Advertisement

Tumor Biology

, Volume 37, Issue 3, pp 3939–3947 | Cite as

MicroRNA-221 targets PTEN to reduce the sensitivity of cervical cancer cells to gefitinib through the PI3K/Akt signaling pathway

  • Juan Du
  • LiNa Wang
  • ChenXi Li
  • HuiLun Yang
  • YuanBo Li
  • Haiyang Hu
  • Hui Li
  • ZongFeng Zhang
Original Article

Abstract

Patients with cervical cancer show minimal clinical response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). The molecular mechanisms underlying sensitivity to gefitinib are unknown. The purpose of this study was to investigate the possible mechanism by which microRNA-221 (miR-221) affects sensitivity to gefitinib. We showed that miR-221 expression was significantly increased in cervical cancer tissues compared with adjacent normal tissues. Upregulation of miR-221 expression in cervical cancer cells decreased PTEN expression levels, resulting in increased pAkt and BCL-2 expression. Importantly, gefitinib sensitivity was decreased by the upregulation of miR-221, which was blocked by pcDNA-PTEN co-transfection or by the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002. These data suggest that miR-221 can reduce the sensitivity of cervical cancer cells to gefitinib through the PTEN/PI3K/Akt signaling pathway. miR-221 represents a potential target to increase the sensitivity to gefitinib in cervical cancer treatment.

Keywords

Cervical cancer miR-221 Gefitinib PTEN 

Abbreviations

NCCN

National Comprehensive Cancer Network

TKIs

Tyrosine kinase inhibitors

NSCLC

Non-small-cell lung cancers

EGFR

Epidermal growth factor receptor

miRNAs

MicroRNAs

PTEN

Phosphatase and tensin homolog deleted on chromosome ten

PI3K

Phosphatidylinositol-3 kinase

DMEM

Dulbecco’s modified Eagle’s medium

DMSO

Dimethyl sulfoxide

MMP-2

Matrix metalloproteinase 2

MAPK

Mitogen-activated protein kinase

MET

Hepatocyte growth factor

Notes

Acknowledgments

This work was supported by a foundation of the Heilongjiang Provincial Educational Department, China (Grant No. 11551163).

Compliance with ethical standards

Written informed consent was obtained from the patients prior to participation in this study.

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999;340(15):1144–53.CrossRefPubMedGoogle Scholar
  3. 3.
    Thomas GM. Improved treatment for cervical cancer—concurrent chemotherapy and radiotherapy. N Engl J Med. 1999;340(15):1198–200.CrossRefPubMedGoogle Scholar
  4. 4.
    Zighelboim I, Wright JD, Gao F, Case AS, Massad LS, Mutch DG, et al. Multicenter phase II trial of topotecan, cisplatin and bevacizumab for recurrent or persistent cervical cancer. Gynecol Oncol. 2013;130(1):64–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Wang CC, Chou HH, Yang LY, Lin H, Liou WS, Tseng CW, et al. A randomized trial comparing concurrent chemoradiotherapy with single-agent cisplatin versus cisplatin plus gemcitabine in patients with advanced cervical cancer: an Asian Gynecologic Oncology Group study. Gynecol Oncol. 2015;137(3):462–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Lorusso D, Petrelli F, Coinu A, Raspagliesi F, Barni S. A systematic review comparing cisplatin and carboplatin plus paclitaxel-based chemotherapy for recurrent or metastatic cervical cancer. Gynecol Oncol. 2014;133(1):117–23.CrossRefPubMedGoogle Scholar
  7. 7.
    Manci N, Marchetti C, Di Tucci C, Giorgini M, Esposito F, Palaia I, et al. A prospective phase II study of topotecan (Hycamtin®) and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer. Gynecol Oncol. 2011;122(2):285–90.CrossRefPubMedGoogle Scholar
  8. 8.
    Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39.CrossRefPubMedGoogle Scholar
  9. 9.
    Kersemaekers AM, Fleuren GJ, Kenter GG, Van den Broek LJ, Uljee SM, Hermans J, et al. Oncogene alterations in carcinomas of the uterine cervix: overexpression of the epidermal growth factor receptor is associated with poor prognosis. Clin Cancer Res. 1999;5(3):577–86.PubMedGoogle Scholar
  10. 10.
    Mathur SP, Mathur RS, Rust PF, Young RC. Human papilloma virus (HPV)-E6/E7 and epidermal growth factor receptor (EGF-R) protein levels in cervical cancer and cervical intraepithelial neoplasia (CIN). Am J Reprod Immunol. 2001;46(4):280–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Goncalves A, Fabbro M, Lhommé C, Gladieff L, Extra JM, Floquet A, et al. A phase II trial to evaluate gefitinib as second- or third-line treatment in patients with recurring locoregionally advanced or metastatic cervical cancer. Gynecol Oncol. 2008;108(1):42–6.CrossRefPubMedGoogle Scholar
  12. 12.
    An J, Zhu X, Wang H, Jin X. A dynamic interplay between alternative polyadenylation and microRNA regulation: implications for cancer (Review). Int J Oncol. 2013;43(4):995–1001.PubMedGoogle Scholar
  13. 13.
    Ke J, Zhao Z, Hong SH, Bai S, He Z, Malik F, et al. Role of microRNA221 in regulating normal mammary epithelial hierarchy and breast cancer stem-like cells. Oncotarget. 2015;6(6):3709–21.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Fu X, Wang Q, Chen J, Huang X, Chen X, Cao L, et al. Clinical significance of miR-221 and its inverse correlation with p27Kip1 in hepatocellular carcinoma. Mol Biol Rep. 2011;38(5):3029–35.CrossRefPubMedGoogle Scholar
  15. 15.
    Sarkar S, Dubaybo H, Ali S, Goncalves P, Kollepara SL, Sethi S, et al. Down-regulation of miR-221 inhibits proliferation of pancreatic cancer cells through up-regulation of PTEN, p27(kip1), p57(kip2), and PUMA. Am J Cancer Res. 2013;3(5):465–77.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Lau MT, Klausen C, Leung PC. E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression. Oncogene. 2011;30(24):2753–66.CrossRefPubMedGoogle Scholar
  17. 17.
    Ruan K, Fang X, Ouyang G. MicroRNAs: novel regulators in the hallmarks of human cancer. Cancer Lett. 2009;285(2):116–26.CrossRefPubMedGoogle Scholar
  18. 18.
    Song X, Shi B, Huang K, Zhang W. miR-133a inhibits cervical cancer growth by targeting EGFR. Oncol Rep. 2015. doi: 10.3892/or.2015.4101.PubMedCentralGoogle Scholar
  19. 19.
    Wang LQ, Zhang Y, Yan H, Liu KJ, Zhang S. MicroRNA-373 functions as an oncogene and targets YOD1 gene in cervical cancer. Biochem Biophys Res Commun. 2015;459(3):515–20.CrossRefPubMedGoogle Scholar
  20. 20.
    Yang F, Wang W, Zhou C, Xi W, Yuan L, Chen X, et al. MiR-221/222 promote human glioma cell invasion and angiogenesis by targeting TIMP2. Tumour Biol. 2015;36(5):3763–73.CrossRefPubMedGoogle Scholar
  21. 21.
    Bae HJ, Jung KH, Eun JW, Shen Q, Kim HS, Park SJ, et al. MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer. J Hepatol. 2015. doi: 10.1016/j.jhep.2015.03.019.Google Scholar
  22. 22.
    Gocze K, Gombos K, Juhasz K, Kovacs K, Kajtar B, Benczik M, et al. Unique microRNA expression profiles in cervical cancer. Anticancer Res. 2013;33(6):2561–7.PubMedGoogle Scholar
  23. 23.
    Sun Y, St Clair DK, Fang F, Warren GW, Rangnekar VM, Crooks PA, et al. The radiosensitization effect of parthenolide in prostate cancer cells is mediated by nuclear factor-kappaB inhibition and enhanced by the presence of PTEN. Mol Cancer Ther. 2007;6(9):2477–86.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8(8):627–44.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Cui B, Zheng B, Zhang X, Stendahl U, Andersson S, Wallin KL. Mutation of PIK3CA: possible risk factor for cervical carcinogenesis in older women. Int J Oncol. 2009;34(2):409–16.PubMedGoogle Scholar
  26. 26.
    Shultz JC, Goehe RW, Wijesinghe DS, Murudkar C, Hawkins AJ, Shay JW, et al. Alternative splicing of caspase 9 is modulated by the phosphoinositide 3-kinase/Akt pathway via phosphorylation of SRp30a. Cancer Res. 2010;70(22):9185–96.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Siddiqa A, Long LM, Li L, Marciniak RA, Kazhdan I. Expression of HER-2 in MCF-7 breast cancer cells modulates anti-apoptotic proteins survivin and Bcl-2 via the extracellular signal-related kinase (ERK) and phosphoinositide-3 kinase (PI3K) signalling pathways. BMC Cancer. 2008. doi: 10.1186/1471-2407-8-129.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Zhang Z, Song T, Jin Y, Pan J, Zhang L, Wang L, et al. Epidermal growth factor receptor regulates MT1-MMP and MMP-2 synthesis in SiHa cells via both PI3-K/AKT and MAPK/ERK pathways. Int J Gynecol Cancer. 2009;19(6):998–1003.CrossRefPubMedGoogle Scholar
  29. 29.
    Chun-Zhi Z, Lei H, An-Ling Z, Yan-Chao F, Xiao Y, Guang-Xiu W, et al. MicroRNA-221 and microRNA-222 regulate gastric carcinoma cell proliferation and radioresistance by targeting PTEN. BMC Cancer. 2010;10:367.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A, et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell. 2009;16(6):498–509.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786–92.CrossRefPubMedGoogle Scholar
  32. 32.
    Shih JY, Gow CH, Yang PC. EGFR mutation conferring primary resistance to gefitinib in non-small-cell lung cancer. N Engl J Med. 2005;353(2):207–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039–43.CrossRefPubMedGoogle Scholar
  34. 34.
    Garofalo M, Romano G, Di Leva G, Nuovo G, Jeon YJ, Ngankeu A, et al. EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med. 2011;18(1):74–82.PubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Juan Du
    • 1
  • LiNa Wang
    • 1
  • ChenXi Li
    • 1
  • HuiLun Yang
    • 1
  • YuanBo Li
    • 1
  • Haiyang Hu
    • 1
  • Hui Li
    • 1
  • ZongFeng Zhang
    • 1
  1. 1.Department of Obstetrics and Gynecology, Second Affiliated HospitalHarbin Medical UniversityHarbinChina

Personalised recommendations