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.

项目总结/摘要 炎性细胞因子白细胞介素（IL）-17已经成为炎症相关的， 自发性和转移性结直肠癌（CRC）模型以及人CRC。事实上，IL-17的升高 与结直肠癌患者的生存率呈负相关，甚至与对两种化疗的耐药性有关。 和靶向治疗。然而，在CRC中控制IL-17-IL-17 R信号传导的主要调节机制 但基本上仍不为人所知。关键发现：我们最近发现了microRNA，miR-146 a， 预防结肠炎症和相关的肿瘤发生。miR-146 a（-/-）缺陷的小鼠高度 对结肠炎相关和自发性CRC敏感，这似乎是由增强的 致瘤性IL-17-IL 17 R信号传导。从机制上讲，我们的数据表明miR-146 a限制了肠道炎症， CRC通过两种相互关联的机制：1）骨髓细胞内的miR-146 a抑制IL-17诱导的细胞因子， 限制IL-17的产生;和2）肠上皮细胞（IEC）内的miR-146 a抑制致瘤性IL-17 R 信号传导，其限制IL-17反应性。在骨髓细胞内，miR-146 a结合RIPK 2，一种NOD 2信号传导途径， 中间体，以限制骨髓细胞来源的IL-17诱导细胞因子，如IL-23，并限制结肠IL-17 程度.因此，骨髓细胞特异性缺失miR-146 a会导致CRC易感性。除了抑制 IL-17、miR-146 a通过结合TRAF 6直接限制IEC内的致瘤性IL-17 R信号传导。与此相对应， miR-146 a的IEC特异性缺失也赋予CRC易感性。重要的是，临床前给予miR-16 146 a模拟物可改善CRC。最后，我们发现miR-146 a似乎类似地靶向RIPK 2， TRAF 6在人类中，包括在CRC患者中，表明miR-146 a也可能限制IL-17-IL-17 R信号传导， 人类控制CRC。假设/目标：我们将通过以下方法检验我们的假设，即miR-146 a可保护CRC： 调节小鼠和人类的结肠炎症和肿瘤发生。在目标1中，我们将利用特定于IEC的 miR-146 a-/-小鼠、IEC祖细胞特异性miR-146 a-/-小鼠、ApcMin/+miR-146 a-/-小鼠、ApcMin/+miR-146 a-/-KrasLSL- G12 D小鼠、miR-146 a沉默/过表达的人IEC和CRC患者样本，以测试miR-146 a是否在 IEC靶向TRAF 6并抑制小鼠和人类中IL-17 R介导的肿瘤发生。在目标2中， 骨髓细胞特异性miR-146 a-/-小鼠、ApcMin/+miR-146 a-/-小鼠和ApcMin/+miR-146 a-/-KrasLSL-G12 D小鼠、miR- 146 a沉默/过表达的人原代骨髓细胞和CRC患者样品，以测试miR-146 a是否在 骨髓细胞靶向RIPK 2，在那里它抑制NOD 2信号传导和IL-17诱导的细胞因子，最终限制 小鼠和人类中的IL-17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-146 a模拟物是否治疗性抑制 肿瘤/化学抗性促进IL-17途径，单独或与化学疗法组合。在 总之，miR-146 a具有独特的意义，因为它构成了调节多个 这些信号通路集中在致瘤性IL-17信号传导上，并可能提供新的干预治疗点。