Elevated STAT3 Signaling-Mediated Upregulation of MMP-2/9 Confers Enhanced Invasion Ability in Multidrug-Resistant Breast Cancer Cells.
Elevated STAT3 Signaling-Mediated Upregulation of MMP-2/9 Confers Enhanced Invasion Ability in Multidrug-Resistant Breast Cancer Cells.
复制标题
STAT3 信号介导的 MMP-2/9 上调增强了多药耐药乳腺癌细胞的侵袭能力
DOI：
10.3390/ijms161024772
复制
发表时间：
2015-10-16
影响因子：
5.6
通讯作者：
Niu R
中科院分区：
文献类型：
--
作者：
Zhang F;Wang Z;Fan Y;Xu Q;Ji W;Tian R;Niu R
多药耐药性的发展极大地阻碍了有效的癌症治疗。癌症研究的最新进展表明，癌细胞获得多药耐药性通常伴随着增强的细胞侵袭性。多项证据表明，在耐药发展过程中，其他信号通路的交叉激活可能会增加多药耐药（MDR）癌细胞的侵袭潜力。然而，这个过程的确切机制在很大程度上是不确定的。为了更好地了解耐药诱导的肿瘤进展的相关分子途径，本研究采用逐步增加浓度的表阿霉素长期暴露，建立了P-糖蛋白过表达的MDR人乳腺癌细胞系SK-BR-3/EPR。SK-BR-3/EPR细胞株的增殖活性降低，但细胞侵袭能力增强。我们发现，转移相关的基质金属蛋白酶（MMP）-2/9在SK-BR-3/EPR细胞中的表达升高。此外，SK-BR-3/EPR细胞显示出STAT 3的活化升高。STAT 3信号的激活通过MMP-2/9的上调负责增强SK-BR-3/EPR细胞的侵袭性。STAT 3是一种众所周知的癌基因，并且经常与肿瘤发生和化疗耐药性有关。我们的研究结果增加了对MDR和癌症侵袭性之间的功能关联的机制的了解。
The development of multidrug resistance greatly impedes effective cancer therapy. Recent advances in cancer research have demonstrated that acquisition of multidrug resistance by cancer cells is usually accompanied by enhanced cell invasiveness. Several lines of evidence indicated that cross activation of other signaling pathways during development of drug resistance may increase invasive potential of multidrug-resistant (MDR) cancer cells. However, the accurate mechanism of this process is largely undefined. In this study, to better understand the associated molecular pathways responsible for cancer progression induced by drug resistance, a MDR human breast cancer cell line SK-BR-3/EPR with P-glycoprotein overexpression was established using stepwise long-term exposure to increasing concentration of epirubicin. The SK-BR-3/EPR cell line exhibited decreased cell proliferative activity, but enhanced cell invasive capacity. We showed that the expression of metastasis-related matrix metalloproteinase (MMP)-2/9 was elevated in SK-BR-3/EPR cells. Moreover, SK-BR-3/EPR cells showed elevated activation of STAT3. Activation of STAT3 signaling is responsible for enhanced invasiveness of SK-BR-3/EPR cells through upregulation of MMP-2/9. STAT3 is a well-known oncogene and is frequently implicated in tumorigenesis and chemotherapeutic resistance. Our findings augment insight into the mechanism underlying the functional association between MDR and cancer invasiveness.