Pleiotropic Effects of PPARD Accelerate Colorectal Tumorigenesis, Progression, and Invasion

Abstract

APC mutations activate aberrant b-catenin signaling to drive initiation of colorectal cancer; however, colorectal cancer progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of b-catenin, is upregulated in colorectal cancer. However, promotion of intestinal tumorigenesis following deletion of PPARD in Apc min mice has raised questions about the effects of PPARD on aberrant b-catenin activation and colorectal cancer. In this study, we used mouse models of PPARD overexpression or deletion combined with APC mutation (Apc D580 ) in intestinal epithelial cells (IEC) to elucidate the contributions of PPARD in colorectal cancer. Overexpression or deletion of PPARD in IEC augmented or suppressed b-catenin activation via up-or downregulation of BMP7/TAK1 signaling and strongly promoted or suppressed colorectal cancer, respectively. Depletion of PPARD in human colorectal cancer organoid cells inhibited BMP7/ b-catenin signaling and suppressed organoid self-renewal.Treatment with PPARD agonist GW501516 enhanced colorectal cancer tumorigenesis in Apc D580 mice, whereas treatment with PPARD antagonist GSK3787 suppressed tumorigenesis. PPARD expression was significantly higher in human colorectal cancer-invasive fronts versus their paired tumor centers and adenomas. Reverse-phase protein microarray and validation studies identified PPARDmediated upregulation of other proinvasive pathways: connexin 43, PDGFRb, AKT1, EIF4G1, and CDK1. Our data demonstrate that PPARD strongly potentiates multiple tumorigenic pathways to promote colorectal cancer progression and invasiveness.Significance: These findings address long-standing, important, and unresolved questions related to the potential role of PPARD in APC mutation-dependent colorectal tumorigenesis by showing PPARD activation enhances APC mutation-dependent tumorigenesis.

Molecular and nanoscale evaluation of N-cadherin expression in invasive bladder cancer cells under control conditions or GW501516 exposure

“…In addition, GW501516-mediated activation of PPARβ/δ led to the reduced expression of MMP-9 after the BCL6 transcriptionnal repressor dissociation and consequently to the decrease of pancreatic cancer cell invasion capacities [ 13 ]. In contrast to our results, other experimental works reported that the activation of PPARβ/δ by GW501516 significantly increased the migration and invasion of highly metastatic melanoma cells through the upregulation of Snail expression (a transcriptional repressor of cdh1 gene encoding for the E-cadherin) and the decrease of E-cadherin expression [ 44 ], enhanced human cholangiocarcinoma cell proliferation [ 45 ], or enhanced colorectal cancer in APC mutated mice [ 46 ].…”

PPAR Beta/Delta and the Hallmarks of Cancer

“…The tumor promoting action of GW501516 in Apc mice was confirmed recently and extended by the findings that the PPARβ/δ antagonist GSK3787 suppressed tumorigenesis. PPARβ/δ expression was significantly higher in human colorectal cancers compared to adenomatous polyps and normal mucosa [50] and also in the malignant cells-invasive front versus their paired tumor centers and adenomas-and proinvasive pathways (connexin 43, PDGFRb, AKT1, EIF4G1 and CDK1) were upregulated in response to PPARβ/δ stimulation [17]. Again, the opposite result has also been published for human and mouse tumor samples [51], while another important report using human colorectal cancer samples confirmed high expression of PPARβ/δ and COX2, which was correlated with the incidence of liver metastasis and identified as significant independent prognostic factor [52].…”

CDK1 and CDC20 overexpression in patients with colorectal cancer are associated with poor prognosis: evidence from integrated bioinformatics analysis

“…Previous studies have shown that CDK1 is involved in the progression of multiple types of cancer, including colorectal cancer, liver cancer, and lung cancer. Furthermore, the upregulation of CDK1 is associated with reduced survival time for these diseases [34][35][36]. Xue et al [37] reported that the activity of CDK1 is highly elevated in CRC tissues compared to noncancerous tissues, and it predicts distant metastasis risk in CRC; CDK1 can promote the progression of CRC through phosphorylation of JAK1 to activate the JAK/ STAT3 signaling pathway.…”