Monday, May 12, 2025
5/12/2025
MicroRNA control of tumor-promoting inflammation in colon cancer - Project Summary/Abstract The inflammatory cytokine, interleukin (IL)-17, has emerged as a major player in inflammation-associated, spontaneous, and metastatic colorectal cancer (CRC) models, as well as human CRC. In fact, elevated IL-17 has been negatively correlated with CRC patient survival, and even linked to resistance to both chemotherapy and targeted therapeutics. However, master regulatory mechanisms that control IL-17-IL-17R signaling in CRC remain largely unknown. Key Findings: We recently uncovered a critical role for the microRNA, miR-146a, in preventing colonic inflammation and associated tumorigenesis. Mice deficient in miR-146a (-/-) are highly susceptible to both colitis-associated and spontaneous CRC, which appears to be mediated by enhanced tumorigenic IL-17-IL17R signaling. Mechanistically, our data suggest miR-146a limits intestinal inflammation and CRC by two interlinked mechanisms: 1) miR-146a within myeloid cells inhibits IL-17-inducing cytokines, which restricts IL-17 production; and 2) miR-146a within intestinal epithelial cells (IECs) inhibits tumorigenic IL-17R signaling, which restricts IL-17 responsiveness. Within myeloid cells, miR-146a binds RIPK2, an NOD2 signaling intermediate, to limit myeloid cell-derived IL-17-inducing cytokines, such as IL-23, and restrict colonic IL-17 levels. Accordingly, myeloid cell-specific deletion of miR-146a leads to CRC susceptibility. In addition to inhibiting IL-17, miR-146a directly limits tumorigenic IL-17R signaling within IECs by binding TRAF6. Correspondingly, IEC-specific deletion of miR-146a also confers CRC susceptibility. Importantly, preclinical administration of miR- 146a mimic can ameliorate CRC. Finally, we show that miR-146a appears to analogously target RIPK2 and TRAF6 in humans, including in CRC patients, suggesting miR-146a may also limit IL-17-IL-17R signaling in humans to control CRC. Hypothesis/Goal: We will test our hypothesis that miR-146a protects against CRC by regulating colonic inflammation and tumorigenesis in mice and humans. In Aim 1, we will leverage IEC-specific miR-146a-/- mice, IEC progenitor-specific miR-146a-/- mice, ApcMin/+miR-146a-/- mice, ApcMin/+miR-146a-/-KrasLSL- G12D mice, miR-146a-silenced/overexpressing human IECs, and CRC patient samples to test if miR-146a within IECs targets TRAF6 and inhibits IL-17R-mediated tumorigenesis in mice and humans. In Aim 2, we will leverage myeloid cell-specific miR-146a-/- mice, ApcMin/+miR-146a-/- mice and ApcMin/+miR-146a-/-KrasLSL-G12D mice, miR- 146a-silenced/overexpressing human primary myeloid cells, and CRC patient samples to test if miR-146a within myeloid cells targets RIPK2, where it inhibits NOD2 signaling and IL-17-inducing cytokines, ultimately restricting IL-17 production and CRC in mice and humans. In Aim 3, we will leverage inflammation-associated CRC, spontaneous CRC, and CRC metastasis models to test if miR-146a mimic therapeutically inhibits tumor/chemoresistance-promoting IL-17 pathways, either alone or in combination with chemotherapy. In summary, miR-146a is of unique significance because it constitutes a single target that modulates multiple pathways converging on tumorigenic IL-17 signaling and may offer novel therapeutic points of intervention.
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