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Rac affects invasion of human renal cell carcinomas by up-regulating tissue inhibitor of metalloproteinases (TIMP)-1

R Engers1, E Springer, F Michiels

  • 1Institute of Pathology, Heinrich-Heine-University, Moorenstrasse 5, 40225 Duesseldorf, Germany. engers@med.uni-duesseldorf.de

The Journal of Biological Chemistry
|September 12, 2001
PubMed

Insights

Increased Rac signaling, specifically through Tiam1, inhibits renal cell carcinoma migration and invasion. This occurs by enhancing cell-cell adhesion and up-regulating tissue inhibitors of metalloproteinases (TIMPs), suggesting a novel anti-invasion mechanism.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Rho-like GTPases (Cdc42, Rac1, RhoA) control cell adhesion, migration, and invasion by regulating the actin cytoskeleton.
  • Tiam1 is a specific activator of Rac, and Tiam1-Rac signaling influences cell migration and invasion in a context-dependent manner.

Purpose of the Study:

  • To investigate the role of Tiam1-Rac signaling in the migration and invasion of human renal cell carcinomas.
  • To elucidate the molecular mechanisms by which Tiam1-Rac signaling affects these cellular processes in renal cancer.

Main Methods:

  • Stable overexpression of Tiam1 or constitutively active V12-Rac1 in a human renal cell carcinoma cell line (clearCa-28).
  • Assessment of cell migration and invasion using standard assays.
  • Analysis of E-cadherin-mediated cell-cell adhesion.
  • Investigation of the expression and activity of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs).

Main Results:

  • Overexpression of Tiam1 or V12-Rac1 significantly inhibited cell migration, primarily by enhancing E-cadherin-mediated cell-cell adhesion.
  • While blocking cell-cell adhesion restored some migration, it did not overcome the inhibition of Matrigel invasion.
  • Tiam1-Rac activation led to transcriptional up-regulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) and post-transcriptional up-regulation of TIMP-2.
  • Exogenous TIMP-1 and TIMP-2 application inhibited invasion, supporting their role in Rac-mediated invasion suppression.

Conclusions:

  • Tiam1-Rac signaling inhibits renal cell carcinoma migration and invasion.
  • Rac signaling impacts invasion through mechanisms beyond cell-cell adhesion, including the up-regulation of TIMP-1 and TIMP-2.
  • This study provides the first evidence that enhanced Rac signaling can inhibit epithelial tumor cell invasion via TIMP up-regulation.

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