MicroRNA-146a limits tumorigenic inflammation in colorectal cancer

Lucien P Garo,Chantal Kuhn,Ryoko Kadowaki-Saga,Mai Fujiwara,Radhika Raheja,Galina Gabriely,Brendan Kenyon,Gopal Murugaiyan,Nathaniel Skillin,Amrendra K Ajay,Shrishti Saxena

doi:10.1038/s41467-021-22641-y

Lucien P Garo, Chantal Kuhn + Show 9 more

Open Access

https://doi.org/10.1038/s41467-021-22641-y

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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.

Highlights

In contrast to miR-146a−/− mice, WT mice showed only few low-grade adenomas (Fig. 1k). These results demonstrated that miR-146a is critical for protection against colitis and colitis-associated colorectal cancer (CRC)
Discussion miR-146a has been associated with clinical outcomes in CRC23,26, our results demonstrate the in vivo function and therapeutic potential of miR-146a in controlling CRC
Mice deficient in miR-146a either globally, within myeloid cells, or within intestinal epithelial cells (IECs), present with enhanced IL-17 signaling and exacerbated CRC, which is abrogated by IL-17 neutralization

Summary

Introduction

MiR-146a targets RIPK2, a NOD2 signaling intermediate, to limit myeloid cell-derived IL-17-inducing cytokines and restrict colonic IL-17. IL-17 has been shown to exert tumorigenic signaling directly within intestinal epithelial cells (IECs) to promote CRC development and progression[7]. IL-17 has been linked to tumor progression and therapy resistance in CRC, the molecular regulatory mechanisms that control IL-17 expression in the colonic microenvironment and CRC development remain largely unknown. Our data show that miR-146a prevents intestinal inflammation and CRC by two interlinked mechanisms as follows: (1) by limiting myeloid cell-mediated inflammatory IL-17 production and (2) by inhibiting tumorigenic IL-17R signaling in IECs. Mice deficient in miR-146a either globally, within myeloid cells, or within IECs, present with enhanced IL-17 signaling and severe CRC. Preclinical administration of miR-146a mimic or direct inhibition of miR-146a targets can ameliorate colonic inflammation and CRC

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