Gene expression analysis of drug-resistant MCF-7 cells: implications for relation to extracellular matrix proteins
- 479 Downloads
Since multidrug resistance is a multifactorial phenomenon, a large-scale expression analysis of drug-resistant cells by using high-density oligonucleotide microarrays may provide information about new candidate genes contributing to resistance. Extracellular matrix (ECM) is responsible for many aspects of proliferation and invasive/metastatic behavior of tumor cells. This study demonstrates alterations in gene expression levels of several ECM components, matrix metalloproteinases (MMPs), adamalysins (ADAMs and ADAMTSs) and tissue inhibitors of metalloproteinases (TIMPs) in paclitaxel, docetaxel, vincristine and doxorubicin-resistant MCF-7 cells.
Resistant MCF-7 cells were developed by stepwise selection of cells in increasing concentrations of drugs. Affymetrix GeneChip® Human Genome U133 Plus 2.0 Array was used for hybridizations. Statistical significance was determined by independent sample t test. The genes having altered expression levels in drug-resistant sublines were selected and filtered by volcano plots.
Genes up/downregulated more than twofolds were selected and listed. Expression of 25 genes encoding ECM proteins (including collagen, finronectin and syndecan) and integrin receptor subunits were found to be upregulated in drug-resistant cells. In addition, expression levels of, 13 genes encoding MMPs, ADAMs, ADAMTSs and TIMPs (including MMP1, MMP9, ADAM9 and TIMP3) were found to be altered in drug-resistant sublines when compared with sensitive MCF-7.
Based on the expression analysis profiles, this report provides a preliminary insight into the relationship between drug resistance and ECM components, which are related to invasion and metastasis. Correlation of each specific ECM component with drug resistance requires further analysis.
KeywordsMultidrug resistance cDNA microarray ECM Integrin MMP ADAM
We gratefully acknowledge advises of Prof. Dr. Ali Uğur Ural and Prof. Dr. Hüseyin Avni Öktem, and METU Molecular Biology Biotechnology Research Center for technical assistance. This study was supported by TUBITAK (SBAG 3297), Turkey.
- 5.Mitsumoto M, Kamura T, Kobayashi H, Sonoda T, Kaku T, Nakano H (1998) Emergence of higher levels of invasive and metastatic properties in the drug-resistant cancer cell lines after the repeated administration of cisplatin in tumor-bearing mice. J Cancer Res Clin Oncol 124:607–614CrossRefPubMedGoogle Scholar
- 8.Iseri ÖD, Kars MD, Eroglu S, Gündüz U (2009) Cross-resistance development and combined applications of anticancer agents in drug resistant MCF-7 cell lines. Int J Hem Oncol 1(19):1–8Google Scholar
- 11.Weinstein RS, Jakate SM, Dominguez JM, Lebovitz MD, Koukoulis GK, Kuszak JR et al (1991) Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. Cancer Res 51(10):2720–2726PubMedGoogle Scholar
- 19.Esparza J, Vilardell C, Calvo J, Juan M, Vives J, Urbano-Márquez A et al (1999) Fibronectin upregulates gelatinase B (MMP-9) and induces coordinated expression of gelatinase A (MMP-2) and its activator MT1-MMP (MMP-14) by human T lymphocyte cell lines A process repressed through RAS/MAP kinase signaling pathways. Blood 94(8):2754–2766PubMedGoogle Scholar