Jul 25, 2019

Hypoxia induces transcriptional and translational downregulation of the type I interferon (IFN) pathway in multiple cancer cell types

BioRxiv : the Preprint Server for Biology
Ana MiarAdrian L Harris

Abstract

Hypoxia is a common phenomenon in solid tumours and is considered a hallmark of cancer. Increasing evidence shows that hypoxia promotes local immune suppression. Type I IFN is involved in supporting cytotoxic T lymphocytes by stimulating the maturation of dendritic cells (DCs) and enhancing their capacity to process and present antigens. However, there is little information about the relationship between hypoxia and the type I interferon (IFN) pathway, which comprises the sensing of double-stranded RNA and DNA (dsRNA/dsDNA), followed by IFNα/β secretion and transcription activation of IFN-stimulated genes (ISGs). The aims of this study were to determine both the effect and mechanisms of hypoxia on the I IFN pathway in breast cancer. There was a downregulation of the type I IFN pathway expression at mRNA and protein level in cancer cell lines under hypoxia in vitro and in vivo in xenografts. This pathway was suppressed at each level of signalling, from the dsRNA sensors (RIG-I, MDA5), the adaptor (MAVS), transcription factors (IRF3, IRF7, STAT1) and several ISGs (RIG-I, IRF7, STAT1, ADAR-p150). There was also lower IFN secretion under hypoxic conditions. HIF1 and HIF2 regulation of gene expression did not explain most of the eff...Continue Reading

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Mentioned in this Paper

Study
In Vivo
Biochemical Pathway
MRNA Maturation
IFIH1
Regulation of Biological Process
RNA, Double-Stranded
DDX58 protein, human
Transcription, Genetic
Cytotoxic T-Lymphocytes

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