PPARδ status and Apc-mediated tumourigenesis in the mouse intestine

Abstract

Based on recent reports that peroxisome proliferatoractivated receptor delta (PPARd) activation promotes tumourigenesis, we have investigated the role of this protein in Apc-mediated intestinal tumourigenesis. We demonstrate that the inactivation of Apc in the adult small intestine, while causing the expected nuclear accumulation of b-catenin, does not cause the expected increase in PPARd mRNA or protein but conversely, the levels of PPARd mRNA and protein are lowered. Furthermore, we find that Apc Min PPARd-null mice exhibit an increased predisposition to intestinal tumourigenesis. Our data suggest that PPARd is not directly regulated by bcatenin, and that inhibition of PPARd activity is unlikely to be an appropriate strategy for the chemoprevention or chemotherapy of intestinal malignancies.

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

“…It has been reported that a polymorphism in PPARd modifies the protective effects of nonsteroidal anti-inflammatory drugs on colorectal adenomas (Siezen et al, 2006), but other investigators have not reached the same conclusions in the context of CRC (McGreavey et al, 2005). As mentioned in the Introduction, PPARd was found to be unnecessary for small intestinal polyp formation (Barak et al, 2002), but PPARd attenuated polyp formation in chemical and genetic models (Harman et al, 2004;Reed et al, 2004). By contrast, it has been reported that inactivation of the PPARd gene results in reduced tumorigenicity and in vivo growth of HCT116 colon cancer cells (Park et al, 2001) and that a specific PPARd agonist enhanced in vivo growth of intestinal adenoma of Apc min mice (Gupta et al, 2004).…”

“…Peroxisome proliferator-activated receptord was found to be unnecessary for small intestinal polyp formation, but might be required for the development of large-sized intestinal polyps (Barak et al, 2002). In addition, PPARd attenuates polyp formation in chemical and genetic models (Harman et al, 2004;Reed et al, 2004). In contrast, activation of PPARd using a synthetic ligand increases the number and size of intestinal polyps (Gupta et al, 2004); indeed, PPARd-deficient CRC cells can establish tumours when grown as xenografts in nude mice (Park et al, 2001).…”

Wnt signaling and gastrointestinal tumorigenesis in mouse models

“…Therefore, tumorigenesis depends on the relatively rare events of LOH. Recently, another Apc gene knockout mutant was reported where both Apc alleles were mutated simultaneously in a tissue-specific manner using the cre-loxP system (Reed et al, 2004). Although it is quite an artificial system, it has revealed early changes in the intestinal cell physiology.…”

“…However, it has been excluded from the direct targets of the Wnt signal. It does not alter the phenotype of mismatch repair deficiency, either (Reed et al, 2004(Reed et al, , 2006. Loss of APC induces histone deacetylase (HDAC)2 expression, depending on the Wnt pathway and c-Myc.…”

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

“…However, other studies conflict with those reports. Targeted deletion of adenomatous polyposis coli alleles reduces PPAR-b expression in mouse intestine (Reed et al, 2004). PPAR-b expressions in human colorectal cancers or intestinal polyps of adenomatous polyposis coli (min) mice are either unchanged or downregulated as compared with normal controls (Orner et al, 2003;Chen et al, 2004;Yang et al, 2006).…”