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Bone marrow stromal cells-derived microRNA-181-containing extracellular vesicles inhibit ovarian cancer cell chemoresistance by downregulating MEST via the Wnt/β-catenin signaling pathway

Cancer Gene Therapy volume 28, pages 785–798 (2021)Cite this article

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Abstract

Cisplatin (DDP)-based strategies are the first-line treatment for cancers; however, resistance to DDP remains a major obstacle to cancer treatment. The current study set out to investigate the effects of microRNA-181c (miR-181c) on the resistance of ovarian cancer cells to DDP. Ovarian cancer-associated miRs as well as the target messenger RNAs were screened using microarray-based analysis followed by determining the expression patterns of miR-181c and mesoderm-specific transcript (MEST) in ovarian cancer tissues with RT-qPCR and Western blot analysis. Subsequently, dual-luciferase reporter gene assay was performed to confirm the targeting relation between miR-181c and MEST. Through gain- or loss-of-function experiments, the study explored the mechanism by which miR-181 regulated MEST to influence the resistance of ovarian cancer cells to DDP via the Wnt/β-catenin signaling pathway. Afterwards, extracellular vesicles (EVs) were isolated from bone marrow stromal cells (BMSCs) and co-cultured with ovarian cancer cells to further investigate the effects of overexpressed miR-181 delivered by BMSCs-derived EVs on ovarian cancer cell resistance to DDP. miR-181c was significantly downregulated, while MEST was up-regulated in ovarian cancer. miR-181c was verified to specifically bind to MEST. Overexpressed miR-181c depleted the expression of MEST to attenuate the resistance of ovarian cancer cells to DDP by inactivating the Wnt/β-catenin signaling pathway. Furthermore, the delivery of overexpressed miR-181c by BMSCs-derived EVs was found to suppress the resistance of ovarian cancer cells to DDP. These findings demonstrate that miR-181c delivered by BMSCs-derived EVs down-regulates MEST, to inactivate the Wnt/β-catenin signaling pathway, thus repressing the resistance of ovarian cancer cells to DDP.

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Fig. 1: Ovarian tissues and cells exhibit downregulated miR-181c.
Fig. 2: Resistance of ovarian cancer cells to chemotherapy drugs is inhibited by up-regulation of miR-181c.
Fig. 3: miR-181c specifically binds to MEST in ovarian cancer cells.
Fig. 4: miR-181 overexpression reduces the expression of MEST to suppress the activation of the Wnt/β-catenin signaling pathway, thus repressing the resistance of ovarian cancer cells to chemotherapeutic drugs.
Fig. 5: The delivery of miR-181c into ovarian cancer cells by BMSCs-derived EVs reduces the expression of MEST, and further represses the resistance of ovarian cancer cells to chemotherapeutic drugs.
Fig. 6: A combination of DDP treatment and delivery of overexpressed miR-181c resulted in hindered tumor growth in ovarian cancer in vivo.

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The datasets generated/analyzed during the current study are available.

References

  1. Doubeni CA, Doubeni AR, Myers AE. Diagnosis and management of ovarian cancer. Am Fam Physician 2016;93:937–944.

    PubMed  Google Scholar 

  2. Torre LA, et al. Ovarian cancer statistics, 2018. CA Cancer J Clin 2018;68:284–296.

    Article  Google Scholar 

  3. La Vecchia C. Ovarian cancer: epidemiology and risk factors. Eur J Cancer Prev 2017;26:55–62.

    Article  Google Scholar 

  4. Wang J, Wu GS. Role of autophagy in cisplatin resistance in ovarian cancer cells. J Biol Chem 2014;289:17163–17173.

    Article  CAS  Google Scholar 

  5. Misganaw B, et al. Optimized prediction of extreme treatment outcomes in ovarian cancer. Cancer Inform 2015;14:45–55.

    CAS  PubMed  Google Scholar 

  6. Natanzon Y, Goode EL, Cunningham JM. Epigenetics in ovarian cancer. Semin Cancer Biol 2018;51:160–169.

    Article  CAS  Google Scholar 

  7. Becker A, et al. Extracellular vesicles in cancer: Cell-to-cell mediators of metastasis. Cancer Cell 2016;30:836–848.

    Article  CAS  Google Scholar 

  8. Soekmadji C, Nelson CC. The emerging role of extracellular vesicle-mediated drug resistance in cancers: Implications in advanced prostate cancer. Biomed Res Int 2015;2015:454837.

    Article  Google Scholar 

  9. Vakhshiteh F, Atyabi F, Ostad SN. Mesenchymal stem cell exosomes: A two-edged sword in cancer therapy. Int J Nanomed 2019;14:2847–2859.

    Article  CAS  Google Scholar 

  10. Whiteside TL. Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment. Semin Immunol 2018;35:69–79.

    Article  CAS  Google Scholar 

  11. Wang J, et al. Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells. Blood 2014;124:555–566.

    Article  CAS  Google Scholar 

  12. Pal MK, et al. Microrna: A new and promising potential biomarker for diagnosis and prognosis of ovarian cancer. Cancer Biol Med 2015;12:328–341.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu M, et al. Microrna-mrna functional pairs for cisplatin resistance in ovarian cancer cells. Chin J Cancer 2014;33:285–294.

    Article  CAS  Google Scholar 

  14. Yao L, et al. Mir181c inhibits ovarian cancer metastasis and progression by targeting prkcd expression. Int J Clin Exp Med 2015;8:15198–15205.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhao L, et al. Upregulation of mir-181c inhibits chemoresistance by targeting st8sia4 in chronic myelocytic leukemia. Oncotarget 2016;7:60074–60086.

    Article  Google Scholar 

  16. Li X, et al. Isoform-specific imprinting of the mest gene in porcine parthenogenetic fetuses. Gene 2015;558:287–290.

    Article  CAS  Google Scholar 

  17. Jung H, Lee SK, Jho EH. Mest/peg1 inhibits wnt signalling through regulation of lrp6 glycosylation. Biochem J 2011;436:263–269.

    Article  CAS  Google Scholar 

  18. Li W, Zhu C, Li Y, Wu Q, Gao R. Mest attenuates ccl4-induced liver fibrosis in rats by inhibiting the wnt/beta-catenin signaling pathway. Gut Liver 2014;8:282–291.

    Article  Google Scholar 

  19. Peng Y, Zhang X, Feng X, Fan X, Jin Z. The crosstalk between micrornas and the wnt/beta-catenin signaling pathway in cancer. Oncotarget 2017;8:14089–14106.

    Article  Google Scholar 

  20. Arend RC, Londono-Joshi AI, Straughn JM Jr., Buchsbaum DJ. The wnt/beta-catenin pathway in ovarian cancer: a review. Gynecol Oncol 2013;131:772–779.

    Article  CAS  Google Scholar 

  21. Zhang G, et al. The anti-oxidative role of micro-vesicles derived from human wharton-jelly mesenchymal stromal cells through nox2/gp91(phox) suppression in alleviating renal ischemia-reperfusion injury in rats. PLoS ONE 2014;9:e92129.

    Article  Google Scholar 

  22. Kumar B, et al. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia 2018;32:575–587.

    Article  CAS  Google Scholar 

  23. Ayuk SM, Abrahamse H, Houreld NN. The role of photobiomodulation on gene expression of cell adhesion molecules in diabetic wounded fibroblasts in vitro. J Photochem Photobiol B 2016;161:368–374.

    Article  CAS  Google Scholar 

  24. Garces AH, Dias MS, Paulino E, Ferreira CG, de Melo AC. Treatment of ovarian cancer beyond chemotherapy: Are we hitting the target? Cancer Chemother Pharmacol 2015;75:221–234.

    Article  CAS  Google Scholar 

  25. Galluzzi L, et al. Molecular mechanisms of cisplatin resistance. Oncogene 2012;31:1869–1883.

    Article  CAS  Google Scholar 

  26. Zabaglia LM, et al. Decreased microrna mir-181c expression associated with gastric cancer. J Gastrointest Cancer 2018;49:97–101.

    Article  CAS  Google Scholar 

  27. Liu J, Xing Y, Rong L. Mir-181 regulates cisplatin-resistant non-small cell lung cancer via downregulation of autophagy through the pten/pi3k/akt pathway. Oncol Rep. 2018;39:1631–1639.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu HN, Qie P, Yang G, Song YB. Mir-181b inhibits chemoresistance in cisplatin-resistant h446 small cell lung cancer cells by targeting bcl-2. Arch Med Sci 2018;14:745–751.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhao J, Nie Y, Wang H, Lin Y. Mir-181a suppresses autophagy and sensitizes gastric cancer cells to cisplatin. Gene 2016;576:828–833.

    Article  CAS  Google Scholar 

  30. Chen L, et al. Zfp57 suppress proliferation of breast cancer cells through down-regulation of mest-mediated wnt/beta-catenin signalling pathway. Cell Death Dis 2019;10:169.

    Article  Google Scholar 

  31. Kadota Y, et al. Gene expression of mesoderm-specific transcript is upregulated as preadipocytes differentiate to adipocytes in vitro. J Physiol Sci 2012;62:403–411.

    Article  CAS  Google Scholar 

  32. Zeng B, Zhou M, Wu H, Xiong Z. Spp1 promotes ovarian cancer progression via integrin beta1/fak/akt signaling pathway. Onco Targets Ther 2018;11:1333–1343.

    Article  Google Scholar 

  33. Hashimoto Y, Akiyama Y, Yuasa Y. Multiple-to-multiple relationships between micrornas and target genes in gastric cancer. PLoS ONE 2013;8:e62589.

    Article  CAS  Google Scholar 

  34. Li X, et al. Exosome derived from human umbilical cord mesenchymal stem cell mediates mir-181c attenuating burn-induced excessive inflammation. EBioMedicine 2016;8:72–82.

    Article  Google Scholar 

  35. Chen L, et al. Bmscs-derived mir-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis. Mol Immunol 2018;93:38–46.

    Article  CAS  Google Scholar 

  36. Yu PN, et al. Downregulation of mir-29 contributes to cisplatin resistance of ovarian cancer cells. Int J Cancer 2014;134:542–551.

    Article  CAS  Google Scholar 

  37. Chen QY, et al. Mir-206 regulates cisplatin resistance and emt in human lung adenocarcinoma cells partly by targeting met. Oncotarget 2016;7:24510–24526.

    Article  Google Scholar 

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Acknowledgements

The authors would like to acknowledge the helpful comments on this paper received from the reviewers.

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  1. These authors contributed equally: Zhengyi Ruan, Lili Lu

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, 200011, Shanghai, P.R. China

    Zhengyi Ruan, Lili Lu, Li Zhang & Min Dong

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  2. Lili Lu
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Contributions

L.Z. and M.D. designed the study. Z.R. and L.L. collated the data, carried out data analyses and produced the initial draft of the manuscript. L.Z. and M.D. contributed to draft the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Li Zhang or Min Dong.

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The authors declare that they have no conflict of interest.

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The experimental design for this study was approved by the Ethics Committee and Experimental Animal Ethics Committee of Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University. Written informed consent was obtained from all participant or their relatives. The animal experiment strictly adhered to the principle to minimize the pain, suffering, and discomfort to experimental animals.

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Ruan, Z., Lu, L., Zhang, L. et al. Bone marrow stromal cells-derived microRNA-181-containing extracellular vesicles inhibit ovarian cancer cell chemoresistance by downregulating MEST via the Wnt/β-catenin signaling pathway. Cancer Gene Ther 28, 785–798 (2021). https://doi.org/10.1038/s41417-020-0195-6

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