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Br J Cancer. 2016 May 24;114(11):1227-34. doi: 10.1038/bjc.2016.105. Epub 2016 Apr 21.

Cancer-associated oxidoreductase ERO1-α drives the production of VEGF via oxidative protein folding and regulating the mRNA level.

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Department of Pathology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
The United Graduate School of Veterinary Sciences, Yamaguchi University, 1677-1, Yoshida, Yamaguchi 753-8511, Japan.
Department of Surgery, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
Joint Department of Veterinary Medicine, Tottori University, 4-101, Koyama-cho Minami 680-8550, Tottori, Japan.
Center for Innovation and Business Promotion, Hokkaido University, N21W11, Kita-ku, Sapporo 001-0021, Japan.



Endoplasmic reticulum disulfide oxidase 1-α (ERO1-α) is an oxidase that exists in the endoplasmic reticulum and has a role in the formation of disulfide bonds of secreted proteins and cell-surface proteins. Recently, we reported that ERO1-α is present in high levels in various types of tumours, and that ERO1-α is a novel factor of poor prognosis. However, how ERO1-α affects a tumour in vivo and why patients who have a tumour with a high expression level of ERO1-α have a poor prognosis are still unknown. Therefore, to clarify the mechanism, we investigated the effect of ERO1-α on a tumour from the point of view of angiogenesis.


The effect of ERO1-α on tumour growth and angiogenesis was analysed by using non-obese diabetic-severe combined immunodeficient mice. The production of vascular endothelial growth factor (VEGF) in MDA-MB-231 cells with ERO1-α- overexpression or with ERO1-α knockdown was measured. The role of ERO1-α on VEGF expression was investigated. In triple-negative breast cancer cases, the relationship between expression of ERO1-α and angiogenesis was analysed.


We found that the expression of ERO1-α promoted tumour growth in a mouse study and angiogenesis. The effects of ERO1-α on angiogenesis were mediated via oxidative protein folding of VEGF and enhancement of VEGF mRNA expression by using MDA-MB-231. In triple-negative breast cancer cases, the expression of ERO1-α related to the number of the blood vessel. Furthermore, we found that ERO1-α was a poor prognosis factor in triple-negative breast cancer.


Our study has established a novel link between expression of ERO1-α and secretion of VEGF, providing new evidence for the effectiveness of ERO1-α-targeted therapy in patients with ERO1-α-expressed cancer.

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