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

被引：87

作者：

Hernandez-Fernaud, Juan R. ^{[1
]}

Ruengeler, Elena ^{[1
]}

Casazza, Andrea ^{[2
]}

Neilson, Lisa J. ^{[1
]}

Pulleine, Ellie ^{[3
]}

Santi, Alice ^{[1
]}

Ismail, Shehab ^{[1
]}

Lilla, Sergio ^{[1
]}

Dhayade, Sandeep ^{[1
]}

MacPherson, Iain R. ^{[4
]}

McNeish, Iain ^{[4
]}

Ennis, Darren ^{[4
]}

Ali, Hala ^{[5
,6
]}

Kugeratski, Fernanda G. ^{[1
]}

Al Khamici, Heba ^{[5
,6
]}

van den Biggelaar, Maartje ^{[7
]}

van den Berghe, Peter V. E. ^{[1
]}

Cloix, Catherine ^{[1
]}

McDonald, Laura ^{[1
]}

Millan, David ^{[8
]}

Hoyle, Aoisha ^{[8
]}

Kuchnio, Anna ^{[9
]}

Carmeliet, Peter ^{[9
]}

Valenzuela, Stella M. ^{[5
,6
]}

Blyth, Karen ^{[1
]}

Yin, Huabing ^{[3
]}

Mazzone, Massimiliano ^{[2
]}

Norman, Jim C. ^{[1
]}

Zanivan, Sara ^{[1
]}

机构：

[1] Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland

[2] VIB, Vesalius Res Ctr, Lab Mol Oncol & Angiogenesis, B-3000 Leuven, Belgium

[3] Univ Glasgow, Sch Engn, Div Biomed Engn, Glasgow G12 8LT, Lanark, Scotland

[4] Univ Glasgow, Wolfson Wohl Canc Res Ctr, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland

[5] Univ Technol Sydney, Sch Life Sci, Sydney, NSW 2007, Australia

[6] Univ Technol Sydney, Ctr Hlth Technol, Sydney, NSW 2007, Australia

[7] Dept Plasma Prot Sanquin Res, NL-1066 CX Amsterdam, Netherlands

[8] Queen Elizabeth Univ Hosp, Dept Pathol, Glasgow G51 4TF, Lanark, Scotland

[9] VIB Ctr Canc Biol, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

欧洲研究理事会;

关键词：

IN-VITRO MODEL; GENE-EXPRESSION; STROMAL CELLS; TUMOR MICROENVIRONMENT; TRANSGLUTAMINASE; LYSYL OXIDASE; HUMAN BREAST; MAJOR ROLE; FIBROBLASTS; INTEGRIN;

D O I：

10.1038/ncomms14206

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：17

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