MicroRNA control of tumor-promoting inflammation in colon cancer

MicroRNA 控制结肠癌促肿瘤炎症

• 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
• 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' 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

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.

项目概要/摘要 炎症细胞因子白细胞介素 (IL)-17 已成为炎症相关、 自发性和转移性结直肠癌 (CRC) 模型以及人类 CRC。事实上，IL-17 升高 与 CRC 患者的生存率呈负相关，甚至与两种化疗的耐药性相关 和靶向治疗。然而，掌握控制 CRC 中 IL-17-IL-17R 信号传导的调控机制 仍然很大程度上不为人知。主要发现：我们最近发现了 microRNA（miR-146a）在 预防结肠炎症和相关的肿瘤发生。 miR-146a (-/-) 缺陷的小鼠高度 易患结肠炎相关性和自发性结直肠癌，这似乎是由增强的介导的 致瘤性 IL-17-IL17R 信号传导。从机制上讲，我们的数据表明 miR-146a 限制肠道炎症和 CRC 通过两个相互关联的机制：1) 骨髓细胞内的 miR-146a 抑制 IL-17 诱导细胞因子，从而 限制 IL-17 的生产； 2) 肠上皮细胞 (IEC) 内的 miR-146a 抑制致瘤性 IL-17R 信号传导，限制 IL-17 反应。在骨髓细胞内，miR-146a 结合 RIPK2（一种 NOD2 信号传导） 中间，限制骨髓细胞衍生的 IL-17 诱导细胞因子，例如 IL-23，并限制结肠 IL-17 水平。因此，骨髓细胞特异性删除 miR-146a 会导致 CRC 易感性。除了抑制 IL-17、miR-146a 通过结合 TRAF6 直接限制 IEC 内的致瘤性 IL-17R 信号传导。相应地， IEC 特异性删除 miR-146a 也会导致 CRC 易感性。重要的是，miR-的临床前给药 146a 类似物可以改善 CRC。最后，我们表明 miR-146a 似乎类似地靶向 RIPK2 和 TRAF6 在人类中，包括在 CRC 患者中，表明 miR-146a 也可能限制 IL-17-IL-17R 信号传导 人类控制CRC。假设/目标：我们将通过以下方式检验我们的假设：miR-146a 可以预防 CRC 调节小鼠和人类的结肠炎症和肿瘤发生。在目标 1 中，我们将利用 IEC 特定的 miR-146a-/- 小鼠、IEC 祖细胞特异性 miR-146a-/- 小鼠、ApcMin/+miR-146a-/- 小鼠、ApcMin/+miR-146a-/-KrasLSL- G12D 小鼠、miR-146a 沉默/过度表达的人类 IEC 和 CRC 患者样本，以测试 miR-146a 是否在 IECs 靶向 TRAF6 并抑制小鼠和人类中 IL-17R 介导的肿瘤发生。在目标 2 中，我们将利用 骨髓细胞特异性 miR-146a-/- 小鼠、ApcMin/+miR-146a-/- 小鼠和 ApcMin/+miR-146a-/-KrasLSL-G12D 小鼠、miR- 146a 沉默/过表达的人原发性骨髓细胞和 CRC 患者样本，以测试 miR-146a 是否在 骨髓细胞以 RIPK2 为目标，抑制 NOD2 信号传导和 IL-17 诱导细胞因子，最终限制 小鼠和人类中 IL-17 的产生和 CRC。在目标 3 中，我们将利用炎症相关的 CRC， 自发性 CRC 和 CRC 转移模型，以测试 miR-146a 模拟物是否具有治疗抑制作用 促进肿瘤/化疗耐药的 IL-17 途径，单独或与化疗联合使用。在 总之，miR-146a 具有独特的意义，因为它构成了调节多个 通路汇聚于致瘤性 IL-17 信号传导，可能提供新的干预治疗点。