Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth

Abstract

Although epidemiologic and experimental evidence strongly implicates chronic inflammation and dietary fats as risk factors for cancer, the mechanisms underlying their contribution to carcinogenesis are poorly understood. Here we present genetic evidence demonstrating that deletion of peroxisome proliferator-activated receptor δ (PPARδ) attenuates colonic inflammation and colitis-associated adenoma formation/growth. Importantly, PPARδ is required for dextran sodium sulfate induction of proinflammatory mediators, including chemokines, cytokines, COX-2, and prostaglandin E 2 (PGE 2 ), in vivo. We further show that activation of PPARδ induces COX-2 expression in colonic epithelial cells. COX-2-derived PGE 2 stimulates macrophages to produce proinflammatory chemokines and cytokines that are responsible for recruitment of leukocytes from the circulation to local sites of inflammation. Our results suggest that PPARδ promotes colonic inflammation and colitis-associated tumor growth via the COX-2-derived PGE 2 signaling axis that mediates cross-talk between tumor epithelial cells and macrophages.colorectal cancer | COX-2/PGE 2

Protective role of +294 T/C (rs2016520) polymorphism of PPARD in Mexican patients with colorectal cancer

“…These receptors modulate many critical cellular functions, including fatty acid metabolism, wound healing, apoptosis, and inflammation. Therefore, PPARD could be involved in the development of several chronic diseases like diabetes (Villegas et al, 2011), cardiovascular disease (Skogsberg et al, 2003b;Lee et al, 2003), and cancer (Glinghammar et al, 2003;Peters et al, 2011;Ticha et al, 2013;Wang et al, 2014;Yang et al, 2014;Nath and Chan, 2016).…”

“…The pathogenesis of CRC is complex and still not fully understood. However, it has been reported that genetic susceptibility to CRC is associated with genes related to cell proliferation, differentiation, and transformation, causing failure of apoptosis and abnormalities in multiple signaling pathways (Fearon and Vogelstein, 1990;Ticha et al, 2013;Wang et al, 2014).…”

“…This gene has nine exons, five of which are coding, and spans around 85 kb of the region 6p21.2 (Skogsberg et al, 2003a,b). PPARD is expressed in diverse tissues with very high expression levels in the gastrointestinal tract (Park et al, 2001;Barak et al, 2002;Lee et al, 2003;Gupta et al, 2004;Harman et al, 2004;Foreman et al, 2011;Peters et al, 2011;Yang et al, 2006Yang et al, , 2008Yang et al, , 2010Yang et al, , 2011Fucci et al, 2012;Wang et al, 2006Wang et al, , 2014Zuo et al, 2009Zuo et al, , 2014. Several PPARD polymorphisms have been involved in regulation of lipid and glucose metabolism and in disorders related to these processes, including cardiovascular disease (Skogsberg et al, 2003a,b), atherosclerosis (Chen et al, 2004), insulin resistance (Hu et al, 2006), diabetes (Villegas et al, 2011), and recently in cancer (Ticha et al, 2013;Yang et al, 2014).…”

Identifying Changes in Punitive Transcriptional Factor Binding Sites Created by PPAR<i>α/δ/γ</i> SNPs Associated with Disease

“…The presence of this TFBS created by one SNP allele and not the other may in part be the reason for its association with intracerebral hemorrhages in Han Chinese [14]. PPARδ promotes inflammation and tumor growth [47] and an increase in HDL-c concentration in cardiovascular disease [48]. The…”

PPARδ and PGE2 signaling pathways communicate and connect inflammation to colorectal cancer

“…A recent report indicated that deletion of PPARδ in intestinal epithelial cells did not affect tumor incidence in AOM/DSS-treated mice [44] . Our recent results revealed that loss of PPARδ by deletion of its exons 4–5 attenuated chronic colonic inflammation and colitis-associated adenoma formation and growth with a reduction of certain pro-inflammatory mediators, including chemokines/cytokines, COX-2, and PGE 2 in both DSS-treated Apc Min/+ mice and AOM-treated Il-10 −/− mice [45] . In this study, we also found that PPARδ activation induced COX-2 expression in colonic tumor epithelial cells.…”