Loss of cell-cell contact is induced by integrin-mediated cell- substratum adhesion in highly-motile and highly-metastatic hepatocellular carcinoma cells

Takuya Genda, Michiie Sakamoto, Takafumi Ichida, Hitoshi Asakura, Setsuo Hirohashi

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

The cadherin-mediated cell-cell adhesion system plays a critical role in normal development and morphogenesis. Inactivation of this system is thought to be responsible for cancer invasion and metastasis. A human hepatocellular carcinoma (HCC) cell line, KYN-2, was observed to have great potential for intrahepatic metastasis when orthotopically implanted into the liver of SCID mice. In vitro cultures of KYN-2 cells showed that they formed trabecular structures in suspension but lost tight cell-cell adhesion and became scattered when attached to a substratum such as collagen or fibronectin. In response to adhesion to the substratum, subcellular colocalization of E- cadherin and actin filaments were shown to be reduced, and a significant amount of α-catenin was dissociated from the E-cadherin-catenin complex in KYN-2 cells. These changes of cell-cell adhesion were blocked by inhibitory monoclonal antibodies against β1 and β5 integrins. We found that c-Src was coimmunoprecipitated with E-cadherin-catenin complex and was tyrosine- dephosphorylated and activated in the adherent cells. The tyrosine dephosphorylation of c-Src was induced by cell adhesion to the substratum and inhibited by addition of inhibitory monoclonal antibodies against β1 and β5 integrins. These findings indicate that integrin-mediated cell-substratum adhesion inhibits cadherin-mediated cell-cell adhesion, possibly through c- Src activation, and suggest that this cross-talk mediates transient inactivation of the cadherin system and plays an important role in intrahepatic metastasis of human HCC. Modulation of this interaction might provide a new approach to prevent metastasis and recurrence of HCC.

Original languageEnglish
Pages (from-to)387-394
Number of pages8
JournalLaboratory Investigation
Volume80
Issue number3
DOIs
Publication statusPublished - 2000 Mar
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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