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

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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.