Abstract
The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA. Moreover, restoring cGAS expression results in an anti-tumour immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harbouring high levels of miR-25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumour progression, and reveal a direct link between hypoxia-responsive miRNAs and adaptive immune responses to the hypoxic tumour microenvironment, thus unveiling potential new therapeutic strategies.
MeSH terms
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Adaptive Immunity
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Animals
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Breast Neoplasms / enzymology*
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Breast Neoplasms / genetics
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Breast Neoplasms / immunology
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Breast Neoplasms / pathology
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DNA, Mitochondrial / genetics
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DNA, Mitochondrial / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Disease Progression
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Epigenesis, Genetic
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Female
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Humans
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MCF-7 Cells
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Mixed Function Oxygenases / genetics
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Mixed Function Oxygenases / metabolism
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Nuclear Receptor Coactivator 3 / genetics
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Nuclear Receptor Coactivator 3 / metabolism
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Nucleotidyltransferases / genetics
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Nucleotidyltransferases / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA Interference
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Receptor, Interferon alpha-beta / deficiency
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Receptor, Interferon alpha-beta / genetics
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Signal Transduction
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Time Factors
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Transfection
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Tumor Escape*
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Tumor Hypoxia
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Tumor Microenvironment
Substances
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DNA, Mitochondrial
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DNA-Binding Proteins
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MIRN25 microRNA, human
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MIRN25 microRNA, mouse
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MIRN93 microRNA, human
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MicroRNAs
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Mirn93 microRNA, mouse
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Proto-Oncogene Proteins
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TET1 protein, mouse
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Receptor, Interferon alpha-beta
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Mixed Function Oxygenases
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TET1 protein, human
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NCOA3 protein, human
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Ncoa3 protein, mouse
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Nuclear Receptor Coactivator 3
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Nucleotidyltransferases
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cGAS protein, human
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cGAS protein, mouse