Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells
Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells
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DOI：
10.3892/or.2014.3131
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发表时间：
2014-06-01
期刊：
影响因子：
4.2
通讯作者：
Tian, Ye
中科院分区：
文献类型：
--
作者：
Fang, Xin Jian;Jiang, Hua;Tian, Ye
CD 44是透明质酸（HA）的主要受体，是一类分类未知的粘附分子的成员，其参与细胞增殖、分化、迁移、血管生成和特异性细胞因子向相应受体的呈递以及细胞信号转导。近年来研究发现，肿瘤干细胞标志物CD 44参与多种肿瘤的耐药和侵袭。CD 44基因中的20个外显子进行选择性剪接，产生许多CD 44亚型，可能包括肿瘤特异性序列。迄今为止，已经发现了数十种CD 44同种型，并且标准CD 44（CD 44 s）同种型是最常见的。我们最近发现，一种新的短尾同种型的CD 44（CD 44 st）在多药耐药的人乳腺癌MCF-7/Adr细胞中表达。此外，新的CD 44 st能够与HA相互作用，调节基质金属蛋白酶（MMP）-2和MMP-9的表达，通过Ras/MAPK信号通路增强MCF-7细胞的侵袭能力。在本研究中，我们证实了MCF-7细胞受到药物压力的发展多药耐药阿霉素，多药耐药蛋白1（MDR 1），CD 44 st和核因子-κ B（NF-κ B）的mRNA和蛋白的表达水平逐渐上调，在剂量依赖性的方式与阿霉素处理的MCF-7细胞。HA通过上调CD 44 st的表达，增加MCF-7多药耐药细胞MMP-2和MMP-9的分泌，影响MCF-7细胞的侵袭能力，这种作用可被NF-κ B特异性抑制剂BMS-345541阻断。
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-kappa B (NF-kappa B) 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-kappa B-specific inhibitor BMS-345541.