We previously showed that integrin αvβ3 expression upon engagement by its major ligand vitronectin (VN) correlated with enhanced human ovarian cancer cell adhesion, motility, and proliferation, by triggering intracellular signaling events, ultimately leading to altered gene expression. In the present study, we characterized cellular VN expression as a function of αvβ3 and noticed significant upregulation of VN protein which was reflected by elevated VN gene transcription. In order to identify specific transcription factors involved in the αvβ3-regulatory effect on VN, we generated different VN promoter mutants. We noticed that disruption of the DNA consensus motif for Rel proteins did not only prominently reduce VN promoter activity but, moreover, led to a loss of responsiveness to αvβ3, suggesting a crucial role of Rel proteins in αvβ3-provoked VN induction. In cell migration studies, we confirmed increased cell motility as a function of αvβ3/VN which was further enhanced by raising cellular Rel transcription factor levels. Thus, the data of the present study elucidated a positive feedback regulatory loop on VN expression by αvβ3 implicating transcription factors of the Rel family. Hence by altering the composition of the extracellular matrix upon additional VN synthesis and deposition, tumor cells might be enabled to modulate their surrounding reactive microenvironment towards enhanced αvβ3/VN-interactions and, consequently, intrinsic intracellular signaling events affecting cancer progression.
Copyright © 2011 Wiley-Liss, Inc.