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Tumor Biology

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14.12.2015 | Original Article

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

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

Erschienen in: Tumor Biology | Ausgabe 6/2016

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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

Titel: MiRNA-21 induces epithelial to mesenchymal transition and gemcitabine resistance via the PTEN/AKT pathway in breast cancer
verfasst von: Zhen-Hua Wu
Zhong-Hua Tao
Jian Zhang
Ting Li
Chen Ni
Jie Xie
Jin-Feng Zhang
Xi-Chun Hu
Publikationsdatum: 14.12.2015
Verlag: Springer Netherlands
Erschienen in: Tumor Biology / Ausgabe 6/2016
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-015-4604-7

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

Abstract

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