Department of Surgery, University of Missouri-Columbia, Columbia, MO, 65212, USA; Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, 65212, USA; Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
Department of Surgery, University of Missouri-Columbia, Columbia, MO, 65212, USA.
Cancer Lett. 2019 Jul 10;454:204-214. doi: 10.1016/j.canlet.2019.04.022. Epub 2019 Apr 17.
Liver-intestine cadherin (CDH17) has been known to function as a tumor stimulator and diagnostic marker for almost two decades. However, its function in highly malignant pancreatic cancer (PC) has yet to be elucidated. Using different strategies including siRNA, shRNA, and CRISPR technology, we successfully induced knockdown and knockout of CDH17 in Panc02-H7 cells and established the corresponding stable cell lines. With these cells, we demonstrated that loss of CDH17 function not only suppressed Panc02-H7 cell growth in vitro but also significantly slowed orthotopic tumor growth in vivo, resulting in the significant life extension. In vitro studies demonstrated that impairing CDH17 inhibited cell proliferation, colony formation, and motility by mechanistically modulating pro- and anti-apoptosis events in PC cells, as CDH17 suppression obviously increased expression of Bad, cytochrome C, cleaved caspase 3, and cleaved PARP, and reduced expression of Bcl-2, Survivin, and pAkt. In vivo studies showed CDH17 knockout resulted in apoptotic PC tumor death through activating caspase-3 activity. Taken together, CDH17 functions as an oncogenic molecule critical to PC growth by regulating tumor apoptosis signaling pathways and CDH17 could be targeted to develop an anti-PC therapeutic approach.
肝肠钙黏蛋白（CDH17）作为肿瘤刺激因子和诊断标志物已有近二十年的历史。然而，其在高度恶性胰腺癌（PC）中的功能尚未阐明。我们使用包括 siRNA、shRNA 和 CRISPR 技术在内的不同策略，成功地诱导了 Panc02-H7 细胞中 CDH17 的敲低和敲除，并建立了相应的稳定细胞系。利用这些细胞，我们证明了 CDH17 功能的丧失不仅抑制了 Panc02-H7 细胞在体外的生长，而且显著减缓了体内原位肿瘤的生长，从而显著延长了生存期。体外研究表明，通过在 PC 细胞中机械地调节促凋亡和抗凋亡事件，破坏 CDH17 抑制细胞增殖、集落形成和迁移，因为 CDH17 的抑制明显增加了 Bad、细胞色素 C、cleaved caspase 3 和 cleaved PARP 的表达，降低了 Bcl-2、Survivin 和 pAkt 的表达。体内研究表明，CDH17 缺失通过激活 caspase-3 活性导致 PC 肿瘤凋亡。总之，CDH17 通过调节肿瘤凋亡信号通路，作为促进 PC 生长的致癌分子发挥作用，CDH17 可能成为开发抗 PC 治疗方法的靶点。
