title: UCH-L1 involved in regulating the degradation of EGFR and promoting malignant properties in drug-resistant breast cancer.
abstract: Ubiquitin carboxy terminal hydrolase-L1 (UCHL1) belongs to the UCH proteases family that deubiquitinates ubiquitin-protein conjugates in the ubiquitin-proteasome system. Our previous research showed that UCH-L1 and EGFR could regulate the expression of P-gp, CD147 and MMPs in multi-drug resistance (MDR) breast cancer cells, respectively. But it is still unclear whether direct regulation exists between the UCH-L1 and EGFR in MDR breast cancer. In order to clarify this, MDR human breast carcinoma cell line MCF7/Adr, that expresses relatively high UCH-L1, and its parental cell line MCF7, that expresses relatively low UCH-L1, were chosen for this study. We added ubiquitin proteasome inhibitor MG-132 into the culture of MCF7/Adr cells and transfected pIRES2-UCH-L1-EGFP plasmid into MCF7 cells, respectively. Using quantitative real-time polymerase chain reaction and western blot analyses, we found accompanying over-expression of UCH-L1, EGFR was up-regulated in both MCF7/ADR and MCF7 cells. Preliminary results indicated the degradation of EGFR might be regulated by ubiquitin level. So we speculated that up-regulated UCH-L1 could promote expression level of EGFR, thereby enhance the invasion and metastasis abilities of tumor cells. Moreover, to further explore the role of UCH-L1 and EGFR, we investigated the expression of UCH-L1, EGFR and P-gp in 65 local advanced breast cancer cases by immunohistochemistry assay. The result showed that the patients not responding to chemotherapy had higher UCH-L1, EGFR and P-gp expression levels and more lymph nodes metastasis. The Kaplan-Meier survival analysis showed that the patients with elevated UCH-L1 expression after chemotherapy presented shorter overall survival and disease free survival times than those with down-regulated or unchanged expression of UCH-L1. Our findings suggest that UCH-L1 may be an indicator of chemotherapy-response and poor-survival in breast cancer. UCH-L1 might be an appropriate target for improving chemo-resistant breast cancer therapy.
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University Shanghai, P. R. China.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University Shanghai, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Fudan University Shanghai, P. R. China.
authors.forename: Jiawen
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University Shanghai, P. R. China.
authors.forename: Hongying
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University Shanghai, P. R. China.
authors.forename: Zijing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University Shanghai, P. R. China.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Chu
authors.affiliation: Department of Pathology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai, P. R. China ; Department of Pathology, School of Basic Medical Sciences, Fudan University Shanghai, P. R. China.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University Shanghai, P. R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zou
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D018432:Drug Resistance, Multiple / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*
chemical_list: C482860:UCHL1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D043222:Ubiquitin Thiolesterase
keywords: EGFR; UCH-L1; breast cancer; multidrug resistance