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Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity.

Title: Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity.
Authors: Hernandez-Fernaud, JR
Ruengeler, E
Casazza, A
Neilson, LJ
Pulleine, E
Santi, A
Ismail, S
Lilla, S
Dhayade, S
MacPherson, IR
McNeish, I
Ennis, D
Ali, H
Kugeratski, FG
Al Khamici, H
Van den Biggelaar, M
Van den Berghe, PVE
Cloix, C
McDonald, L
Millan, D
Hoyle, A
Kuchnio, A
Carmeliet, P
Valenzuela, SM
Blyth, K
Yin, H
Mazzone, M
Norman, JC
Zanivan, S
Item Type: Journal Article
Abstract: The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion.
Issue Date: 15-Feb-2017
Date of Acceptance: 6-Dec-2016
URI: http://hdl.handle.net/10044/1/53441
DOI: https://dx.doi.org/10.1038/ncomms14206
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 8
Copyright Statement: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ ©The Author(s) 2017
Keywords: MD Multidisciplinary
Publication Status: Published online
Article Number: 14206
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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