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Nat Cell Biol. 2017 Oct;19(10):1286-1296. doi: 10.1038/ncb3615. Epub 2017 Sep 18.

miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS.

Author information

1
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
2
Universidad Católica de Murcia (UCAM), Campus de los Jerónimos, 135, Guadalupe 30107, Spain.
3
Research Center for Tumor Medical Science, Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan.
4
Department of Dental Hygiene, China Medical University, Taichung 40402, Taiwan.
5
Department of Pathology, National Defense Medical Centre and Tri-Service General Hospital, Taipei 114, Taiwan.
6
Flow Cytometry Core Facility, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
7
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
8
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
9
Division of Biological Sciences, University of California, San Diego, La Jolla, California 92037, USA.
10
Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California 92037, USA.
11
Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Centre and Tri-Service General Hospital, Taipei 114, Taiwan.
12
Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan.
13
Moores Cancer Center, University of California, San Diego, La Jolla, California 92037, USA.
14
Center for Microbiome Innovation, University of California, San Diego, La Jolla, California 92037, USA.

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.

PMID:
28920955
PMCID:
PMC5658024
DOI:
10.1038/ncb3615
[Indexed for MEDLINE]
Free PMC Article

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