Hypoxia-Inducible Ero1a Alpha Promotes Cancer Progression Through Modulation Of Integrin-Beta 1 Modification And Signalling In Hct116 Colorectal Cancer Cells

Endoplasmic reticulum disulphide oxidase 1 alpha (ERO1 alpha) is an oxidase localized in the endoplasmic reticulum that plays a role in the formation of disulphide bonds of secreted and cell-surface proteins. We previously showed that ERO1a is overexpressed in various types of cancer and we further identified ERO1 alpha expression as a novel factor related to poor prognosis in cancer. However, the biological functions of ERO1 alpha in cancer remain unclear. Here, we investigated the cell biological roles of ERO1 alpha in the human colon-cancer cell line HCT116. ERO1 alpha knockout (KO) by using CRISPR/Cas9 resulted in decreased tumourigenicity in vivo and reduced cell proliferation only under hypoxia in vitro, which suggested that ERO1 alpha promotes cancer progression specifically in a low-oxygen environment. Thus, we evaluated the function of ERO1 alpha in cell proliferation under hypoxia, and found that under hypoxic conditions, ERO1 alpha KO resulted in a contact-inhibited morphology and diminished motility of cells. We further showed that ERO1 alpha KO induced a change in integrin-beta 1 glycosylation and thus an attenuation of cell-surface integrin-beta 1 expression, which resulted in the aforementioned phenotype. Our study has established a previously unrecognized link between ERO1 alpha expression and integrin activation, and thus provides new evidence for the effectiveness of ERO1 alpha-targeted therapy for colorectal carcinoma.