Loss of free fatty acid receptor 2 enhances colonic adenoma development and reduces the chemopreventive effects of black raspberries in ApcMin/+ mice

摘要

We previously showed that black raspberries (BRBs) have beneficial effects in human colorectal cancer and a mouse model of colorectal cancer (Apc^Min/+). The current study investigated the role of free fatty acid receptor 2 (FFAR2) in colon carcinogenesis and whether the FFAR2 signaling pathway contributes to BRB-mediated chemoprevention in mice. FFAR2 (also named GPR43) is a member of the G-protein-coupled receptor family that is expressed in leukocytes and colon. Apc^Min/+ and Apc^Min/+-FFAR2^−/− mice were given a control diet or the control diet supplemented with 5% BRBs for 8 weeks. FFAR2 deficiency promoted colonic polyp development, with 100% incidence and increased polyp number and size. The Apc^Min/+ mice developed colonic tubular adenoma, whereas the Apc^Min/+-FFAR2^−/− mice developed colonic tubular adenoma with high-grade dysplasia. FFAR2 deficiency also enhanced the cAMP-PKA-CREB-HDAC pathway, downstream of FFAR2 signaling, and increased activation of the Wnt pathway, and raised the percentage of GR-1⁺ neutrophils in colonic lamina propria (LP) and increased infiltration of GR-1⁺ neutrophils into colonic polyps. BRBs suppressed colonic polyp development and inhibited the cAMP-PKA-CREB-HDAC and Wnt pathways in the Apc^Min/+ mice but not the Apc^Min/+-FFAR2^−/− mice. They also increased the percentage of GR-1⁺ neutrophils and cytokine secretion in colonic LP and decreased the infiltration of GR-1⁺ neutrophils and IL-1β expression in colon polyps of Apc^Min/+ mice but not Apc^Min/+-FFAR2^−/− mice. These results suggest that loss of FFAR2 drives colon tumorigenesis and that BRBs require functional FFAR2 to be chemopreventive. BRBs have the potential to modulate the host immune system, thereby enhancing the antitumor immune microenvironment.