p62/SQSTM1 interacts with vimentin to enhance breast cancer metastasis

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Title: p62/SQSTM1 interacts with vimentin to enhance breast cancer metastasis
Authors: Lam, EW
Yao, S
Dallman, M
Bugeon
Bella, L
Item Type: Journal Article
Abstract: The signalling adaptor p62 is frequently overexpressed in numerous cancer types. Here, we found that p62 expression was elevated in metastatic breast cancer and its overexpression correlated with reduced metastasis-free and relapse-free survival times. Analysis of p62 expression in breast cancer cell lines demonstrated that high p62 expression was associated with the invasive phenotypes of breast cancer. Indeed, silencing p62 expression attenuated the invasive phenotypes of highly metastatic cells, whereas overexpressing p62 promoted the invasion of non-metastatic cells in in vitro microfluidic model. Moreover, MDA-MB-231 cells with p62 depletion which were grown in a three-dimensional culture system exhibited a loss of invasive protrusions. Consistently, genetic ablation of p62 suppressed breast cancer metastasis in both zebrafish embryo and immunodeficient mouse models, as well as decreased tumorigenicity in vivo. To explore the molecular mechanism by which p62 promotes breast cancer invasion, we performed a co-immunoprecipitation (co-IP)-MS analysis and revealed that p62 interacted with vimentin, which mediated the function of p62 in promoting breast cancer invasion. Vimentin protein expression was downregulated upon p62 suppression and upregulated with p62 overexpression in breast cancer cells. Linear regression analysis of clinical breast cancer specimens showed a positive correlation between p62 and vimentin protein expression. Together, our findings provide strong evidence that p62 functions as a tumour metastasis promoter by binding vimentin and promoting its expression. This finding might help to develop novel molecular therapeutic strategies for breast cancer metastasis treatment.
Issue Date: 12-Sep-2017
Date of Acceptance: 4-Sep-2017
URI: http://hdl.handle.net/10044/1/50621
DOI: 10.1093/carcin/bgx099
ISSN: 1460-2180
Publisher: Oxford University Press (OUP)
Start Page: 1092
End Page: 1103
Journal / Book Title: Carcinogenesis
Volume: 38
Issue: 11
Sponsor/Funder: Breast Cancer Now
Breast Cancer Now
Imperial College Trust
Medical Research Council (MRC)
Funder's Grant Number: 2012NovemberPhD016
2012MayPR070
N/A
MR/N012097/1
Keywords: 1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published online
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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