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01-06-2016 | Original Article

MiRNA-21 induces epithelial to mesenchymal transition and gemcitabine resistance via the PTEN/AKT pathway in breast cancer

Authors: Zhen-Hua Wu, Zhong-Hua Tao, Jian Zhang, Ting Li, Chen Ni, Jie Xie, Jin-Feng Zhang, Xi-Chun Hu

Published in: Tumor Biology | Issue 6/2016

Abstract

Acquisition of gemcitabine resistance in breast cancer has not been fully clarified. Prior studies suggest that miRNAs are important to chemoresistance in solid tumors and we confirmed that miR-21 is involved in the development of gemcitabine resistance. Epithelial-to-mesenchymal transition (EMT) and AKT pathway activation were noted to be important to this resistance as well. PTEN, a direct target gene of miR-21, was significantly downregulated in gemcitabine-resistant breast cancer cells and restoration of PTEN expression blocked miR-21-induced EMT and gemcitabine resistance. Our data offer novel insight into gemcitabine resistance in breast cancer and suggest that miR-21 may be used to predict optimal breast cancer therapy and may be a potential therapeutic target for reversing gemcitabine resistance.

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Zhang J, Wang Z, Hu X, Wang B, Wang L, Yang W, et al. Cisplatin and gemcitabine as the first line therapy in metastatic triple negative breast cancer. Int J Cancer. 2015;136(1):204–11. doi:10.1002/ijc.28966.CrossRefPubMed

Hu XC, Zhang J, Xu BH, Cai L, Ragaz J, Wang ZH, et al. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015;16(4):436–46. doi:10.1016/S1470-2045(15)70064-1.CrossRefPubMed

Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Ann Oncol. 2006;17 Suppl 5:v7–v12. doi:10.1093/annonc/mdj941.CrossRefPubMed

Bergman AM, Pinedo HM, Peters GJ. Determinants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine). Drug Resist Updat. 2002;5(1):19–33.CrossRefPubMed

Andersson R, Aho U, Nilsson BI, Peters GJ, Pastor-Anglada M, Rasch W, et al. Gemcitabine chemoresistance in pancreatic cancer: molecular mechanisms and potential solutions. Scand J Gastroenterol. 2009;44(7):782–6. doi:10.1080/00365520902745039.CrossRefPubMed

Kim MP, Gallick GE. Gemcitabine resistance in pancreatic cancer: picking the key players. Clin Cancer Res. 2008;14(5):1284–5. doi:10.1158/1078-0432.CCR-07-2247.CrossRefPubMed

Hagmann W, Jesnowski R, Lohr JM. Interdependence of gemcitabine treatment, transporter expression, and resistance in human pancreatic carcinoma cells. Neoplasia. 2010;12(9):740–7.CrossRefPubMedPubMedCentral

Davidson JD, Ma L, Flagella M, Geeganage S, Gelbert LM, Slapak CA. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Res. 2004;64(11):3761–6. doi:10.1158/0008-5472.CAN-03-3363.CrossRefPubMed

Rha SY, Jeung HC, Choi YH, Yang WI, Yoo JH, Kim BS, et al. An association between RRM1 haplotype and gemcitabine-induced neutropenia in breast cancer patients. Oncologist. 2007;12(6):622–30. doi:10.1634/theoncologist.12-6-622.CrossRefPubMed

10.

Ye FG, Song CG, Cao ZG, Xia C, Chen DN, Chen L, et al. Cytidine deaminase axis modulated by miR-484 differentially regulates cell proliferation and chemoresistance in breast cancer. Cancer Res. 2015;75(7):1504–15. doi:10.1158/0008-5472.CAN-14-2341.CrossRefPubMed

11.

Xia C, Ye F, Hu X, Li Z, Jiang B, Fu Y, et al. Liver kinase B1 enhances chemoresistance to gemcitabine in breast cancer MDA-MB-231 cells. Oncol Lett. 2014;8(5):2086–92. doi:10.3892/ol.2014.2446.PubMedPubMedCentral

12.

Sebastiani V, Ricci F, Rubio-Viqueira B, Kulesza P, Yeo CJ, Hidalgo M, et al. Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival. Clin Cancer Res. 2006;12(8):2492–7. doi:10.1158/1078-0432.CCR-05-2655.CrossRefPubMedPubMedCentral

13.

Ambros V. The functions of animal microRNAs. Nature. 2004;431(7006):350–5. doi:10.1038/nature02871.CrossRefPubMed

14.

Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.CrossRefPubMed

15.

Garg M. Targeting microRNAs in epithelial-to-mesenchymal transition-induced cancer stem cells: therapeutic approaches in cancer. Expert Opin Ther Targets. 2015;19(2):285–97. doi:10.1517/14728222.2014.975794.CrossRefPubMed

16.

Wang Z, Li Y, Ahmad A, Azmi AS, Kong D, Banerjee S, et al. Targeting miRNAs involved in cancer stem cell and EMT regulation: an emerging concept in overcoming drug resistance. Drug Resist Updat. 2010;13(4-5):109–18. doi:10.1016/j.drup.2010.07.001.CrossRefPubMedPubMedCentral

17.

Tao ZH, Wan JL, Zeng LY, Xie L, Sun HC, Qin LX, et al. miR-612 suppresses the invasive-metastatic cascade in hepatocellular carcinoma. J Exp Med. 2013;210(4):789–803. doi:10.1084/jem.20120153.CrossRefPubMedPubMedCentral

18.

Shi Z, Zhang J, Qian X, Han L, Zhang K, Chen L, et al. AC1MMYR2, an inhibitor of dicer-mediated biogenesis of Oncomir miR-21, reverses epithelial-mesenchymal transition and suppresses tumor growth and progression. Cancer Res. 2013;73(17):5519–31. doi:10.1158/0008-5472.CAN-13-0280.CrossRefPubMed

19.

Wu Q, Wang R, Yang Q, Hou X, Chen S, Hou Y, et al. Chemoresistance to gemcitabine in hepatoma cells induces epithelial-mesenchymal transition and involves activation of PDGF-D pathway. Oncotarget. 2013;4(11):1999–2009.CrossRefPubMedPubMedCentral

20.

Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD, et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008;451(7175):147–52. doi:10.1038/nature06487.CrossRefPubMedPubMedCentral

21.

Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene. 2007;26(19):2799–803. doi:10.1038/sj.onc.1210083.CrossRefPubMed

22.

Bao L, Yan Y, Xu C, Ji W, Shen S, Xu G, et al. MicroRNA-21 suppresses PTEN and hSulf-1 expression and promotes hepatocellular carcinoma progression through AKT/ERK pathways. Cancer Lett. 2013;337(2):226–36. doi:10.1016/j.canlet.2013.05.007.CrossRefPubMed

23.

Chan JK, Blansit K, Kiet T, Sherman A, Wong G, Earle C, et al. The inhibition of miR-21 promotes apoptosis and chemosensitivity in ovarian cancer. Gynecol Oncol. 2014;132(3):739–44. doi:10.1016/j.ygyno.2014.01.034.CrossRefPubMed

24.

Yang SM, Huang C, Li XF, Yu MZ, He Y, Li J. miR-21 confers cisplatin resistance in gastric cancer cells by regulating PTEN. Toxicology. 2013;306:162–8. doi:10.1016/j.tox.2013.02.014.CrossRefPubMed

25.

Li B, Ren S, Li X, Wang Y, Garfield D, Zhou S, et al. MiR-21 overexpression is associated with acquired resistance of EGFR-TKI in non-small cell lung cancer. Lung Cancer. 2014;83(2):146–53. doi:10.1016/j.lungcan.2013.11.003.CrossRefPubMed

26.

Gong C, Yao Y, Wang Y, Liu B, Wu W, Chen J, et al. Up-regulation of miR-21 mediates resistance to trastuzumab therapy for breast cancer. J Biol Chem. 2011;286(21):19127–37. doi:10.1074/jbc.M110.216887.CrossRefPubMedPubMedCentral

27.

Wang P, Zhuang L, Zhang J, Fan J, Luo J, Chen H, et al. The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL. Mol Oncol. 2013;7(3):334–45. doi:10.1016/j.molonc.2012.10.011.CrossRefPubMed

28.

Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13(10):714–26. doi:10.1038/nrc3599.CrossRefPubMed

29.

Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15(6):740–6.CrossRefPubMed

30.

Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90. doi:10.1016/j.cell.2009.11.007.CrossRefPubMed

31.

Banerji S, Cibulskis K, Rangel-Escareno C, Brown KK, Carter SL, Frederick AM, et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature. 2012;405–9. doi:10.1038/nature11154.

32.

Tomaskovic-Crook E, Thompson EW, Thiery JP. Epithelial to mesenchymal transition and breast cancer. Breast Cancer Res. 2009;11(6):213. doi:10.1186/bcr2416.CrossRefPubMedPubMedCentral

33.

Zhao X, Lu Y, Nie Y, Fan D. MicroRNAs as critical regulators involved in regulating epithelial-mesenchymal transition. Curr Cancer Drug Targets. 2013;13(9):935–44.CrossRefPubMed

34.

De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13(2):97–110. doi:10.1038/nrc3447.CrossRefPubMed

35.

Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593–601. doi:10.1038/ncb1722.CrossRefPubMed

36.

Zhu W, Xu B. MicroRNA-21 identified as predictor of cancer outcome: a meta-analysis. PLoS One. 2014;9(8):e103373. doi:10.1371/journal.pone.0103373.CrossRefPubMedPubMedCentral

37.

Liu ZL, Wang H, Liu J, Wang ZX. MicroRNA-21 (miR-21) expression promotes growth, metastasis, and chemo- or radioresistance in non-small cell lung cancer cells by targeting PTEN. Mol Cell Biochem. 2013;372(1-2):35–45. doi:10.1007/s11010-012-1443-3.CrossRefPubMed

38.

Zhang JX, Mai SJ, Huang XX, Wang FW, Liao YJ, Lin MC, et al. MiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of beta-catenin signaling. Ann Oncol. 2014;25(11):2196–204. doi:10.1093/annonc/mdu439.CrossRefPubMed

39.

Li J, Zhou BP. Activation of beta-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer. 2011;11:49. doi:10.1186/1471-2407-11-49.CrossRefPubMedPubMedCentral

40.

Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, et al. Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem. 2007;282(15):11221–9. doi:10.1074/jbc.M611871200.CrossRefPubMedPubMedCentral

Title: MiRNA-21 induces epithelial to mesenchymal transition and gemcitabine resistance via the PTEN/AKT pathway in breast cancer
Authors: Zhen-Hua Wu
Zhong-Hua Tao
Jian Zhang
Ting Li
Chen Ni
Jie Xie
Jin-Feng Zhang
Xi-Chun Hu
Publication date: 01-06-2016
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 6/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-015-4604-7

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