Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells

Fang,Xin Jian; Jiang,Hua; Zhu,Ya Qun; Zhang,Li Yuan; Fan,Qiu Hong; Tian,Ye

doi:10.3892/or.2014.3131

Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells

Authors:
- Xin Jian Fang
- Hua Jiang
- Ya Qun Zhu
- Li Yuan Zhang
- Qiu Hong Fan
- Ye Tian
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Affiliations: Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China, Department of Medical Oncology, The Second People's Hospital of Lianyungang (Lianyungang Hospital Affiliated to Bengbu Medical College), Lianyungang, Jiangsu 222000, P.R. China
Published online on: April 7, 2014 https://doi.org/10.3892/or.2014.3131
Pages: 2735-2742

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Abstract

CD44, a major receptor for hyaluronan (HA), is a member of a class of adhesion molecules of unknown classification involved in cell proliferation, differentiation, migration, angiogenesis, and the presentation of specific cytokines to the corresponding receptors as well as in cell signaling transduction. It has recently been discovered that CD44, a marker of tumor stem cells, is involved in the drug resistance and invasion of multiple types of tumors. The 20 exons in the CD44 gene that are alternatively spliced, give rise to many CD44 isoforms, possibly including tumor-specific sequences. Dozens of CD44 isoforms have been found, to date, and the standard CD44 (CD44s) isoform is the most common. We recently showed that a novel short-tail isoform of CD44 (CD44st) was expressed in multidrug-resistant human breast cancer MCF-7/Adr cells. Moreover, the novel CD44st was able to interact with HA and regulate the expression of matrix metalloproteinase (MMP)-2 and MMP-9, which increased the invasive capability of MCF-7 cells through the Ras/MAPK signaling pathway. In the present study, we verified that MCF-7 cells subjected to drug pressure develop multidrug resistance to doxorubicin, and the expression levels of multidrug resistance protein 1 (MDR1), CD44st and nuclear factor-κB (NF-κB) mRNA and protein were gradually upregulated in a dose‑dependent manner in MCF-7 cells treated with doxorubicin. HA increases the secretion of MMP-2 and MMP-9 in multidrug-resistant MCF-7 cells and affected the invasive ability of MCF-7 cells through the upregulation of CD44st expression, and such an effect was blocked by the NF-κB-specific inhibitor BMS-345541.

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1	Hanahan D and Weinberg RA: Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
2	Fang XJ, Jiang H, Zhao XP and Jiang WM: The role of a new CD44st in increasing the invasion capability of the human breast cancer cell line MCF-7. BMC Cancer. 11:2902011. View Article : Google Scholar : PubMed/NCBI
3	Zhang J, Lu M, Zhou F, Sun H, Hao G, Wu X and Wang G: Key role of nuclear factor-κB in the cellular pharmacokinetics of adriamycin in MCF-7/Adr cells: the potential mechanism for synergy with 20(S)-ginsenoside Rh2. Drug Metab Dispos. 40:1900–1908. 2012.
4	Sun J, Yeung CA, Co NN, et al: Clitocine reversal of P-glycoprotein associated multi-drug resistance through down-regulation of transcription factor NF-κB in R-HepG2 cell line. PLoS One. 7:e407202012.PubMed/NCBI
5	Xia Q, Wang ZY, Li HQ, et al: Reversion of p-glycoprotein-mediated multidrug resistance in human leukemic cell line by diallyl trisulfide. Evid Based Complement Alternat Med. 2012:7198052012.PubMed/NCBI
6	Damm S, Koefinger P, Stefan M, et al: HGF-promoted motility in primary human melanocytes depends on CD44v6 regulated via NF-kappa B, Egr-1, and C/EBP-beta. J Invest Dermatol. 130:1893–1903. 2010. View Article : Google Scholar : PubMed/NCBI
7	Wu Y, Zhang X, Zhou H, et al: Factor VIIa regulates the expression of caspase-3, MMP-9, and CD44 in SW620 colon cancer cells involving PAR2/MAPKs/NF-κB signaling pathways. Cancer Invest. 31:7–16. 2013.PubMed/NCBI
8	Bourguignon LY, Peyrollier K, Xia W and Gilad E: Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J Biol Chem. 283:17635–17651. 2008. View Article : Google Scholar : PubMed/NCBI
9	Bourguignon LY, Spevak CC, Wong G, Xia W and Gilad E: Hyaluronan-CD44 interaction with protein kinase Cɛ promotes oncogenic signaling by the stem cell marker Nanog and the production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells. J Biol Chem. 284:26533–26546. 2009.
10	Fang XJ, Xu WL, Gong JL, Chen C, Fang LL and Chen QY: CD44 variant increases the invasive ability of human breast cancer cell line MCF-7 cells. Zhonghua Zhong Liu Za Zhi. 32:22–28. 2010.(In Chinese).
11	Fang XJ, Wu XL, Zhang X, Qian H, Chen C, Fang LL and Chen QY: Construction of human CD44 eukaryotic expression vector and its expression in mammary carcinoma cells. J Jiangsu Univ Med Ed. 19:102–106. 2009.
12	Zou W, Yang H, Hou X, Zhang W, Chen B and Xin X: Inhibition of CD147 gene expression via RNA interference reduces tumor cell invasion, tumorigenicity and increases chemosensitivity to paclitaxel in HO-8910pm cells. Cancer Lett. 248:211–218. 2007. View Article : Google Scholar : PubMed/NCBI
13	Kuang YH, Chen X, Su J, et al: RNA interference targeting the CD147 induces apoptosis of multi-drug resistant cancer cells related to XIAP depletion. Cancer Lett. 276:189–195. 2009. View Article : Google Scholar : PubMed/NCBI
14	Li QQ, Wang WJ, Xu JD, Cao XX, Chen Q, Yang JM and Xu ZD: Up-regulation of CD147 and matrix metalloproteinase-2, -9 induced by P-glycoprotein substrates in multidrug resistant breast cancer cells. Cancer Sci. 98:1767–1774. 2007. View Article : Google Scholar : PubMed/NCBI
15	Weinstein RS, Jakate SM, Dominguez JM, et al: Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymphnode metastasis. Cancer Res. 51:2720–2726. 1991.PubMed/NCBI
16	Radenkovic S, Konjevic G, Jurisic V, et al: Values of MMP-2 and MMP-9 in tumor tissue of basal-like breast cancer patients. Cell Biochem Biophys. 68:143–152. 2014. View Article : Google Scholar : PubMed/NCBI
17	Kung CI, Chen CY, Yang CC, Lin CY, Chen TH and Wang HS: Enhanced membrane-type 1 matrix metalloproteinase expression by hyaluronan oligosaccharides in breast cancer cells facilitates CD44 cleavage and tumor cell migration. Oncol Rep. 28:1808–1814. 2012.
18	Golshani R, Lopez L, Estrella V, Kramer M, Iida N and Lokeshwar VB: Hyaluronic acid synthase-1 expression regulates bladder cancer growth, invasion, and angiogenesis through CD44. Cancer Res. 68:483–491. 2008. View Article : Google Scholar : PubMed/NCBI
19	Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T, Sherlock G, Lewicki J, Shedden K and Clarke MF: The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med. 356:217–226. 2007. View Article : Google Scholar : PubMed/NCBI
20	Charafe-Jauffret E, Ginestier C and Birnbaum D: Breast cancer stem cells: tools and models to rely on. BMC Cancer. 9:2022009. View Article : Google Scholar : PubMed/NCBI
21	Park D, Kim Y, Kim H, et al: Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGFβ receptor interaction via CD44-PKCδ. Mol Cells. 33:563–574. 2012.
22	Lin Y, Zhong Y, Guan H, Zhang X and Sun Q: CD44⁺/CD24⁻ phenotype contributes to malignant relapse following surgical resection and chemotherapy in patients with invasive ductal carcinoma. J Exp Clin Cancer Res. 31:592012.
23	Bourquiqnon LY: Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin Cancer Biol. 18:251–259. 2008. View Article : Google Scholar : PubMed/NCBI
24	Palafox M, Ferrer I, Pellegrini P, Vila S, Hernandez-Ortega S, Urruticoechea A, Climent F, Soler MT, Muñoz P, Viñals F, Tometsko M, Branstetter D, Dougall WC and González-Suárez E: RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Res. 72:2879–2888. 2012. View Article : Google Scholar : PubMed/NCBI
25	Park SY, Lee HE, Li H, Shipitsin M, Gelman R and Polyak K: Heterogeneity for stem cell-related markers according to tumor subtype and histologic stage in breast cancer. Clin Cancer Res. 16:876–887. 2010. View Article : Google Scholar : PubMed/NCBI
26	Ricardo S, Vieira AF, Gerhard R, Leitão D, Pinto R, Cameselle-Teijeiro JF, Milanezi F, Schmitt F and Paredes J: Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. J Clin Pathol. 64:937–946. 2011. View Article : Google Scholar : PubMed/NCBI
27	Gong JL, Xu WL, Li J, Yang J, Wu XJ and Chen QY: Expression of the new CD44 variant (CD44v17) and its clinical significance in breast cancer tissues. J Jiangsu Univ Med Ed. 20:248–252. 2010.