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Hypoxia-inducible ERO1? promotes cancer progression through modulation of integrin-?1 modification and signalling in HCT116 colorectal cancer cells.

ABSTRACT: Endoplasmic reticulum disulphide oxidase 1? (ERO1?) 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 ERO1? is overexpressed in various types of cancer and we further identified ERO1? expression as a novel factor related to poor prognosis in cancer. However, the biological functions of ERO1? in cancer remain unclear. Here, we investigated the cell biological roles of ERO1? in the human colon-cancer cell line HCT116. ERO1? 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? promotes cancer progression specifically in a low-oxygen environment. Thus, we evaluated the function of ERO1? in cell proliferation under hypoxia, and found that under hypoxic conditions, ERO1? KO resulted in a contact-inhibited morphology and diminished motility of cells. We further showed that ERO1? KO induced a change in integrin-?1 glycosylation and thus an attenuation of cell-surface integrin-?1 expression, which resulted in the aforementioned phenotype. Our study has established a previously unrecognized link between ERO1? expression and integrin activation, and thus provides new evidence for the effectiveness of ERO1?-targeted therapy for colorectal carcinoma.

SUBMITTER: Takei N

PROVIDER: S-EPMC5571208 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Hypoxia-inducible ERO1α promotes cancer progression through modulation of integrin-β1 modification and signalling in HCT116 colorectal cancer cells.

Takei Norio N Yoneda Akihiro A Sakai-Sawada Kaori K Kosaka Marina M Minomi Kenjiro K Tamura Yasuaki Y

Scientific reports 20170824 1

Endoplasmic reticulum disulphide oxidase 1α (ERO1α) 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 ERO1α is overexpressed in various types of cancer and we further identified ERO1α expression as a novel factor related to poor prognosis in cancer. However, the biological functions of ERO1α in cancer remain unclear. Here, we investigated the cell biological roles of ERO1α i ...[more]

PMID: 28839225

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Project description:BackgroundReduced chemosensitivity of solid cancer cells represents a pivotal obstacle in clinical oncology. Hence, the molecular characterization of pathways regulating chemosensitivity is a central prerequisite to improve cancer therapy. The hypoxia-inducible factor HIF-1alpha has been linked to chemosensitivity while the underlying molecular mechanisms remain largely elusive. Therefore, we comprehensively analysed HIF-1alpha's role in determining chemosensitivity focussing on responsible molecular pathways.Methodology and principal findingsRNA interference was applied to inactivate HIF-1alpha or p53 in the human gastric cancer cell lines AGS and MKN28. The chemotherapeutic agents 5-fluorouracil and cisplatin were used and chemosensitivity was assessed by cell proliferation assays as well as determination of cell cycle distribution and apoptosis. Expression of p53 and p53 target proteins was analyzed by western blot. NF-kappaB activity was characterized by means of electrophoretic mobility shift assay. Inactivation of HIF-1alpha in gastric cancer cells resulted in robust elevation of chemosensitivity. Accordingly, HIF-1alpha-competent cells displayed a significant reduction of chemotherapy-induced senescence and apoptosis. Remarkably, this phenotype was completely absent in p53 mutant cells while inactivation of p53 per se did not affect chemosensitivity. HIF-1alpha markedly suppressed chemotherapy-induced activation of p53 and p21 as well as the retinoblastoma protein, eventually resulting in cell cycle arrest. Reduced formation of reactive oxygen species in HIF-1alpha-competent cells was identified as the molecular mechanism of HIF-1alpha-mediated inhibition of p53. Furthermore, loss of HIF-1alpha abrogated, in a p53-dependent manner, chemotherapy-induced DNA-binding of NF-kappaB and expression of anti-apoptotic NF-kappaB target genes. Accordingly, reconstitution of the NF-kappaB subunit p65 reversed the increased chemosensitivity of HIF-1alpha-deficient cells.Conclusion and significanceIn summary, we identified HIF-1alpha as a potent regulator of p53 and NF-kappaB activity under conditions of genotoxic stress. We conclude that p53 mutations in human tumors hold the potential to confound the efficacy of HIF-1-inhibitors in cancer therapy.

Dataset Information

Hypoxia-inducible ERO1? promotes cancer progression through modulation of integrin-?1 modification and signalling in HCT116 colorectal cancer cells.

Publications

Hypoxia-inducible ERO1α promotes cancer progression through modulation of integrin-β1 modification and signalling in HCT116 colorectal cancer cells.

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