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

描述（由申请人提供）：高脂肪饮食（HFD）诱导的肥胖增加结直肠癌（CRC）的风险。可能将肥胖与结直肠癌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¿s）是炎症的主要来源；然而，目前还没有系统的评估它们在hfd增强的CRC中的调节作用。miRNA-155 （miR-155）抑制可抑制炎症的M¿s信号通路。它在炎症反应中被上调，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CRC中的作用的报道。由于其低毒性和靶向炎症的能力，膳食化合物引起了人们的兴趣；然而，对它们的有效性及其作用机制的理解存在根本性的差距。长期目标是开发类黄酮槲皮素作为预防/治疗肥胖增强的结直肠癌的策略。本研究的目的是评估在肥胖增强的结直肠癌中，miR-155是否调节M¿-诱导的炎症，以及饮食中的槲皮素是否可以靶向这一过程。核心假设是，在肥胖增强的结直肠癌中，M¿诱导的炎症调节是通过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结直肠癌之间的分子联系，并确定针对这些行为的策略，将转化为更有效的预防/治疗方法，用于hfd增强型结直肠癌。这一假设将在两个特定目的下进行验证：1)确定miR-155在hfd增强CRC中调控M¿-诱导炎症中的作用；2)评估膳食槲皮素在hfd增强的结直肠癌中是否可以靶向miR-155。在aim 1中，我们将使用a

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.