Critical involvement of ILK in TGFbeta1-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 TGFbeta1-stimulated invasion/migration of human ovarian cancer cells. We investigated TGFbeta1 regulation of ILK, and effects of ILK knockdown on TGFbeta1-stimulated invasion/migration and the associated proteinase systems, urokinase plasminogen activator (uPA) and matrix metalloproteinases (MMPs) in SKOV3 cells. TGFbeta1 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 TGFbeta1-stimulated invasion and migration. Further, ILK-H reduced the basal and TGFbeta1-stimulated secretion of uPA, and increased the secretion of its inhibitor (PAI-1). Conversely, ILK-H did not affect TGFbeta1-stimulated secretion of MMP2 and its cell-associated activator MT1-MMP. Additionally, TGFbeta1 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, TGFbeta1 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 TGFbeta1 regulation of uPA/PAI-1 system critical for the invasiveness of human ovarian cancer cells. And ILK is a potential target for cancer therapy.
Lin
Sui-Wen
SW
Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Ke
Ferng-Chun
FC
Hsiao
Pei-Wen
PW
Lee
Ping-Ping
PP
Lee
Ming-Ting
MT
Hwang
Jiuan-Jiuan
JJ
D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D000099200:Scaffold Protein ILK
D020778:Matrix Metalloproteinase 2; D017395:Plasminogen Activator Inhibitor 1; D017346:Protein Serine-Threonine Kinases; D053773:Transforming Growth Factor beta1; D014568:Urokinase-Type Plasminogen Activator; D000099200:Scaffold Protein ILK; C051321:SERPINE1 protein, human