Article

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

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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.

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Acknowledgements

We are grateful to M. C. Ku of the Next Generation Sequencing Core, and C. Benner and M. Shokhirev of the Integrative Genomics and Bioinformatics Core, at Salk Institute for Biological Studies for technical assistance. We would also like to thank D. O’Keefe for his help in preparing the manuscript. This work was supported by The Razavi Newman Integrative Genomics and Bioinformatics Core Facility and the NGS Core Facility of the Salk institute with funding from NIH-NCI CCSG: P30014195, the Chapman Foundation and the Helmsley Charitable Trust. Work in the laboratory of J.C.I.B. was supported by the G. Harold and Leila Y. Mathers Charitable Foundation, The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002), Fundacion Dr. Pedro Guillen, The Moxie Foundation and UCAM.

Author information

Affiliations

  1. Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Min-Zu Wu
    • , Lorena Martin
    •  & Juan Carlos Izpisua Belmonte
  2. Universidad Católica de Murcia (UCAM), Campus de los Jerónimos, 135, Guadalupe 30107, Spain

    • Min-Zu Wu
    •  & Lorena Martin
  3. Research Center for Tumor Medical Science, Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan

    • Wei-Chung Cheng
    •  & Kou-Juey Wu
  4. Department of Dental Hygiene, China Medical University, Taichung 40402, Taiwan

    • Su-Feng Chen
  5. Department of Pathology, National Defense Medical Centre and Tri-Service General Hospital, Taipei 114, Taiwan

    • Su-Feng Chen
    •  & Shin Nieh
  6. Flow Cytometry Core Facility, The Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Carolyn O’Connor
  7. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan

    • Chia-Lin Liu
  8. Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Wen-Wei Tsai
  9. Division of Biological Sciences, University of California, San Diego, La Jolla, California 92037, USA

    • Cheng-Jang Wu
    •  & Li-Fan Lu
  10. Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California 92037, USA

    • Lorena Martin
  11. Department of Otolaryngology—Head and Neck Surgery, National Defense Medical Centre and Tri-Service General Hospital, Taipei 114, Taiwan

    • Yaoh-Shiang Lin
  12. Department of Otolaryngology—Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan

    • Yaoh-Shiang Lin
  13. Moores Cancer Center, University of California, San Diego, La Jolla, California 92037, USA

    • Li-Fan Lu
  14. Center for Microbiome Innovation, University of California, San Diego, La Jolla, California 92037, USA

    • Li-Fan Lu

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Contributions

M.-Z.W., L.-F.L. and J.C.I.B. conceived and designed the project. W.-C.C. and K.-J.W. performed TCGA analysis with help from L.M. S.-F.C., S.N. and C.-L.L. performed studies on tissue microarrays of human patient samples with help from Y.-S.L. C.O’C. and C.-J.W. assisted in FACS analysis and samples preparation. W.-W.T. contributed to ChIP experiments as well as discussion and revision of the manuscript. M.-Z.W., L.-F.L. and J.C.I.B. wrote the manuscript with input from all other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Juan Carlos Izpisua Belmonte.

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