Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Cancer Res. 2019 Mar 1;79(5):954-969. doi: 10.1158/0008-5472.CAN-18-1790. Epub 2019 Jan 24.
mutations activate aberrant β-catenin signaling to drive initiation of colorectal cancer; however, colorectal cancer progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of β-catenin, is upregulated in colorectal cancer. However, promotion of intestinal tumorigenesis following deletion of PPARD in mice has raised questions about the effects of PPARD on aberrant β-catenin activation and colorectal cancer. In this study, we used mouse models of PPARD overexpression or deletion combined with mutation ( ) in intestinal epithelial cells (IEC) to elucidate the contributions of PPARD in colorectal cancer. Overexpression or deletion of PPARD in IEC augmented or suppressed β-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/β-catenin signaling and suppressed organoid self-renewal. Treatment with PPARD agonist GW501516 enhanced colorectal cancer tumorigenesis in 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, PDGFRβ, 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 mutation-dependent colorectal tumorigenesis by showing PPARD activation enhances mutation-dependent tumorigenesis.
突变激活异常的β-连环蛋白信号，驱动结直肠癌的发生；然而，结直肠癌的进展需要额外的分子机制。PPAR-δ（PPARD）是β-连环蛋白的下游靶点，在结直肠癌中上调。然而，在小鼠中删除 PPARD 会促进肠道肿瘤发生，这引发了关于 PPARD 对异常β-连环蛋白激活和结直肠癌影响的问题。在这项研究中，我们使用了 PPARD 过表达或缺失的小鼠模型，并结合 IEC 中的 突变（），以阐明 PPARD 在结直肠癌中的作用。IEC 中 PPARD 的过表达或缺失通过上调或下调 BMP7/TAK1 信号分别增强或抑制β-连环蛋白激活，并强烈促进或抑制结直肠癌。在人结直肠类器官细胞中耗尽 PPARD 抑制 BMP7/β-连环蛋白信号并抑制类器官自我更新。PPARD 激动剂 GW501516 增强了 小鼠的结直肠癌肿瘤发生，而 PPARD 拮抗剂 GSK3787 抑制了肿瘤发生。与配对的肿瘤中心和腺瘤相比，PPARD 在人结直肠癌侵袭前沿的表达明显更高。反相蛋白质微阵列和验证研究确定了 PPARD 介导的其他促侵袭途径的上调：连接蛋白 43、PDGFRβ、AKT1、EIF4G1 和 CDK1。我们的数据表明，PPARD 强烈增强多种致癌途径，以促进结直肠癌的进展和侵袭性。意义：这些发现通过显示 PPARD 激活增强 突变依赖性肿瘤发生，解决了与 PPARD 在 突变依赖性结直肠肿瘤发生中的潜在作用相关的长期存在的、重要的和未解决的问题。
