Overexpression of ubiquitin carboxyl terminal hydrolase-L1 enhances multidrug resistance and invasion/metastasis in breast cancer by activating the MAPK/Erk signaling pathway

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• 作者：Wenjuan Wang ; Liping Zou ; Danmei Zhou ; Zhongwen Zhou ; Feng Tang ; Zude Xu and Xiuping Liu
• 刊名：Molecular Carcinogenesis
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：55
• 期：9
• 页码：1329-1342
• 全文大小：3563K
• ISSN：1098-2744

文摘

Multidrug resistant (MDR) cancer cells overexpressing P-glycoprotein (P-gp) exhibit enhanced invasive/metastatic ability as compared with the sensitive cells. We aimed to clarify the mechanism underlying this observation and found that during the development of drug resistance to adriamycin in MCF7 cells, the elevated expression of UCH-L1 coincides with the up-regulation of MDR1, CD147, MMP2, and MMP9 as well as increased cellular migration/invasion. Overexpression of UCH-L1 in MCF7 cells up-regulated MDR1, CD147, MMP2, and MMP9, which conferred MDR and promoted migration/invasion. On the other hand, silencing of UCH-L1 in MCF7/Adr cells led to the opposite effect. Immunohistochemistry in 203 breast cancer samples revealed that UCH-L1 expression is positively correlated with P-gp, CD147, MMP2, and MMP9 expression and standard tumor spread indicators. Kaplan–Meier survival analysis indicated a correlation between UCH-L1 expression and shorter recurrent and survival times. Moreover, UCH-L1-overexpressing clones treated with U0126 (an Erk1/2-specific inhibitor) significantly decreased the expression of MDR1, CD147, MMP2, and MMP9. These data indicate that UCH-L1 may assume a dual role, because it had intrinsic stimulatory effects on tumor migration/invasion and increased MDR.