Advertisement

Cytotechnology

, Volume 70, Issue 1, pp 203–213 | Cite as

MiR-221/222 promote chemoresistance to cisplatin in ovarian cancer cells by targeting PTEN/PI3K/AKT signaling pathway

  • Zeinab Amini-Farsani
  • Mohammad Hossein Sangtarash
  • Mehdi Shamsara
  • Hossein Teimori
Article

Abstract

Cisplatin resistance is one of the main limitations in the treatment of ovarian cancer, and its mechanism has not been fully understood. The objectives of this study were to determine the role of miR-221/222 and its underlying mechanism in chemoresistance of ovarian cancer. We demonstrated that miR-221/222 expression levels were higher in A2780/CP cells compared with A2780 S cells. An in vitro cell viability assay showed that downregulation of miR-221/222 sensitized A2780/CP cells to cisplatin-induced cytotoxicity. Moreover, we found that knockdown of miR-221/222 by its specific inhibitors promoted the cisplatin-induced apoptosis in A2780/CP cells. Using bioinformatic analysis and luciferase reporter assay, miR-221/222 were found to directly target PTEN. Moreover, knockdown of miR-221/222 in A2780/CP cells significantly upregulated PTEN and downregulated PI3KCA and p-Akt expression. In conclusion, our results demonstrated that miR-221/222 induced cisplatin resistance by targeting PTEN mediated PI3K/Akt pathway in A2780/CP cells, suggesting that miR-221/222/PTEN/PI3K/Akt may be a promising prognostic and therapeutic target to overcome cisplatin resistance and treat ovarian cancer in the future.

Keywords

Cisplatin MiR-221/222 PTEN Ovarian cancer Apoptosis 

Notes

Acknowledgements

This work was supported by Shahrekord University of Medical Sciences, Shahrekord, Iran (Research Grant: 1837). We would also like to acknowledge the staffs at the Cellular and Molecular Research Center for their sincere cooperation.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interests.

References

  1. Abbosh PH, Montgomery JS, Starkey JA, Novotny M, Zuhowski EG, Egorin MJ, Moseman AP, Golas A, Brannon KM, Balch C, Huang TH, Nephew KP (2006) Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells. Cancer Res 66:5582–5591CrossRefGoogle Scholar
  2. Atlanta GA (2013) American Cancer Society. Cancer facts and figures 2013. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2013
  3. Cai Y, Tan X, Liu J, Shen Y, Wu D, Ren M, Huang P, Yu D (2014) Inhibition of PI3K/Akt/mTOR signaling pathway enhances the sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatin in vitro. Chin J Cancer Res 26:564–572Google Scholar
  4. Cai G, Qiao Sh, Chen K (2015) Suppression of miR-221 inhibits glioma cells proliferation and invasion via targeting SEMA3B. Biol Res 48:37CrossRefGoogle Scholar
  5. Chatterjee A, Chattopadhyay D, Chakrabarti G (2014) MiR-17-5p downregulation contributes to paclitaxel resistance of lung cancer cells through altering beclin1 expression. PLoS ONE 9:e95716CrossRefGoogle Scholar
  6. Felli N, Fontana L, Pelosi E, Botta R, Bonci D, Facchiano F, Liuzzi F, Lulli V, Morsilli O, Santoro S, Valtieri M, Calin GA, Liu CG, Sorrentino A, Croce CM, Peschle C (2005) MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci USA 102:18081–18086CrossRefGoogle Scholar
  7. Fu X, Wang Q, Chen J, Huang X, Chen X, Cao L, Tan H, Li W, Zhang L, Bi J, Su Q, Chen L (2011) Clinical significance of miR-221 and its inverse correlation with p27Kip1 in hepatocellular carcinoma. Mol Biol Rep 38:3029–3035CrossRefGoogle Scholar
  8. Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A, Taccioli C, Pichiorri F, Alder H, Secchiero P, Gasparini P, Gonelli A, Costinean S, Acunzo M, Condorelli G, Croce CM (2009) miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 16:498–509CrossRefGoogle Scholar
  9. Garofalo M, Quintavalle C, Romano G, Croce CM, Condorelli G (2012) miR221/222 in cancer: their role in tumor progression and response to therapy. Curr Mol Med 12:27–33CrossRefGoogle Scholar
  10. Hafsi S, Pezzino M, Candido S, Ligresti G, Spandidos DA, Soua Z, McCubrey JA, Travali S, Libra M (2012) Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance. Int J Oncol 40:639–644Google Scholar
  11. Harapan H, Andalas M (2015) The role of microRNAs in the proliferation, differentiation, invasion, and apoptosis of trophoblasts during the occurrence of preeclampsiad. Tzu Chi Med J 27:54–64CrossRefGoogle Scholar
  12. Kigawa J (2013) New strategy for overcoming resistance to chemotherapy of ovarian cancer. Yonago Acta Med 56:43–50Google Scholar
  13. Komeili-Movahhed T, Fouladdel S, Barzegar E, Atashpour S, Hossein Ghahremani M, Nasser Ostad S, Madjd Z, Azizi E (2015) PI3K/Akt inhibition and down-regulation of BCRP re-sensitize MCF7 breast cancer cell line to mitoxantrone chemotherapy. Iran J Basic Med Sci 18:472–477Google Scholar
  14. Lee S, Choi EJ, Jin C, Kim DH (2005) Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol 97:26–34CrossRefGoogle Scholar
  15. Li B, Ren S, Li X, Wang Y, Garfield D, Zhou S, Chen X, Su C, Chen M, Kuang P, Gao G, He Y, Fan L, Fei K, Zhou C, Schmit-Bindert G (2014) MiR-21 overexpression is associated with acquired resistance of EGFR-TKI in non-small cell lung cancer. Lung Cancer 83:146–153CrossRefGoogle Scholar
  16. Li B, Lu Y, Wang H, Han X, Mao J, Li J, Yu L, Wang B, Fan S, Yu X, Song B (2016) miR-221/222 enhance the tumorigenicity of human breast cancer stem cells via modulation of PTEN/Akt pathway. Biomed Pharmacother 79:93–101CrossRefGoogle Scholar
  17. Ling H, Fabbri M, Calin GA (2013) MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 12:847–865CrossRefGoogle Scholar
  18. Liu X, Yu J, Jiang L, Shi F, Ye H, Zhou X (2009) MicroRNA-222 regulates cell invasion by targeting matrix metalloproteinase 1 (MMP1) and manganese superoxide dismutase 2 (SOD2) in tongue squamous cell carcinoma cell lines. Cancer Genom Proteom 6:131–139Google Scholar
  19. Liu Z, Zhu G, Getzenberg RH, Veltri RW (2015) The upregulation of PI3K/Akt and MAP kinase pathways is associated with resistance of microtubule-targeting drugs in prostate cancer. J Cell Biochem 116:1341–1349CrossRefGoogle Scholar
  20. Magee P, Shi L, Garofalo M (2015) Role of microRNAs in chemoresistance. Ann Transl Med 3:332Google Scholar
  21. Matsuoka T, Yashiro M (2014) The role of PI3K/Akt/mTOR signaling in gastric carcinoma. Cancers (Basel) 6:1441–1463CrossRefGoogle Scholar
  22. Mccubrey JA, Steelmana LS, Abramsa SL, Leea JT, Changa F, Bertranda FE (2006) Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Enzyme Regul 46:249–279CrossRefGoogle Scholar
  23. Miller TE, Ghoshal K, Ramaswamy B, Roy S, Datta J, Shapiro CL, Jacob S, Majumder S (2008) MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem 283:29897–29903CrossRefGoogle Scholar
  24. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Canc Cell 6:117–127CrossRefGoogle Scholar
  25. Rao X, Di Leva G, Li M, Fang F, Devlin C, Hartman-Frey C, Burow ME, Ivan M, Croce CM, Nephew KP (2011) MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways. Oncogene 30:1082–1097CrossRefGoogle Scholar
  26. Stinson S, Lackner MR, Adai AT, Yu N, Kim HJ, O’Brien C, Spoerke J, Jhunjhunwala S, Boyd Z, Januario T, Newman RJ, Yue P, Bourgon R, Modrusan Z, Stern HM, Warming S, de Sauvage FJ, Amler L, Yeh RF, Dornan D (2011) TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer. Sci Signal 4:ra41CrossRefGoogle Scholar
  27. Tsai MS, Kuo YH, Chiu YF, Su YC, Lin YW (2010) Down-regulation of Rad51 expression overcomes drug resistance to gemcitabine in human Non–Small-Cell Lung cancer cells. JPET 335:830–840CrossRefGoogle Scholar
  28. Wang DD, Yang SJ, Chen X, Shen HY, Luo LJ, Zhang XH, Zhong SL, Zhao JH, Tang JH (2016) miR-222 induces adriamycin resistance in breast cancer through PTEN/Akt/p27kip1 pathway. Tumour Biol 37:15315–15324CrossRefGoogle Scholar
  29. Yuge K, Kikuchi E, Hagiwara M, Yasumizu Y, Tanaka N, Kosaka T, Miyajima A, Oya M (2015) Nicotine induces tumor growth and chemoresistance through activation of the PI3K/Akt/mTOR pathway in bladder cancer. Mol Canc Ther 14:2112–2120CrossRefGoogle Scholar
  30. Zhang C, Zhang J, Zhang A, Wang Y, Han L, You Y, Pu P, Kang C (2010) PUMA is a novel target of miR-221/222 in human epithelial cancers. Int J Oncol 37:1621–1626CrossRefGoogle Scholar
  31. Zhao G, Cai Ch, Yang T, Qiu X, Liao B, Li W, Ji Z, Zhao J, Zhao H, Guo M, Ma Q, Xiao C, Fan Q, Ma B (2013) MicroRNA-221 induces cell survival and cisplatin resistance through PI3K/Akt pathway in human osteosarcoma. PLoS ONE 8:e53906CrossRefGoogle Scholar
  32. Zheng ZG, Xu H, Suo SS, Xu XL, Ni MW, Gu LH, Chen W, Wang LY, Zhao Y, Tian B, Hua YJ (2016) The essential role of H19 contributing to cisplatin resistance by regulating glutathione metabolism in high-grade serous ovarian cancer. Sci Rep 19:26093CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  • Zeinab Amini-Farsani
    • 1
  • Mohammad Hossein Sangtarash
    • 1
  • Mehdi Shamsara
    • 2
  • Hossein Teimori
    • 3
  1. 1.Department of BiologyUniversity of Sistan and BaluchestanZahedanIran
  2. 2.National Research Center for Transgenic MouseNational Institute of Genetic Engineering and BiotechnologyTehranIran
  3. 3.Cellular and Molecular Research Center, Basic Health Sciences InstituteShahrekord University of Medical SciencesRahmatiyeh, ShahrekordIran

Personalised recommendations