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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Tsutomu Tanaka, Goro Kutomi, Toshimitsu Kajiwara, Kazuharu Kukita, Vitaly Kochin, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Toshihiko Torigoe, Yoshiharu Okamoto, Koichi Hirata, Noriyuki Sato, Yasuaki Tamura
• Journal: British journal of cancer (Br J Cancer) Vol. 114 Issue 11 Pg. 1227-34 (05 24 2016) ISSN: 1532-1827 [Electronic] England
• PMID: 27100727 (Publication Type: Journal Article)

Chemical References

• Disulfides
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Membrane Glycoproteins
• Neoplasm Proteins
• RNA, Messenger
• RNA, Neoplasm
• Reactive Oxygen Species
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• ERO1A protein, human
• Oxidoreductases

Topics

• Animals
• Breast Neoplasms (blood supply, pathology)
• Cell Line, Tumor
• Disulfides (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Membrane Glycoproteins (genetics, physiology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Proteins (genetics, physiology)
• Neoplasm Transplantation
• Neovascularization, Pathologic (enzymology)
• Oxidation-Reduction
• Oxidoreductases (genetics, physiology)
• Protein Folding
• RNA, Messenger (biosynthesis, genetics)
• RNA, Neoplasm (biosynthesis, genetics)
• Reactive Oxygen Species (metabolism)
• Triple Negative Breast Neoplasms (blood supply, enzymology, genetics)
• Vascular Endothelial Growth Factor A (biosynthesis, genetics, metabolism)