nach oben

Tumor Biology

Erschienen in:

19.10.2015 | Original Article

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

verfasst von: Juan Du, LiNa Wang, ChenXi Li, HuiLun Yang, YuanBo Li, Haiyang Hu, Hui Li, ZongFeng Zhang

Erschienen in: Tumor Biology | Ausgabe 3/2016

Einloggen, um Zugang zu erhalten

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.

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed

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.CrossRefPubMed

Thomas GM. Improved treatment for cervical cancer—concurrent chemotherapy and radiotherapy. N Engl J Med. 1999;340(15):1198–200.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.PubMedPubMedCentral

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.CrossRefPubMed

17.

Ruan K, Fang X, Ouyang G. MicroRNAs: novel regulators in the hallmarks of human cancer. Cancer Lett. 2009;285(2):116–26.CrossRefPubMed

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.PubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.

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.PubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.PubMed

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.CrossRefPubMedPubMedCentral

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.PubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMedPubMedCentral

Titel: MicroRNA-221 targets PTEN to reduce the sensitivity of cervical cancer cells to gefitinib through the PI3K/Akt signaling pathway
verfasst von: Juan Du
LiNa Wang
ChenXi Li
HuiLun Yang
YuanBo Li
Haiyang Hu
Hui Li
ZongFeng Zhang
Publikationsdatum: 19.10.2015
Verlag: Springer Netherlands
Erschienen in: Tumor Biology / Ausgabe 3/2016
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-015-4247-8

Neu im Fachgebiet Onkologie

24.04.2024 | DGIM 2024 | Nachrichten

Springer Medizin

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

Abstract

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2016

Extracellular vesicles in breast cancer drug resistance and their clinical application

Recurrence of squamous cell lung carcinoma is associated with the co-presence of reactive lesions in tumor-adjacent bronchial epithelium

Detection of Epstein-Barr virus genome and latent infection gene expression in normal epithelia, epithelial dysplasia, and squamous cell carcinoma of the oral cavity

Prognostic impact of cytological fluid tumor markers in non-small cell lung cancer

HNRNPC as a candidate biomarker for chemoresistance in gastric cancer

Immunotherapy of biliary tract cancer

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie