Abstract
Abstract APC mutations activate aberrant β-catenin signaling to drive colorectal cancer (CRC) initiation. CRC progression however requires additional molecular mechanisms. PPAR-delta (PPARD) is a downstream target of β-catenin and upregulated in CRC. PPARD germline genetic deletion has however been reported to promote intestinal tumorigenesis in Apcmin mice, which has questioned PPARD effects on β-catenin aberrant activation and CRC. Addressing this knowledge gap is important because PPARD is a druggable protein. Mice with targeted PPARD overexpression/deletion into intestinal epithelial cells (IECs) were bred with mice with intestinally targeted ApcΔ580 mutation via CDX2-cre (ApcΔ580) or CDX2-cre-ERT2 (ApcΔ580-TMX). APCΔ580 mice treated with PPARD agonist (GW501516) or antagonist (GSK3787), and human CRC organoid cells were also tested. PPARD expression was examined in human CRC invasive fronts and their paired colorectal adenomas and cancer centers. PPARD’s mechanisms to promote CRC were screened by Functional Proteomics Reverse Phase Protein Assay (RPPA) and subsequently validated in in-vitro and in-vivo studies. PPARD overexpression/deletion in IECs in mice augmented/suppressed β-catenin activation via upregulation/downregulation of BMP7/TAK1 signaling and strongly promoted/suppressed CRC .PPARD downregulation by siRNA in human CRC organoid cells inhibited BMP7/β-catenin signaling and suppressed organoid self-renewals. GW501516 enhanced while GSK3787 suppressed CRC tumorigenesis in ApcΔ580 mice. PPARD expression was significantly higher in human CRC invasive fronts versus their paired invasive tumor centers and adenomas. RPPA and validation studies identified PPARD upregulation of multiple other pro-invasive pathways: PDGFRβ, connexin 43, AKT1, EIF4G1 and CDK1, Our data demonstrate that PPARD strongly potentiates multiple pro-tumorigenic pathways to promote CRC progression and invasiveness. Citation Format: Yi Liu, Yasunori Deguchi, Rui Tian, Daoyan Wei, Ling Wu, Weidong Chen, Weiguo Xu, Min Xu, Fuyao Liu, Shen Gao, Jonathan C. Jaoude, Sarah P. Chrieki, Micheline J. Moussalli, Mihai Gagea, Jeffrey S. Morris, Russell Broaddus, Xiangsheng Zuo, Imad Shureiqi. Pleiotropic effects of PPARD accelerate colorectal tumorigenesis progression and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2599.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call