Cancer-associated oxidoreductase ERO1-α drives the production of VEGF via oxidative protein folding and regulating the mRNA level.
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.
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.
Tsutomu
T
Tanaka
Department of Surgery, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
Goro
G
Kutomi
Department of Pathology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
Toshimitsu
T
Kajiwara
Department of Surgery, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
Kazuharu
K
Kukita
Department of Pathology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
Vitaly
V
Kochin
Department of Pathology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
Takayuki
T
Kanaseki
Department of Pathology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
Tomohide
T
Tsukahara
Department of Pathology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
Yoshihiko
Y
Hirohashi
Department of Pathology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
Toshihiko
T
Torigoe
Joint Department of Veterinary Medicine, Tottori University, 4-101, Koyama-cho Minami 680-8550, Tottori, Japan.
Yoshiharu
Y
Okamoto
Department of Surgery, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
Koichi
K
Hirata
Department of Pathology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
Noriyuki
N
Sato
Center for Innovation and Business Promotion, Hokkaido University, N21W11, Kita-ku, Sapporo 001-0021, Japan.
Yasuaki
Y
Tamura
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology; D045744:Cell Line, Tumor; D004220:Disulfides / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000235:genetics / Q000502:physiology*; D017510:Protein Folding; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D004220:Disulfides; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017382:Reactive Oxygen Species; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C405327:ERO1A protein, human; D010088:Oxidoreductases