Regulation of Macrophages by miRNA-155 in Colon Cancer: Benefits of Quercetin

结肠癌中 miRNA-155 调节巨噬细胞：槲皮素的益处

• 批准号: 8637442
• 负责人: ELIZABETH ANGELA MURPHY
• 金额: $ 17.42万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637442
• 关键词: Address; Adipose tissue; Adoptive Transfer; Behavior; CCL2 gene; Chronic; Colon; Colon Carcinoma; Colorectal Cancer; Data; Development; Diet; Dietary Flavonoid; Dietary Intervention; Disease; Effectiveness; Epidemiologic Studies; Evaluation; Fat-Restricted Diet; Fatty acid glycerol esters; Flavonoids; Food; Goals; Immune; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intestines; Investigation; Laboratories; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Molecular; Mus; Obesity; Play; Prevention; Process; Quercetin; Regulation; Reporting; Risk; Role; Severities; Signal Pathway; Source; Symptoms; Testing; Therapeutic; Tissues; Toxic effect; Translating; cancer risk; chemokine; feeding; in vivo; interest; macrophage; mouse model; preclinical study; prevent; public health relevance; tumor; tumor microenvironment; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): High-fat diet (HFD)-induced obesity increases the risk for colorectal cancer (CRC). A pathophysiological mechanism that may link obesity to CRC risk is inflammation. Adipose tissue macrophages (ATM¿s) are a primary source of inflammation; however, there has been no systematic evaluation of their regulation in HFD-enhanced CRC. miRNA-155 (miR-155) inhibits signaling pathways in M¿s that can suppress inflammation. It is upregulated during the M¿ inflammatory response and has been implicated in playing a role in the link between inflammation and cancer. However, there are no reports of a role of miR-155 in HFD-enhanced CRC. Dietary compounds are of interest given their low toxicity profiles and their ability to target inflammation; however, there is a fundamental gap in the understanding of their effectiveness and their mechanism(s) of action. The long-term goal is to develop the flavonoid quercetin as a preventative/therapeutic strategy for obesity-enhanced CRC. The objective of this investigation is to evaluate whether M¿-induced inflammation is regulated by miR-155 in obesity-enhanced CRC, and whether dietary quercetin can target this process. The central hypothesis is that regulation of M¿-induced inflammation in obesity-enhanced CRC is mediated through miR-155, which may be an important mediator of quercetin action. The rationale is that elucidating the molecular links between obesity and CRC and identifying strategies to target these actions will translate to a more effective prevention/treatment approach in HFD-enhanced CRC. This hypothesis will be tested under two specific aims: 1) Determine the role of miR-155 in the regulation of M¿-induced inflammation in HFD-enhanced CRC; 2) Evaluate whether miR-155 can be targeted by dietary quercetin in HFD-enhanced CRC. In aim 1, we will use a miR-155-/- mouse in which obesity will be induced by HFD and CRC will be induced using AOM/DSS. We will examine inflammation and M¿ behavior in adipose tissue, immune regulation and inflammation in the tumor microenvironment, as well as tumorigenesis. Further, adoptive transfer of ATM¿s from both HFD wildtype and HFD miR-155-/- donor mice to wildtype recipient mice will be performed to determine if the effects of HFD on CRC are directly mediated through ATM¿s, and moreover, if this process is regulated by miR-155. In aim 2, we will determine if quercetin feedings can decrease expression of miR-155 in ATM¿s and if this is associated with a decrease in M¿-induced inflammation and reduced tumorigenesis. Further, using miR-155-/- mice we will determine if quercetin is mediating its effects through this miRNA. We will use adoptive transfer of ATM¿s from WT and miR-155-/- mice fed quercetin to directly determine if the benefits of quercetin on inflammation in HFD-enhanced CRC are mediated through ATM¿s. The proposed investigation is significant as it addresses prevention of incidence and progression of obesity-enhanced CRC by using a dietary food component to target M¿-induced inflammation, which is thought to at the mechanistic core of this disease.

描述（由申请人提供）：高脂饮食（HFD）诱导的肥胖会增加结直肠癌（CRC）的风险。 可能将肥胖与CRC风险联系起来的病理生理机制是炎症。 脂肪组织巨噬细胞（ATM）是炎症的主要来源;然而，在HFD增强的CRC中，尚未对其调节进行系统评价。 miRNA-155（miR-155）抑制M？s中可以抑制炎症的信号通路。 它在M？炎症反应期间上调，并在炎症和癌症之间的联系中发挥作用。 然而，没有关于miR-155在HFD增强的CRC中的作用的报道。 膳食化合物由于其低毒性特征和靶向炎症的能力而受到关注;然而，在对其有效性及其作用机制的理解方面存在根本性的差距。 长期目标是开发类黄酮槲皮素作为肥胖增强的CRC的预防/治疗策略。 本研究的目的是评估肥胖增强的CRC中M ²诱导的炎症是否受miR-155调节，以及饮食槲皮素是否可以靶向这一过程。 中心假设是，在肥胖增强的CRC中，M ²诱导的炎症的调节是通过miR-155介导的，miR-155可能是槲皮素作用的重要介质。 其基本原理是阐明肥胖和CRC之间的分子联系并确定针对这些行动的策略将转化为HFD增强的CRC的更有效的预防/治疗方法。 这一假设将在两个特定目标下进行测试：1）确定miR-155在HFD增强的CRC中调节M？诱导的炎症中的作用; 2）评估miR-155是否可以在HFD增强的CRC中被饮食槲皮素靶向。 在目标1中，我们将使用 将使用AOM/DSS诱导其中肥胖将由HFD诱导和CRC将由HFD诱导的miR-155-/-小鼠。 我们将研究脂肪组织中的炎症和M？行为，肿瘤微环境中的免疫调节和炎症，以及肿瘤发生。 此外，将进行ATM从HFD野生型和HFD miR-155-/-供体小鼠到野生型受体小鼠的过继转移，以确定HFD对CRC的作用是否直接通过ATM介导，此外，该过程是否受miR-155调节。 在目标2中，我们将确定槲皮素喂养是否可以降低ATM中miR-155的表达，以及这是否与M诱导的炎症减少和肿瘤发生减少有关。 此外，使用miR-155-/-小鼠，我们将确定槲皮素是否通过这种miRNA介导其作用。 我们将使用来自喂食槲皮素的WT和miR-155-/-小鼠的ATM的过继转移来直接确定槲皮素对HFD增强的CRC中的炎症的益处是否通过ATM介导。 拟议的研究是重要的，因为它解决了预防肥胖增强CRC的发病率和进展，通过使用膳食食物成分来靶向M？诱导的炎症，这被认为是这种疾病的机制核心。