MicroRNA-146a limits tumorigenic inflammation in colorectal cancer

Lucien P. Garo, Amrendra K. Ajay, Mai Fujiwara, Galina Gabriely, Radhika Raheja, Chantal Kuhn, Brendan Kenyon, Nathaniel Skillin, Ryoko Kadowaki-Saga, Shrishti Saxena and Gopal Murugaiyan ()
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Lucien P. Garo: Brigham and Women’s Hospital and Harvard Medical School
Amrendra K. Ajay: Brigham and Women’s Hospital and Harvard Medical School
Mai Fujiwara: Brigham and Women’s Hospital and Harvard Medical School
Galina Gabriely: Brigham and Women’s Hospital and Harvard Medical School
Radhika Raheja: Brigham and Women’s Hospital and Harvard Medical School
Chantal Kuhn: Brigham and Women’s Hospital and Harvard Medical School
Brendan Kenyon: Brigham and Women’s Hospital and Harvard Medical School
Nathaniel Skillin: Brigham and Women’s Hospital and Harvard Medical School
Ryoko Kadowaki-Saga: Brigham and Women’s Hospital and Harvard Medical School
Shrishti Saxena: Brigham and Women’s Hospital and Harvard Medical School
Gopal Murugaiyan: Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Chronic inflammation can drive tumor development. Here, we have identified microRNA-146a (miR-146a) as a major negative regulator of colonic inflammation and associated tumorigenesis by modulating IL-17 responses. MiR-146a-deficient mice are susceptible to both colitis-associated and sporadic colorectal cancer (CRC), presenting with enhanced tumorigenic IL-17 signaling. Within myeloid cells, miR-146a targets RIPK2, a NOD2 signaling intermediate, to limit myeloid cell-derived IL-17-inducing cytokines and restrict colonic IL-17. Accordingly, myeloid-specific miR-146a deletion promotes CRC. Moreover, within intestinal epithelial cells (IECs), miR-146a targets TRAF6, an IL-17R signaling intermediate, to restrict IEC responsiveness to IL-17. MiR-146a within IECs further suppresses CRC by targeting PTGES2, a PGE2 synthesis enzyme. IEC-specific miR-146a deletion therefore promotes CRC. Importantly, preclinical administration of miR-146a mimic, or small molecule inhibition of the miR-146a targets, TRAF6 and RIPK2, ameliorates colonic inflammation and CRC. MiR-146a overexpression or miR-146a target inhibition represent therapeutic approaches that limit pathways converging on tumorigenic IL-17 signaling in CRC.

Date: 2021
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DOI: 10.1038/s41467-021-22641-y

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