Department of Biological Sciences, Middle East Technical University, 06531, Ankara, Turkey.
Cancer Chemother Pharmacol. 2010 Feb;65(3):447-55. doi: 10.1007/s00280-009-1048-z. Epub 2009 Jun 19.
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.
由于多药耐药是一种多因素现象，因此使用高密度寡核苷酸微阵列对耐药细胞进行大规模表达分析可能会提供有关有助于耐药的新候选基因的信息。细胞外基质 (ECM) 负责肿瘤细胞增殖和侵袭/转移行为的许多方面。本研究证明了紫杉醇、多西他赛、长春新碱和阿霉素耐药 MCF-7 细胞中几种 ECM 成分、基质金属蛋白酶 (MMPs)、解整合素金属蛋白酶 (ADAMs 和 ADAMTSs) 和金属蛋白酶组织抑制剂 (TIMPs) 的基因表达水平发生了变化。
通过逐步选择细胞在药物浓度增加的情况下，开发耐药 MCF-7 细胞。Affymetrix GeneChip Human Genome U133 Plus 2.0 Array 用于杂交。通过独立样本 t 检验确定统计学意义。通过火山图选择和过滤具有改变表达水平的基因。
选择并列出了表达上调/下调超过两倍的基因。发现耐药细胞中编码 ECM 蛋白（包括胶原蛋白、纤维连接蛋白和 syndecan）和整合素受体亚基的 25 个基因表达上调。此外，与敏感 MCF-7 相比，耐药亚系中发现 13 个编码 MMPs、ADAMs、ADAMTSs 和 TIMPs（包括 MMP1、MMP9、ADAM9 和 TIMP3）的基因表达水平发生了改变。
基于表达分析谱，本报告初步探讨了药物耐药性与 ECM 成分之间的关系，这些成分与侵袭和转移有关。每个特定的 ECM 成分与耐药性的相关性需要进一步分析。
