title: Overexpression of ubiquitin carboxyl terminal hydrolase-L1 enhances multidrug resistance and invasion/metastasis in breast cancer by activating the MAPK/Erk signaling pathway.
abstract: 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. © 2015 Wiley Periodicals, Inc.
authors: Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China.
authors: Wenjuan
authors: W
authors: Wang
authors: Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China.
authors: Liping
authors: L
authors: Zou
authors: Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China.
authors: Danmei
authors: D
authors: Zhou
authors: Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China.
authors: Zhongwen
authors: Z
authors: Zhou
authors: Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China.
authors: Feng
authors: F
authors: Tang
authors: Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China.|Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors: Zude
authors: Z
authors: Xu
authors: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|Department of Pathology, the Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
authors: Xiuping
authors: X
authors: Liu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D043222:Ubiquitin Thiolesterase / Q000032:analysis / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; C482860:UCHL1 protein, human; D004317:Doxorubicin; D043222:Ubiquitin Thiolesterase
keywords: breast cancer; invasion; metastasis; multidrug resistance; ubiquitin carboxy terminal hydrolase-L1