TY - JOUR
T1 - Pleiotropic effects of PPARD accelerate colorectal tumorigenesis, progression, and invasion
AU - Liu, Yi
AU - Deguchi, Yasunori
AU - Tian, Rui
AU - Wei, Daoyan
AU - Wu, Ling
AU - Chen, Weidong
AU - Xu, Weiguo
AU - Xu, Min
AU - Liu, Fuyao
AU - Gao, Shen
AU - Jaoude, Jonathan C.
AU - Chrieki, Sarah P.
AU - Moussalli, Micheline J.
AU - Gagea, Mihai
AU - Morris, Jeffrey
AU - Broaddus, Russell R.
AU - Zuo, Xiangsheng
AU - Shureiqi, Imad
N1 - Funding Information:
This work was supported by the Cancer Prevention and Research Institute of Texas (RP140224 to I. Shureiqi) and the NCI (R01-CA142969, R01-CA195686, and R01-CA206539 to I. Shureiqi). This study made use of the MD Anderson Cancer Center Genetically Engineered Mouse Facility, Functional Proteomics Reverse-Phase Protein Array Core, Sequencing and Microarray Facility, and Research Animal Support Facility at Houston, supported by Cancer Center Support Grant CA016672.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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 PPARD-mediated 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.
AB - 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 PPARD-mediated 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.
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U2 - 10.1158/0008-5472.CAN-18-1790
DO - 10.1158/0008-5472.CAN-18-1790
M3 - Article
C2 - 30679176
AN - SCOPUS:85062260898
SN - 0008-5472
VL - 79
SP - 954
EP - 969
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -