Critical involvement of ILK in TGFβ1-stimulated invasion/migration of human ovarian cancer cells is associated with urokinase plasminogen activator system

The present study investigated the role of integrin-linked kinase (ILK) in TGF beta 1-stimulated invasion/migration of human ovarian cancer cells. We investigated TGF beta 1 regulation of ILK, and effects of ILK knockdown on TGF beta 1-stimulated invasion/migration and the associated proteinase systems, urokinase plasminogen activator (uPA) and matrix metalloproteinases (MMPs) in SKOV3 cells. TGF beta 1 stimulated ILK kinase activity, and had no effect on ILK protein/mRNA levels. Transient transfection of an ILK-specific siRNA (ILK-H) reduced ILK protein level, mRNA level and kinase activity. ILK knockdown by ILK-H suppressed the basal and TGF beta 1-stimulated invasion and migration. Further, ILK-H reduced the basal and TGF beta 1-stimulated secretion of EIPA, and increased the secretion of its inhibitor (PAI-1). Conversely, ILK-H did not affect TGF beta 1-stimulated secretion of MMP2 and its cell-associated activator MT1-MMP. Additionally, TGF beta 1 activated Smad2 phosphorylation, and this was not affected by ILK knockdown. Earlier reports indicate that Smad2 activation increased the expression of MMP2 and MT1-MMP. Thus, TGF beta 1 may act through ILK-independent and Smad2-dependent signaling in regulating MMP2 and MT1-MMP in SKOV3 cells. Collectively, this study suggests that ILK serves as a key mediator in TGF beta 1 regulation of uPA/PAI-1 system critical for the invasiveness of human ovarian cancer cells. And ILK is a potential target for cancer therapy. (c) 2006 Elsevier Inc. All rights reserved.