhances efficacy of 5-fluorouracil-based treatment in breast cancer stem cells by targeting XIAP. Oncotarget. 2017;8:113837–46.

    PubMed  PubMed Central  Google Scholar 

  2. Douville J, Beaulieu R, Balicki D. ALDH1 as a functional marker of cancer stem and progenitor cells. Stem Cells Dev. 2008;18:17–26.

    Article  Google Scholar 

  3. Chakraborty C, Chin K-Y, Das S. miRNA-regulated cancer stem cells: understanding the property and the role of miRNA in carcinogenesis. Tumor Biol. 2016;37:13039–48.

    Article  CAS  Google Scholar 

  4. Tuna M, Machado Andreia S, Calin George A. Genetic and epigenetic alterations of microRNAs and implications for human cancers and other diseases. Genes Chromosomes Cancer. 2016;55:193–214.

    Article  CAS  Google Scholar 

  5. Frixa T, Donzelli S, Blandino G. Oncogenic microRNAs: key players in malignant transformation. Cancers. 2015;7:2466–85.

  6. Shimono Y, Mukohyama J, Nakamura S-I, Minami H. MicroRNA regulation of human breast cancer stem cells. J Clin Med. 2016;5:2.

  7. Takata A, Otsuka M, Yoshikawa T, Kishikawa T, Hikiba Y, Obi S, et al. MicroRNA‐140 acts as a liver tumor suppressor by controlling NF‐κB activity by directly targeting DNA methyltransferase 1 (Dnmt1) expression. Hepatology. 2012;57:162–70.

    Article  Google Scholar 

  8. Lu Y, Qin T, Li J, Wang L, Zhang Q, Jiang Z, et al. MicroRNA-140-5p inhibits invasion and angiogenesis through targeting VEGF-A in breast cancer. Cancer Gene Ther. 2017;24:386-92.

    Article  CAS  Google Scholar 

  9. Ji X, Wang E, Tian F. MicroRNA-140 suppresses osteosarcoma tumor growth by enhancing anti-tumor immune response and blocking mTOR signaling. Biochem Biophys Res Commun. 2018;495:1342–8.

    Article  CAS  Google Scholar 

  10. Fang Z, Yin S, Sun R, Zhang S, Fu M, Wu Y, et al. miR-140-5p suppresses the proliferation, migration and invasion of gastric cancer by regulating YES1. Mol Cancer. 2017;16:139.

    Article  Google Scholar 

  11. Li J, Zou K, Yu L, Zhao W, Lu Y, Mao J, et al. MicroRNA-140 inhibits the epithelial-mesenchymal transition and metastasis in colorectal cancer. Mol Ther Nucleic Acids. 2018;10:426–37.

    Article  CAS  Google Scholar 

  12. Song B, Wang Y, Xi Y, Kudo K, Bruheim S, Botchkina GI, et al. Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells. Oncogene. 2009;28:4065–74.

    Article  CAS  Google Scholar 

  13. Wolfson B, Eades G, Zhou Q. Roles of microRNA-140 in stem cell-associated early stage breast cancer. World J Stem Cells. 2014;6:591–7.

    Article  Google Scholar 

  14. Prakash N, Wurst W. A Wnt signal regulates stem cell fate and differentiation in vivo. Neurodegener Dis. 2007;4:333–8.

    Article  CAS  Google Scholar 

  15. El Helou R, Pinna G, Cabaud O, Wicinski J, Bhajun R, Guyon L, et al. miR-600 Acts as a bimodal switch that regulates breast cancer stem cell fate through WNT signaling. Cell Rep. 2017;18:2256–68.

    Article  CAS  Google Scholar 

  16. McCarthy N. Small losses, big gains with microRNAs. Nat Rev Genet. 2009;11:8.

    Article  Google Scholar 

  17. Jardim MJ, Fry RC, Jaspers I, Dailey L, Diaz-Sanchez D. Disruption of microRNA expression in human airway cells by diesel exhaust particles is linked to tumorigenesis-associated pathways. Environ Health Perspect. 2009;117:1745–51.

    Article  CAS  Google Scholar 

  18. Armstrong Cameron M, Liu C, Lou W, Lombard Alan P, Evans Christopher P, Gao Allen C. MicroRNA‐181a promotes docetaxel resistance in prostate cancer cells. Prostate. 2017;77:1020–8.

    Article  CAS  Google Scholar 

  19. Bisson I, Prowse DM. WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res. 2009;19:683–97.

    Article  CAS  Google Scholar 

  20. Yan H, Bu P. Non-coding RNAs in cancer stem cells. Cancer Lett. 2018;421:121–6.

  21. Han XR, Wen X, Wang YJ, Wang S, Shen M, Zhang ZF, et al. MicroRNA‐140‐5p elevates cerebral protection of dexmedetomidine against hypoxic–ischaemic brain damage via the Wnt/β‐catenin signalling pathway. J Cell Mol Med. 2018;22:3167-82.

  22. Xu C, Sun X, Qin S, Wang H, Zheng Z, Xu S, et al. Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells. Cell Cycle. 2015;14:1686–97.

    Article  CAS  Google Scholar 

  23. Yu F, Deng H, Yao H, Liu Q, Su F, Song E. Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells. Oncogene. 2010;29:4194-204.

    Article  CAS  Google Scholar 

  24. Choi AR, Park J-R, Kim R-J, Kim S-R, Cho S-D, Jung J-Y, et al. Inhibition of Wnt1 expression reduces the enrichment of cancer stem cells in a mouse model of breast cancer. Biochem Biophys Res Commun. 2012;425:436–42.

    Article  CAS  Google Scholar 

  25. Kim R-J, Nam J-S. OCT4 expression enhances features of cancer stem cells in a mouse model of breast cancer. Lab Anim Res. 2011;27:147–52.

    Article  Google Scholar 

  26. Lee Min Y, Lim Hyun W, Lee Sang H, Han Ho J. Smad, PI3K/Akt, and Wnt‐dependent signaling pathways are involved in BMP‐4‐induced ESC self‐renewal. Stem Cells. 2009;27:1858–68.

    Article  Google Scholar 

  27. Arrigoni E, Galimberti S, Petrini M, Danesi R, Di Paolo A. ATP-binding cassette transmembrane transporters and their epigenetic control in cancer: an overview. Expert Opin Drug Metab Toxicol. 2016;12:1419–32.

    Article  CAS  Google Scholar 

  28. Ji P, Zhang Y, Wang S-J, Ge H-L, Zhao G-P, Xu Y-C, et al. CD44hiCD24lo mammosphere-forming cells from primary breast cancer display resistance to multiple chemotherapeutic drugs. Oncol Rep. 2016;35:3293–302.

    Article  CAS  Google Scholar 

  29. Lee Yh, Yang HW, Yang LC, Lu MY, Tsai LL, Yang SF, et al. DHFR and MDR1 upregulation is associated with chemoresistance in osteosarcoma stem-like cells. Oncol Lett. 2017;14: 171–9.

  30. Flamini V, Jiang WG, Cui Y. Therapeutic role of MiR-140-5p for the treatment of non-small cell lung cancer. Anticancer Res. 2017;37:4319–27.

    CAS  PubMed  Google Scholar 

  31. Huang G-L, Song W, Zhou P, Fu Q-R, Lin C-L, Chen Q-X, et al. Oncogenic retinoic acid receptor γ knockdown reverses multi-drug resistance of human colorectal cancer via Wnt/β-catenin pathway. Cell Cycle. 2017;16:685–92.

    Article  CAS  Google Scholar 

  32. Stein U, Fleuter C, Siegel F, Smith J, Kopacek A, Scudiero DA, et al. Impact of mutant β-catenin on ABCB1 expression and therapy response in colon cancer cells. Br J Cancer. 2012;106:1395.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 81502561) and Tumor Stem Cell Research Key Laboratory of Liaoning Province.

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Authors and Affiliations

  1. Department of Clinical Laboratory, The Second Hospital of Tianjian Medical University, 300211, Tianjin, China

    Dawei Wu

  2. Department of Pathology, Dalian Medical University, 116044, Dalian, China

    Jun Zhang, Song Bo, Lianhong Li, Lu Wang, Qingqing Zhang & Jun Mao

  3. Teaching Laboratory of Morphology, Dalian Medical University, 116044, Dalian, China

    Ying Lu & Jun Mao

  4. Key Laboratory of Tumor Stem Cell Research of Liaoning Province, Dalian Medical University, 116044, Dalian, China

    Lianhong Li & Jun Mao

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  1. Dawei Wu
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Correspondence to Jun Mao.

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Wu, D., Zhang, J., Lu, Y. et al. miR-140-5p inhibits the proliferation and enhances the efficacy of doxorubicin to breast cancer stem cells by targeting Wnt1. Cancer Gene Ther 26, 74–82 (2019). https://doi.org/10.1038/s41417-018-0035-0

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