Intraperitoneal delivery of a small interfering RNA targeting NEDD1 prolongs the survival of scirrhous gastric cancer model mice

Cancer Sci. 2013 Feb;104(2):214-22. doi: 10.1111/cas.12054. Epub 2012 Dec 13.

Abstract

The prognosis of patients with advanced diffuse-type gastric cancer (GC), especially scirrhous gastric cancer (SGC) remains extremely poor. Peritoneal carcinomatosis is a frequent form of metastasis of SGC. With survival rates of patients with peritoneal metastasis at 3 and 5 years being only 9.8% and 0%, respectively, development of a new treatment is urgently crucial. For such development, the establishment of a therapeutic mouse model is required. Among the 11 GC cell lines we examined, HSC-60 showed the most well-preserved expression profiles of the Hedgehog and epithelial-mesenchymal transition pathways found in primary SGCs. After six cycles of harvest of ascitic tumor cells and their orthotopic inoculation in scid mice, a highly metastatic subclone of HSC-60, 60As6 was obtained, by means of which we successfully developed peritoneal metastasis model mice. The mice treated with small interfering (si) RNA targeting NEDD1, which encodes a gamma-tubulin ring complex-binding protein, by the atelocollagen-mediated delivery system showed a significantly prolonged survival. Our mouse model could thus be useful for the development of a new therapeutic modality. Intraperitoneal administration of siRNAs of targeted genes such as NEDD1 could provide a new opportunity in the treatment of the peritoneal metastasis of SGC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Scirrhous / genetics*
  • Adenocarcinoma, Scirrhous / pathology
  • Adenocarcinoma, Scirrhous / secondary
  • Adenocarcinoma, Scirrhous / therapy*
  • Animals
  • Cell Line, Tumor
  • Collagen / administration & dosage
  • Disease Models, Animal
  • Drug Delivery Systems / methods
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Hedgehog Proteins / genetics
  • Homeodomain Proteins / genetics
  • Humans
  • Injections, Intraperitoneal
  • Mice
  • Mice, SCID
  • Microtubule-Associated Proteins / genetics*
  • Neoplasm Metastasis
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / pathology
  • Peritoneal Neoplasms / secondary
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / genetics*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Stomach Neoplasms / therapy*
  • Xenograft Model Antitumor Assays
  • ets-Domain Protein Elk-1 / genetics

Substances

  • ELK1 protein, human
  • Hedgehog Proteins
  • Homeodomain Proteins
  • MSX2 protein
  • Microtubule-Associated Proteins
  • NEDD1 protein, human
  • RNA, Small Interfering
  • atelocollagen
  • ets-Domain Protein Elk-1
  • Nedd1 protein, mouse
  • Collagen