1. MicroRNA-146a limits tumorigenic inflammation in colorectal cancer
- Author
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Nathaniel Skillin, Amrendra Kumar Ajay, Radhika Raheja, Lucien P. Garo, Shrishti Saxena, Brendan Kenyon, Galina Gabriely, Gopal Murugaiyan, Chantal Kuhn, Mai Fujiwara, and Ryoko Kadowaki-Saga
- Subjects
0301 basic medicine ,Myeloid ,Colorectal cancer ,Carcinogenesis ,General Physics and Astronomy ,medicine.disease_cause ,0302 clinical medicine ,NOD2 ,Cells, Cultured ,Cancer ,chemistry.chemical_classification ,Mice, Knockout ,Multidisciplinary ,Interleukin-17 ,Colitis ,Small molecule ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Tumour immunology ,medicine.symptom ,Colorectal Neoplasms ,Signal Transduction ,Science ,Immunology ,Inflammation ,Mice, Transgenic ,digestive system ,General Biochemistry, Genetics and Molecular Biology ,Article ,RIPK2 ,03 medical and health sciences ,Receptor-Interacting Protein Serine-Threonine Kinase 2 ,medicine ,Animals ,Humans ,TNF Receptor-Associated Factor 6 ,business.industry ,General Chemistry ,medicine.disease ,digestive system diseases ,Mice, Inbred C57BL ,MicroRNAs ,030104 developmental biology ,Enzyme ,chemistry ,Cancer research ,business - 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., Activation of interleukin-17 (IL-17) receptor signaling within intestinal epithelial cells (IECs) promotes colorectal cancer development. Here, the authors show that miR-146a limits inflammation-induced colorectal carcinogenesis by inhibiting both IL-17 induction from myeloid cells and inhibiting IL-17R signaling within IECs.
- Published
- 2020