miR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling

Matthew Knarr, Rita A. Avelar, Sreeja C. Sekhar, Lily J. Kwiatkowski, Michele L. Dziubinski, Jessica McAnulty, Stephanie Skala, Stefanie Avril, Ronny Drapkin and Analisa DiFeo ()
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Matthew Knarr: Case Western Reserve University
Rita A. Avelar: The University of Michigan
Sreeja C. Sekhar: The University of Michigan
Lily J. Kwiatkowski: Case Western Reserve University
Michele L. Dziubinski: The University of Michigan
Jessica McAnulty: The University of Michigan
Stephanie Skala: The University of Michigan
Stefanie Avril: Case Western Reserve University
Ronny Drapkin: University of Pennsylvania
Analisa DiFeo: The University of Michigan

Nature Communications, 2020, vol. 11, issue 1, 1-21

Abstract: Abstract Genomic instability (GI) predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high degree of genomic instability remain unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells through the inhibition of RB1 and stimulator-of-interferon-genes (STING) to propagate cells with a high degree of GI. MiR-181a targeting of RB1 leads to profound nuclear defects and GI generating aberrant cytoplasmic DNA, however simultaneous miR-181a mediated inhibition of STING allows cells to bypass interferon mediated cell death. We also found that high miR-181a is associated with decreased IFNγ response and lymphocyte infiltration in patient tumors. DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation, thus, our findings are the first to identify a miRNA that can downregulate STING expression to suppress activation of intrinsic interferon signaling. This study introduces miR-181a as a putative biomarker and identifies the miR-181a-STING axis as a promising target for therapeutic exploitation.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17030-w

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DOI: 10.1038/s41467-020-17030-w

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