Cancer Chemotherapy and Pharmacology

, Volume 81, Issue 5, pp 935–947 | Cite as

MircroRNA-139 sensitizes ovarian cancer cell to cisplatin-based chemotherapy through regulation of ATP7A/B

  • Fang Xiao
  • Yueran Li
  • Yajun Wan
  • Min Xue
Original Article



Ovarian cancer remains a most malignant female cancer nowadays. The acquisition of chemoresistance to common-used cisplatin-based chemotherapy results in a decreased overall patient survival. The present study is aimed to investigate the role and mechanism by which miR-139/ ATPases7A/B axis modulates the chemoresistance of ovarian cancer to cisplatin-based chemotherapy.


The expression of miR-139 in cisplatin-sensitive (n = 23) and cisplatin-resistant (n = 14) ovarian cancer tissues and cell lines (CAOV-3 and SNU119) was determined using real-time PCR assays; its effect on ovarian cancer cell chemoresistance to different concentrations of cisplatin was then assessed by measuring the cell viability using MTT assays. Next, miR-139 binding to the 3′UTR of ATP7A/B was confirmed using luciferase reporter gene assays. Finally, the combined effect of miR-139 and ATP7A/B on the chemoresistance of ovarian cancer cell was assessed.


miR-139 expression was down-regulated in cisplatin-resistant ovarian cancer tissues (**P < 0.01) and reduced by cisplatin treatment in ovarian cell lines (*P < 0.05, **P < 0.01); miR-139 could enhance cisplatin-induced suppression on ovarian cancer cell viability, shown as reduced lC50 values; ATP7A and ATP7B protein levesincreased approximately 2 ~ fold-changein cisplatin-resistant cell lines. MiR-139 directly bound to the 3′UTR of ATP7A/B, respectively; miR-139 inhibition increased lC50 values whereas ATP7A/B knockdown reduced lC50 values of CAOV-3 and SNU119 cell lines under cisplatin treatment; the effect of miR-139 inhibition could be partially attenuated by ATP7A/B knockdown.


MiR-139/ATP7A/B axis can be a reliable biomarker for ovarian cancer diagnosis, and may affect the chemoresistance of ovarian cancer to cisplatin-based chemotherapy; rescuing miR-139 expression thus to inhibit ATP7A/B might contribute to dealing with the chemoresistance of ovarian cancer.


Ovarian cancer Chemoresistance Cisplatin (cDDP) MiR-139 ATP7A ATP7B 


Author contributions statement

Fang Xiao designed and performed the experiments, wrote the manuscript. Fang Xiao and Yueran Li have contributed to experimental work and data analysis. Yajun Wan and Min Xue conducted the experiments and revised the manuscript. All authors have read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

Author Fang Xiao declares that she has no conflict of interest. Author Yueran Li declares that she has no conflict of interest. Author Yajun Wan declares that she has no conflict of interest. Author Min Xue declares that she has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

280_2018_3548_MOESM1_ESM.tif (773 kb)
Fig. S1 Transfection efficiency and expression level confirmation (A-B) miR-139 mimics was transfected into CAOV3 and SNU119 cells to achieve ectopic miR-139 expression, as verified using real-time PCR assays. (C) The expression of ATP7A in CAOV3, SNU119, CAOV3/cDDP and SNU119/cDDP cells was determined by Immunoblotting. (D) The expression of miR-139 in CAOV3, SNU119, CAOV3/cDDP and SNU119/cDDP cells was determined by RT-PCR. (E) CAOV3 and SNU119 cells were transfected with miR-139 inhibitor to achieve miR-139 inhibition, as verified using real-time PCR assays. (F) The expression of ATP7B in CAOV3, SNU119, CAOV3/cDDP and SNU119/cDDP cells was determined by Immunoblotting. (TIF 773 KB)
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  1. 1.
    Webb PM, Jordan SJ (2017) Epidemiology of epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol 41:3–14. CrossRefPubMedGoogle Scholar
  2. 2.
    Jayde V, White K, Blomfield P (2009) Symptoms and diagnostic delay in ovarian cancer: a summary of the literature. Contemp Nurse 34(1):55–65CrossRefPubMedGoogle Scholar
  3. 3.
    Jayde V, Boughton M (2012) The diagnostic journey of ovarian cancer: a review of the literature and suggestions for practice. Contemp Nurse 41(1):5–17. CrossRefPubMedGoogle Scholar
  4. 4.
    Winner KR, Steinkamp MP, Lee RJ, Swat M, Muller CY, Moses ME, Jiang Y, Wilson BS (2016) Spatial modeling of drug delivery routes for treatment of disseminated ovarian cancer. Cancer Res 76(6):1320–1334. CrossRefPubMedGoogle Scholar
  5. 5.
    Ween MP, Armstrong MA, Oehler MK, Ricciardelli C (2015) The role of ABC transporters in ovarian cancer progression and chemoresistance. Crit Rev Oncol Hematol 96(2):220–256. CrossRefPubMedGoogle Scholar
  6. 6.
    Ali AY, Farrand L, Kim JY, Byun S, Suh JY, Lee HJ, Tsang BK (2012) Molecular determinants of ovarian cancer chemoresistance: new insights into an old conundrum. Ann N Y Acad Sci 1271:58–67. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mihanfar A, Fattahi A, Nejabati HR (2017) MicroRNA-mediated drug resistance in ovarian cancer. J Cell Physiol. PubMedGoogle Scholar
  8. 8.
    van Jaarsveld MT, Helleman J, Berns EM, Wiemer EA (2010) MicroRNAs in ovarian cancer biology and therapy resistance. Int J Biochem Cell Biol 42(8):1282–1290. CrossRefPubMedGoogle Scholar
  9. 9.
    Yang N, Kaur S, Volinia S, Greshock J, Lassus H, Hasegawa K, Liang S, Leminen A, Deng S, Smith L, Johnstone CN, Chen XM, Liu CG, Huang Q, Katsaros D, Calin GA, Weber BL, Butzow R, Croce CM, Coukos G, Zhang L (2008) MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer. Cancer Res 68(24):10307–10314. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Cochrane DR, Spoelstra NS, Howe EN, Nordeen SK, Richer JK (2009) MicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents. Mol Cancer Ther 8(5):1055–1066. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Pal MK, Jaiswar SP, Dwivedi VN, Tripathi AK, Dwivedi A, Sankhwar P (2015) MicroRNA: a new and promising potential biomarker for diagnosis and prognosis of ovarian cancer. Cancer Biol Med 12(4):328–341. PubMedPubMedCentralGoogle Scholar
  12. 12.
    Hu Y, Deng C, Zhang H, Zhang J, Peng B, Hu C (2017) Long non-coding RNA XIST promotes cell growth and metastasis through regulating miR-139-5p mediated Wnt/beta-catenin signaling pathway in bladder cancer. Oncotarget 8(55):94554–94568. PubMedPubMedCentralGoogle Scholar
  13. 13.
    Huang P, Xi J, Liu S (2016) MiR-139-3p induces cell apoptosis and inhibits metastasis of cervical cancer by targeting NOB1. Biomed Pharmacother 83:850–856. CrossRefPubMedGoogle Scholar
  14. 14.
    Yue S, Wang L, Zhang H, Min Y, Lou Y, Sun H, Jiang Y, Zhang W, Liang A, Guo Y, Chen P, Lv G, Wang L, Zong Q, Li Y (2015) miR-139-5p suppresses cancer cell migration and invasion through targeting ZEB1 and ZEB2 in GBM. Tumour Biol 36(9):6741–6749. CrossRefPubMedGoogle Scholar
  15. 15.
    Zhang HD, Sun DW, Mao L, Zhang J, Jiang LH, Li J, Wu Y, Ji H, Chen W, Wang J (2015) MiR-139-5p inhibits the biological function of breast cancer cells by targeting Notch1 and mediates chemosensitivity to docetaxel. Biochem Biophys Res Commun 465(4):702–713CrossRefPubMedGoogle Scholar
  16. 16.
    Liu H, Yin Y, Hu Y, Feng Y, Bian Z, Yao S, Li M, You Q, Huang Z (2016) miR-139-5p sensitizes colorectal cancer cells to 5-fluorouracil by targeting NOTCH-1. Pathol Res Pract 212(7):643–649CrossRefPubMedGoogle Scholar
  17. 17.
    Ke X, Ke S, Xin L, Li Y, Nagao N, Li J, Liu J, Yin P (2016) MiR-139-5p reverses CD44+/CD133+-associated multidrug resistance by downregulating NOTCH1 in colorectal carcinoma cells. Oncotarget 7(46):75118Google Scholar
  18. 18.
    Li Q, Liang X, Wang Y, Meng X, Xu Y, Cai S, Wang Z, Liu J, Cai G (2016) miR-139-5p inhibits the epithelial-mesenchymal transition and enhances the chemotherapeutic sensitivity of colorectal cancer cells by downregulating BCL2. Sci Rep 6:27157CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sun S, Cai J, Yang Q, Zhao S, Wang Z (2017) The association between copper transporters and the prognosis of cancer patients undergoing chemotherapy: a meta-analysis of literatures and datasets. Oncotarget 8(9):16036–16051. PubMedGoogle Scholar
  20. 20.
    Mangala LS, Zuzel V, Schmandt R, Leshane ES, Halder JB, Armaiz-Pena GN, Spannuth WA, Tanaka T, Shahzad MM, Lin YG, Nick AM, Danes CG, Lee JW, Jennings NB, Vivas-Mejia PE, Wolf JK, Coleman RL, Siddik ZH, Lopez-Berestein G, Lutsenko S, Sood AK (2009) Therapeutic targeting of ATP7B in ovarian carcinoma. Clin Cancer Res 15(11):3770–3780. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kalayda GV, Wagner CH, Buss I, Reedijk J, Jaehde U (2008) Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with cisplatin resistance in human ovarian carcinoma cells. BMC Cancer 8(1):175CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sabbatini G, Baldoni G (2004) Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B. Mol Pharmacol 66(1):25–32CrossRefGoogle Scholar
  23. 23.
    Safaei R, Holzer AK, Katano K, Samimi G, Howell SB (2004) The role of copper transporters in the development of resistance to Pt drugs. J Inorg Biochem 98(10):1607–1613CrossRefPubMedGoogle Scholar
  24. 24.
    Samimi G, Varki NM, Wilczynski S, Safaei R, Alberts DS, Howell SB (2003) Increase in expression of the copper transporter ATP7A during platinum drug-based treatment is associated with poor survival in ovarian cancer patients. Clin Cancer Res 9(16 Pt 1):5853PubMedGoogle Scholar
  25. 25.
    Nakayama K, Kanzaki A, Terada K, Mutoh M, Ogawa K, Sugiyama T, Takenoshita S, Itoh K, Yaegashi N, Miyazaki K (2004) Prognostic value of the Cu-transporting ATPase in ovarian carcinoma patients receiving cisplatin-based chemotherapy. Clin Cancer Res 10(8):2804–2811CrossRefPubMedGoogle Scholar
  26. 26.
    Agarwal V, Bell GW, Nam JW, Bartel DP (2015) Predicting effective microRNA target sites in mammalian mRNAs. Elife. Google Scholar
  27. 27.
    Current FIGO. staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia (2009). Int J Gynaecol Obstet 105 (1):3–4Google Scholar
  28. 28.
    Scully RE, Sobin LH (1987) Histologic typing of ovarian tumors. Arch Pathol Lab Med 111(9):794–795PubMedGoogle Scholar
  29. 29.
    Shepherd JH (1989) Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol 96(8):889–892CrossRefPubMedGoogle Scholar
  30. 30.
    Zhu X, Shen H, Yin X, Long L, Chen X, Feng F, Liu Y, Zhao P, Xu Y, Li M, Xu W, Li Y (2017) IL-6R/STAT3/miR-204 feedback loop contributes to cisplatin resistance of epithelial ovarian cancer cells. Oncotarget 8(24):39154–39166. PubMedPubMedCentralGoogle Scholar
  31. 31.
    Wang Y, Kim S, Kim IM (2014) Regulation of metastasis by microRNAs in ovarian cancer. Front Oncol 4:143. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Park YT, Jeong JY, Lee MJ, Kim KI, Kim TH, Kwon YD, Lee C, Kim OJ, An HJ (2013) MicroRNAs overexpressed in ovarian ALDH1-positive cells are associated with chemoresistance. J Ovarian Res 6(1):18. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Cheng W, Liu T, Wan X, Gao Y, Wang H (2012) MicroRNA-199a targets CD44 to suppress the tumorigenicity and multidrug resistance of ovarian cancer-initiating cells. FEBS J 279(11):2047–2059. CrossRefPubMedGoogle Scholar
  34. 34.
    Wang Z, Ting Z, Li Y, Chen G, Lu Y, Hao X (2013) microRNA-199a is able to reverse cisplatin resistance in human ovarian cancer cells through the inhibition of mammalian target of rapamycin. Oncol Lett 6(3):789–794. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Chen X, Lu P, Wang DD, Yang SJ, Wu Y, Shen HY, Zhong SL, Zhao JH, Tang JH (2016) The role of miRNAs in drug resistance and prognosis of breast cancer formalin-fixed paraffin-embedded tissues. Gene 595(2):221–226. CrossRefPubMedGoogle Scholar
  36. 36.
    Chen Y, Gao DY, Huang L (2015) In vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv Drug Deliv Rev 81:128–141. CrossRefPubMedGoogle Scholar
  37. 37.
    Aigner A (2011) MicroRNAs (miRNAs) in cancer invasion and metastasis: therapeutic approaches based on metastasis-related miRNAs. J Mol Med (Berl) 89(5):445–457. CrossRefGoogle Scholar
  38. 38.
    Dwivedi SK, Mustafi SB, Mangala LS, Jiang D, Pradeep S, Rodriguez-Aguayo C, Ling H, Ivan C, Mukherjee P, Calin GA, Lopez-Berestein G, Sood AK, Bhattacharya R (2016) Therapeutic evaluation of microRNA-15a and microRNA-16 in ovarian cancer. Oncotarget 7(12):15093–15104. CrossRefPubMedGoogle Scholar
  39. 39.
    Zhao M, Su Z, Zhang S, Zhuang L, Xie Y, Li X (2016) Suppressive role of MicroRNA-148a in cell proliferation and invasion in ovarian cancer through targeting transforming growth factor-beta-induced 2. Oncol Res 24(5):353–360. CrossRefPubMedGoogle Scholar
  40. 40.
    Zhao S, Wen Z, Liu S, Liu Y, Li X, Ge Y, Li S (2015) MicroRNA-148a inhibits the proliferation and promotes the paclitaxel-induced apoptosis of ovarian cancer cells by targeting PDIA3. Mol Med Rep 12(3):3923–3929. CrossRefPubMedGoogle Scholar
  41. 41.
    Zhou X, Zhao F, Wang ZN, Song YX, Chang H, Chiang Y, Xu HM (2012) Altered expression of miR-152 and miR-148a in ovarian cancer is related to cell proliferation. Oncol Rep 27(2):447–454. PubMedGoogle Scholar
  42. 42.
    Wen Z, Zhao S, Liu S, Liu Y, Li X, Li S (2015) MicroRNA-148a inhibits migration and invasion of ovarian cancer cells via targeting sphingosine-1-phosphate receptor 1. Mol Med Rep 12(3):3775–3780. CrossRefPubMedGoogle Scholar
  43. 43.
    Benson EA, Skaar TC, Liu Y, Nephew KP, Matei D (2015) Carboplatin with decitabine therapy, in recurrent platinum resistant ovarian cancer, alters circulating miRNAs concentrations: A Pilot Study. PLoS One 10(10):e0141279. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Gynecology and ObstetricsThe Third Xiangya Hospital of Central South UniversityChangshaChina

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