Introduction Aberrant Wnt/B-catenin signaling activation due to mutations in the adenomatous poliposis coli gene, APC, is a critical event in colorectal cancer (CRC). However, to drive CRC tumorigenesis, aberrant Wnt/B-catenin activation requires additional enhancing regulatory mechanisms. The peroxisome proliferator-activated receptor delta gene (PPARD), which is upregulated in CRC, is a downstream target of aberrant Wnt/B-catenin activation in human colon cancer cells. However, PPARD has also been reported to inhibit intestinal tumorigenesis in mice with germline APCmin mutations. Thus, the mechanistic interaction between PPARD and Wnt/β-catenin remains poorly understood. PPARD is a druggable protein for which agonists and antagonists are being developed. Determining PPARD effects on Wnt/B-catenin activation would define the direction of its therapeutic targeting in cancer and other diseases.
Methods We developed a novel mouse model that simulates PPARD overexpression in CRC by inducing PPARD overexpression in intestinal epithelial cells via a villin promoter (villin-PPARD mice). We bred villin-PPARD mice with mice that have Apc580 mutation in intestinal epithelial cells induced by CDX2-Cre recombinase expression (Apc580mu mice) to generate Apc580mu-PPARD-Gut mice. Apc580mu-PPARD-Gut mice and Apc580mu control mice were monitored for CRC tumorigenesis. We also assessed the effects of PPARD expression modulation on Wnt/B-catenin activation in human colon cancer cell lines.
Results PPARD overexpression in colonic epithelial cells increased CRC tumorigenesis in mice with Apc580 mutation. At 10 weeks of age, 100% of Apc580mu-PPARD-Gut mice but only 60% of Apc580mu mice had tumors of any size, and the mean number of tumors per Apc580mu-PPARD-Gut mouse (1.6 ± 2.5) was significantly higher than that per Apc580mu mouse (0.6 ± 0.25; P = 0.02). Tumors >3.5 mm were present in all Apc580mu-PPARD-Gut mice but only 20% of Apc580mu mice, and the mean number of tumors >3.5 mm per Apc580mu-PPARD-Gut mouse (1.4 ± 2.5) was significantly higher than that per Apc580mu mouse (0.2 ± 0.2; p = 0.005). In mice, colonic epithelial PPARD overexpression increased activated B-catenin protein levels and Wnt/B-catenin target gene mRNA levels. In human colon cancer cells, PPARD increased the levels of activated β-catenin, its nuclear localization and transcriptional activity.
Conclusion Our findings indicate that PPARD augments Wnt/B-catenin signaling to promote CRC tumorigenesis and thus support the targeted inhibition of PPARD to suppress CRC tumorigenesis.
Citation Format: Xiangsheng Zuo, Rui Tian, Shen Gao, Micheline J. Moussalli, Weidong Chen Chen, Ling Wu, Imad Shureiqi. PPAR-delta promotes Wnt/B-catenin-driven colorectal tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3819.