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MicroRNA control of tumor-promoting inflammation in colon cancer

MicroRNA 控制结肠癌促肿瘤炎症

基本信息

批准号：
10346323
负责人：
Murugaiyan Gopal
金额：
$ 38.63万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-08 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10346323
关键词：
ApcMin/+ mice Binding Cancer Etiology Cancer Model Cessation of life Chemoresistance Chronic Clinical Colitis Colon Carcinoma Colonic inflammation Colorectal Cancer Combination Drug Therapy Crohn&apos s disease Data Development Disease Epithelial Cells Experimental Models Genetic Polymorphism Goals Growth Human Immune Immune response In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interleukin-17 Interleukins Intervention Lesion Link Malignant - descriptor Malignant Neoplasms Mediating MicroRNAs Modeling Molecular Probes Mus Myeloid Cells Outcome Pathway interactions Patients Predisposition Production Prognosis RIPK2 gene Resistance Risk Factors Role Sampling Signal Transduction System TRAF6 gene Testing Therapeutic Therapeutic Intervention Ulcerative Colitis Untranslated RNA base chemotherapy colon cancer patients colon tumorigenesis colorectal cancer metastasis cytokine epithelial stem cell gut inflammation in vivo innovation interest interleukin-23 intestinal epithelium metastatic colorectal new therapeutic target novel therapeutics overexpression pre-clinical premalignant prevent stem cells targeted treatment tool tumor tumorigenesis tumorigenic

项目摘要

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.

项目总结/文摘