Disruption of oncogenic liver-intestine cadherin (CDH17) drives apoptotic pancreatic cancer death

Cancer Lett. 2019 Jul 10:454:204-214. doi: 10.1016/j.canlet.2019.04.022. Epub 2019 Apr 17.

Abstract

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.

Keywords: CRISPR; Cadherin-17 (CDH17); Oncogene; Panc02-H7 cells; Tumorigenesis; shRNA; siRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cadherins / biosynthesis
  • Cadherins / genetics*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Gene Knockdown Techniques
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Transfection

Substances

  • CDH17 protein, human
  • Cadherins
  • Cdh17 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-akt