Inactivation of ELF/TGF-beta Signaling in Human Gastrointestinal Cancer

Oncogene. 2005 Dec 1;24(54):8012-24. doi: 10.1038/sj.onc.1208946.

Abstract

TGF-beta/Smads regulate a wide variety of biological responses through transcriptional regulation of target genes. ELF, a beta-spectrin, plays a key role in the transmission of TGF-beta-mediated transcriptional response through Smads. ELF was originally identified as a key protein involved in endodermal stem/progenitor cells committed to foregut lineage. Also, as a major dynamic adaptor and scaffolding protein, ELF is important for the generation of functionally distinct membranes, protein sorting and the development of polarized differentiated epithelial cells. Disruption of elf results in the loss of Smad3/Smad4 activation and, therefore, a disruption of the TGF-beta pathway. These observations led us to pursue the function of ELF in gastrointestinal (GI) epithelial cell-cell adhesion and tumor suppression. Here, we show a significant loss of ELF and reduced Smad4 expression in human gastric cancer tissue samples. Also, of the six human gastric cancer cell lines examined, three show deficient ELF expression. Furthermore, we demonstrate the rescue of E-cadherin-dependent homophilic cell-cell adhesion by ectopic expression of full-length elf. Our results suggest that ELF has an essential role in tumor suppression in GI cancers.

Publication types

  • Comparative Study

MeSH terms

  • Antibodies, Monoclonal / metabolism
  • Blotting, Western
  • Cadherins / metabolism
  • Cell Adhesion
  • Cell Line, Tumor
  • Ephrin-A2 / metabolism*
  • Gastrointestinal Neoplasms / genetics
  • Gastrointestinal Neoplasms / metabolism*
  • Gastrointestinal Neoplasms / pathology*
  • Humans
  • Immunohistochemistry
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Microscopy, Confocal
  • Precipitin Tests
  • Signal Transduction*
  • Smad4 Protein / metabolism
  • Transforming Growth Factor beta / metabolism*

Substances

  • Antibodies, Monoclonal
  • Cadherins
  • Ephrin-A2
  • SMAD4 protein, human
  • Smad4 Protein
  • Transforming Growth Factor beta