MiR-363 inhibits cisplatin chemoresistance of epithelial ovarian cancer by regulating snail-induced epithelial-mesenchymal transition

  • Cao, Lanqin (Department of Obstetrics, Xiangya Hospital, Central South University) ;
  • Wan, Qian (Department of Obstetrics, Xiangya Hospital, Central South University) ;
  • Li, Fengjie (Department of Obstetrics, Xiangya Hospital, Central South University) ;
  • Tang, Can-e (The Institute of Medical Science Research, Xiangya Hospital, Central South University)
  • Received : 2018.05.08
  • Accepted : 2018.07.20
  • Published : 2018.09.30


Chemoresistance is a major barrier to successful cisplatin-based chemotherapy for epithelial ovarian cancer (EOC), and emerging evidences suggest that microRNAs (miRNAs) are involved in the resistance. In this study, it was indicated that miR-363 downregulation was significantly correlated with EOC carcinogenesis and cisplatin resistance. Moreover, miR-363 overexpression could resensitise cisplatin-resistant EOC cells to cisplatin treatment both in vitro and in vivo. In addition, data revealed that EMT inducer Snail was significantly upregulated in cisplatin-resistant EOC cell lines and EOC patients and was a functional target of miR-363 in EOC cells. Furthermore, snail overexpression could significantly attenuate miR-363-suppressed cisplatin resistance of EOC cells, suggesting that miR-363-regulated cisplatin resistance is mediated by snail-induced EMT in EOC cells. Taken together, findings suggest that miR-363 may be a biomarker for predicting responsiveness to cisplatin-based chemotherapy and a potential therapeutic target in EOC.


Supported by : National Natural Science Fundation of China


  1. Chiu WT, Huang YF, Tsai HY et al (2015) FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells. Oncotarget 6, 2349-2365
  2. Kuchenbaecker KB, Ramus SJ, Tyrer J et al (2015) Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat Genet 47, 164-171
  3. Raghavan R, Hyter S, Pathak HB et al (2016) Drug discovery using clinical outcome-based Connectivity Mapping: application to ovarian cancer. BMC Genomics 17, 811
  4. Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22, 7265-7279
  5. Zamble DB and Lippard SJ (1995) Cisplatin and DNA repair in cancer chemotherapy. Trends Biochem Sci 20, 435-439
  6. Siegel R, Naishadham D and Jemal A (2012) Cancer statistics for Hispanics/Latinos, 2012. CA Cancer J Clin 62, 283-298
  7. Polyak K and Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9, 265-273
  8. Marchini S, Fruscio R, Clivio L et al (2013) Resistance to platinum-based chemotherapy is associated with epithelial to mesenchymal transition in epithelial ovarian cancer. Eur J Cancer 49, 520-530
  9. Calin GA and Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6, 857-866
  10. Chang TC, Yu D, Lee YS et al (2008) Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet 40, 43-50
  11. Johnson CD, Esquela-Kerscher A, Stefani G et al (2007) The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res 67, 7713-7722
  12. Tsai WC, Hsu SD, Hsu CS et al (2012) MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest 122, 2884-2897
  13. Liu J, Li Q, Li R, Ren P and Dong S (2017) MicroRNA-363-3p inhibits papillary thyroid carcinoma progression by targeting PIK3CA. Am J Cancer Res 7, 148-158
  14. Zhang PF, Sheng LL, Wang G et al (2016) miR-363 promotes proliferation and chemo-resistance of human gastric cancer via targeting of FBW7 ubiquitin ligase expression. Oncotarget 7, 35284-35292
  15. Hu F, Min J, Cao X et al (2016) MiR-363-3p inhibits the epithelial-to-mesenchymal transition and suppresses metastasis in colorectal cancer by targeting Sox4. Biochem Biophys Res Commun 474, 35-42
  16. Zhang R, Li Y, Dong X, Peng L and Nie X (2014) MiR-363 sensitizes cisplatin-induced apoptosis targeting in Mcl-1 in breast cancer. Med Oncol 31, 347
  17. Li Y, Chen D, Li Y et al (2016) Oncogenic cAMP responsive element binding protein 1 is overexpressed upon loss of tumor suppressive miR-10b-5p and miR-363-3p in renal cancer. Oncol Rep 35, 1967-1978
  18. Chen Y, Lu X, Wu B, Su Y, Li J and Wang H (2015) MicroRNA 363 mediated positive regulation of c-myc translation affect prostate cancer development and progress. Neoplasma 62, 191-198
  19. Conti A, Romeo SG, Cama A et al (2016) MiRNA expression profiling in human gliomas: upregulated miR-363 increases cell survival and proliferation. Tumour Biol 37, 14035-14048
  20. Lin Y, Xu T, Zhou S and Cui M (2017) MicroRNA-363 inhibits ovarian cancer progression by inhibiting NOB1. Oncotarget 8, 101649-101658
  21. Huang H, Chen J, Ding CM, Jin X, Jia ZM and Peng J (2018) LncRNA NR2F1-AS1 regulates hepatocellular carcinoma oxaliplatin resistance by targeting ABCC1 via miR-363. J Cell Mol Med 22, 3238-3245
  22. Zhang P, Zhang P, Shi B et al (2014) Galectin-1 overexpression promotes progression and chemoresistance to cisplatin in epithelial ovarian cancer. Cell Death Dis 5, e991
  23. Boyerinas B, Park SM, Murmann AE et al (2012) Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1. Int J Cancer 130, 1787-1797
  24. Chin LJ, Ratner E, Leng S et al (2008) A SNP in a let-7 microRNA complementary site in the KRAS 3' untranslated region increases non-small cell lung cancer risk. Cancer Res 68, 8535-8540
  25. Liu C, Kelnar K, Vlassov AV, Brown D, Wang J and Tang DG (2012) Distinct microRNA expression profiles in prostate cancer stem/progenitor cells and tumor-suppressive functions of let-7. Cancer Res 72, 3393-3404
  26. Yu F, Yao H, Zhu P et al (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131, 1109-1123
  27. Cai J, Yang C, Yang Q et al (2013) Deregulation of let-7e in epithelial ovarian cancer promotes the development of resistance to cisplatin. Oncogenesis 2, e75
  28. Hsu DS, Lan HY, Huang CH et al (2010) Regulation of excision repair cross-complementation group 1 by Snail contributes to cisplatin resistance in head and neck cancer. Clin Cancer Res 16, 4561-4571
  29. Kaufhold S and Bonavida B (2014) Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res 33, 62
  30. Haslehurst AM, Koti M, Dharsee M et al (2012) EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer 12, 91
  31. Zhuo W, Wang Y, Zhuo X, Zhang Y, Ao X and Chen Z (2008) Knockdown of Snail, a novel zinc finger transcription factor, via RNA interference increases A549 cell sensitivity to cisplatin via JNK/mitochondrial pathway. Lung Cancer 62, 8-14