Loss of Smad4 Correlates With Loss of the Invasion Suppressor E-cadherin in Advanced Colorectal Carcinomas

J Pathol. 2004 Apr;202(4):412-20. doi: 10.1002/path.1516.

Abstract

Smad4 is a tumour suppressor gene predominantly involved in gastrointestinal carcinogenesis. Loss of Smad4 is considered to be a genetically late step and occurs in up to 30% of metastatic colorectal carcinomas. Smad4, originally characterized as an intracellular transmitter of transforming growth factor-beta (TGF-beta) signals, is a transcriptional co-modulator capable of integrating cellular responses to multiple signalling cascades. Thus, there are many Smad4 target genes and they are presumably strongly context-dependent. It was recently shown that re-expression of Smad4 in Smad4-deficient SW480 human colon carcinoma cells restored epithelioid morphology and induced P-cadherin and E-cadherin transcription. The cadherins are key players in cell-cell adhesion connecting adjacent cells via the cadherin-catenin adhesion complex. Frequent loss of E-cadherin expression in human cancers has been a long-standing observation, but the underlying mechanisms are not yet fully understood. To assess the role of Smad4 in E-cadherin regulation in colorectal carcinogenesis further, the present study has analysed Smad4 and E-cadherin RNA and protein expression in colorectal carcinoma cell lines and in 51 late-stage colorectal carcinomas. In primary tumours, loss of Smad4 expression correlated highly significantly with loss of E-cadherin expression, thus providing further evidence for involvement of the tumour suppressor Smad4 in the control of expression of the tumour and invasion suppressor E-cadherin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / genetics
  • Cadherins / metabolism*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Cytoskeletal Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasm Invasiveness
  • Neoplasm Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Neoplasm / genetics
  • Repressor Proteins / metabolism
  • Smad4 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Tumor Cells, Cultured
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cadherins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • Repressor Proteins
  • SMAD4 protein, human
  • Smad4 Protein
  • Trans-Activators
  • beta Catenin