Other
18 Authors
- Moussalli MJ,
- Xu W,
- Deguchi Y,
- Xu M,
- Broaddus RR,
- Wu L,
- Liu F,
- Liu Y,
- Gao S,
- Gagea M,
- Morris J,
- Wei D,
- Chrieki SP,
- Jaoude JC,
- Zuo X,
- Tian R,
- Chen W,
- Shureiqi I
| First Author | Liu Y | Year | 2019 |
| Journal | Cancer Res | Volume | 79 |
| Issue | 5 | Pages | 954-969 |
| PubMed ID | 30679176 | Mgi Jnum | J:273221 |
| Mgi Id | MGI:6285278 | Doi | 10.1158/0008-5472.CAN-18-1790 |
| Citation | Liu Y, et al. (2019) Pleiotropic Effects of PPARD Accelerate Colorectal Tumorigenesis, Progression, and Invasion. Cancer Res 79(5):954-969 |
| abstractText | APC mutations activate aberrant beta-catenin signaling to drive initiation of colorectal cancer; however, colorectal cancer progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of beta-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 beta-catenin activation and colorectal cancer. In this study, we used mouse models of PPARD overexpression or deletion combined with APC mutation (Apc(Delta580) ) in intestinal epithelial cells (IEC) to elucidate the contributions of PPARD in colorectal cancer. Overexpression or deletion of PPARD in IEC augmented or suppressed beta-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/beta-catenin signaling and suppressed organoid self-renewal. Treatment with PPARD agonist GW501516 enhanced colorectal cancer tumorigenesis in Apc(Delta580) 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 PPARD-mediated upregulation of other proinvasive pathways: connexin 43, PDGFRbeta, 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. |
