Loss of miR‑873 contributes to gemcitabine resistance in triple‑negative breast cancer via targeting ZEB1

Wang,Gangyue; Dong,Yi; Liu,Heng; Ji,Nan; Cao,Jilei; Liu,Aihui; Tang,Xin; Ren,Yu

doi:10.3892/ol.2019.10697

Loss of miR‑873 contributes to gemcitabine resistance in triple‑negative breast cancer via targeting ZEB1

Authors:
- Gangyue Wang
- Yi Dong
- Heng Liu
- Nan Ji
- Jilei Cao
- Aihui Liu
- Xin Tang
- Yu Ren
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Affiliations: Department of Breast Surgery, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100006, P.R. China
Published online on: August 1, 2019 https://doi.org/10.3892/ol.2019.10697
Pages: 3837-3844

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Abstract

Gemcitabine‑based chemotherapy is commonly applied for the treatment of breast cancer in a clinical setting. However, acquired resistance to chemotherapy primarily results in treatment failure and eventually culminates in patient mortality. Aberrant expression of microRNAs (miRNAs) has been demonstrated to be implicated in the development of chemoresistance; however, the role of miR‑873 in the chemoresistance of breast cancer and its underlying mechanism have not been completely elucidated. Herein, using cell viability assays, the present study demonstrated that overexpression of miR‑873 sensitized triple‑negative breast cancer (TNBC) cells (MDA‑MB‑231 and BT549) towards gemcitabine treatment, while inhibition of miR‑873 promoted resistance of TNBC cells to gemcitabine exposure. The 3' untranslated region of zinc finger E‑box binding homeobox 1 (ZEB1) was predicted as a candidate target of miR‑873, and the regulatory association between ZEB1 and miR‑873 was validated with a dual luciferase assay. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis confirmed that miR‑873 mimics reduced ZEB1 at mRNA and protein levels in MDA‑MB‑231 and BT549 cells. As ZEB1 was previously reported to interact with Yes associated protein (YAP) to promote cancer progression. The present study observed that miR‑873 overexpression decreased the expression of YAP target genes AXL receptor tyrosine kinase, connective tissue growth factor and cysteine rich angiogenic inducer 61 at mRNA and protein levels. Additionally, elevation of the ZEB1 level and reduction of the miR‑873 level were detected in gemcitabine‑resistant MDA‑MB‑231 (MDA‑MB‑231GEMr) cells, which were accompanied with stronger proliferative ability, compared with parental cells. Overexpression of miR‑873 or ZEB1 knockdown reversed chemoresistance of MDA‑MB‑231GEMr cells by inducing a notable cell growth arrest upon gemcitabine exposure. In conclusion, the data obtained by the present study demonstrated that the decrease of miR‑873 promoted the development of gemcitabine resistance in TNBC via elevation of ZEB1 expression, which indicated that miR‑873 may be a promising predictor for gemcitabine sensitivity in patients with TNBC.

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1	Oakman C, Viale G and Di Leo A: Management of triple negative breast cancer. Breast. 19:312–321. 2010. View Article : Google Scholar : PubMed/NCBI
2	Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML and Perou CM: The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 13:2329–2334. 2007. View Article : Google Scholar : PubMed/NCBI
3	Papa AL, Sidiqui A, Balasubramanian SU, Sarangi S, Luchette M, Sengupta S and Harfouche R: PEGylated liposomal Gemcitabine: Insights into a potential breast cancer therapeutic. Cell Oncol (Dordr). 36:449–457. 2013. View Article : Google Scholar : PubMed/NCBI
4	Ueno H, Kiyosawa K and Kaniwa N: Pharmacogenomics of gemcitabine: Can genetic studies lead to tailor-made therapy? Br J Cancer. 97:145–151. 2007. View Article : Google Scholar : PubMed/NCBI
5	Samanta D, Gilkes DM, Chaturvedi P, Xiang L and Semenza GL: Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. Proc Natl Acad Sci USA. 111:E5429–E5438. 2014. View Article : Google Scholar : PubMed/NCBI
6	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
7	Liu B, Li J and Cairns MJ: Identifying miRNAs, targets and functions. Brief Bioinform. 15:1–19. 2014. View Article : Google Scholar : PubMed/NCBI
8	Wang J, Yang M, Li Y and Han B: The role of MicroRNAs in the chemoresistance of breast cancer. Drug Dev Res. 76:368–374. 2015. View Article : Google Scholar : PubMed/NCBI
9	Li HY, Liang JL, Kuo YL, Lee HH, Calkins MJ, Chang HT, Lin FC, Chen YC, Hsu TI, Hsiao M, et al: miR-105/93-3p promotes chemoresistance and circulating miR-105/93-3p acts as a diagnostic biomarker for triple negative breast cancer. Breast Cancer Res. 19:1332017. View Article : Google Scholar : PubMed/NCBI
10	Wang RJ, Li JW, Bao BH, Wu HC, Du ZH, Su JL, Zhang MH and Liang HQ: MicroRNA-873 (miRNA-873) inhibits glioblastoma tumorigenesis and metastasis by suppressing the expression of IGF2BP1. J Biol Chem. 290:8938–8948. 2015. View Article : Google Scholar : PubMed/NCBI
11	Cui J, Yang Y, Li H, Leng Y, Qian K, Huang Q, Zhang C, Lu Z, Chen J, Sun T, et al: MiR-873 regulates ERα transcriptional activity and tamoxifen resistance via targeting CDK3 in breast cancer cells. Oncogene. 34:40182015. View Article : Google Scholar : PubMed/NCBI
12	Chen X, Zhang Y, Shi Y, Lian H, Tu H, Han S, Peng B, Liu W and He X: MiR-873 acts as a novel sensitizer of glioma cells to cisplatin by targeting Bcl-2. Int J Oncol. 47:1603–1611. 2015. View Article : Google Scholar : PubMed/NCBI
13	Wu DD, Li XS, Meng XN, Yan J and Zong ZH: MicroRNA-873 mediates multidrug resistance in ovarian cancer cells by targeting ABCB1. Tumour Biol. 37:10499–10506. 2016. View Article : Google Scholar : PubMed/NCBI
14	Zhang P, Sun Y and Ma L: ZEB1: At the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle. 14:481–487. 2015. View Article : Google Scholar : PubMed/NCBI
15	De Craene B and Berx G: Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 13:97–110. 2013. View Article : Google Scholar : PubMed/NCBI
16	Onder TT, Gupta PB, Mani SA, Yang J, Lander ES and Weinberg RA: Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 68:3645–3654. 2008. View Article : Google Scholar : PubMed/NCBI
17	Karihtala P, Auvinen P, Kauppila S, Haapasaari KM, Jukkola-Vuorinen A and Soini Y: Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: Association with an aggressive tumour phenotype. Breast Cancer Res Treat. 138:81–90. 2013. View Article : Google Scholar : PubMed/NCBI
18	Giordano A, Gao H, Anfossi S, Cohen E, Mego M, Lee BN, Tin S, De Laurentiis M, Parker CA, Alvarez RH, et al: Epithelial-mesenchymal transition and stem cell markers in patients with HER2-positive metastatic breast cancer. Mol Cancer Ther. 11:2526–2534. 2012. View Article : Google Scholar : PubMed/NCBI
19	Lehmann W, Mossmann D, Kleemann J, Mock K, Meisinger C, Brummer T, Herr R, Brabletz S, Stemmler MP and Brabletz T: ZEB1 turns into a transcriptional activator by interacting with YAP1 in aggressive cancer types. Nat Commun. 7:104982016. View Article : Google Scholar : PubMed/NCBI
20	Davidson JD, Ma L, Flagella M, Geeganage S, Gelbert LM and 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. 64:3761–3766. 2004. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Sánchez-Tilló E, Lázaro A, Torrent R, Cuatrecasas M, Vaquero EC, Castells A, Engel P and Postigo A: ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene. 29:3490–3500. 2010. View Article : Google Scholar : PubMed/NCBI
23	Podo F, Buydens LM, Degani H, Hilhorst R, Klipp E, Gribbestad IS, Van Huffel S, van Laarhoven HW, Luts J, Monleon D, et al: Triple-negative breast cancer: Present challenges and new perspectives. Mol Oncol. 4:209–229. 2010. View Article : Google Scholar : PubMed/NCBI
24	O'Reilly EA, Gubbins L, Sharma S, Tully R, Guang MH, Weiner-Gorzel K, McCaffrey J, Harrison M, Furlong F, Kell M and McCann A: The fate of chemoresistance in triple negative breast cancer (TNBC). BBA Clin. 3:257–275. 2015. View Article : Google Scholar : PubMed/NCBI
25	Yang F, Zhang W, Shen Y and Guan X: Identification of dysregulated microRNAs in triple-negative breast cancer (review). Int J Oncol. 46:927–932. 2015. View Article : Google Scholar : PubMed/NCBI
26	Liu X, Tang H, Chen J, Song C, Yang L, Liu P, Wang N and Xie X, Lin X and Xie X: MicroRNA-101 inhibits cell progression and increases paclitaxel sensitivity by suppressing MCL-1 expression in human triple-negative breast cancer. Oncotarget. 6:20070–20083. 2015.PubMed/NCBI
27	Tan X, Peng J, Fu Y, An S, Rezaei K, Tabbara S, Teal CB, Man YG, Brem RF and Fu SW: miR-638 mediated regulation of BRCA1 affects DNA repair and sensitivity to UV and cisplatin in triple-negative breast cancer. Breast Cancer Res. 16:4352014. View Article : Google Scholar : PubMed/NCBI
28	Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M, Mikulits W, Brabletz T, Strand D, Obrist P, et al: The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene. 26:6979–6988. 2007. View Article : Google Scholar : PubMed/NCBI
29	Kahlert UD, Maciaczyk D, Doostkam S, Orr BA, Simons B, Bogiel T, Reithmeier T, Prinz M, Schubert J, Niedermann G, et al: Activation of canonical WNT/β-catenin signaling enhances in vitro motility of glioblastoma cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition. Cancer Lett. 325:42–53. 2012. View Article : Google Scholar : PubMed/NCBI
30	Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S and Nakshatri H: NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: Potential involvement of ZEB-1 and ZEB-2. Oncogene. 26:711–724. 2007. View Article : Google Scholar : PubMed/NCBI
31	Korpal M, Lee ES, Hu G and Kang Y: The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 283:14910–14914. 2008. View Article : Google Scholar : PubMed/NCBI
32	Peitzsch C, Kurth I, Kunz-Schughart L, Baumann M and Dubrovska A: Discovery of the cancer stem cell related determinants of radioresistance. Radiother Oncol. 108:378–387. 2013. View Article : Google Scholar : PubMed/NCBI
33	Allegra A, Alonci A, Penna G, Innao V, Gerace D, Rotondo F and Musolino C: The cancer stem cell hypothesis: A guide to potential molecular targets. Cancer Invest. 32:470–495. 2014. View Article : Google Scholar : PubMed/NCBI