Critical Involvement of Proteinases and Integrin-Linked Kinase in TGFb1-Stimulated Invasion /Migration in Human Ovarian Cancer Cells

• Main Authors: Sui-Wen Lin, 林淑玟
• Other Authors: Jiuan-Jiuan Hwang
• Format: Others
• Language: en_US
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/23545390332133821853

博士 === 國立陽明大學 === 生理學研究所 === 95 === Ovarian cancers are the most common fatal gynecological malignancy. The metastatic capacity of cancer cells is considered to be the main cause for cancer death. And TGFβ is an important regulator in tumorigenesis. The purpose of the present study was to investigate the mechanism of TGFβ1 stimulation of invasion/migration in human ovarian cancer cells. There were two specific aims. The role of matrix metalloproteinases (MMP) and plasminogen activator (PA) in tumor cell-mediated matrix remodeling is well established. Therefore, the first specific aim was to study the role of MMP in TGFβ1-stimulated invasion in human ovarian cancer SKOV3 cells. Further, integrin-linked kinase (ILK) expression was reported to increase in ovarian cancers, and it is involved in the regulation of matrix-degrading proteinases. Thus, the second specific aim was to explore the role of ILK in TGFβ1-stimulated invasion/migration in human ovarian cancer cells. TGFβ1 stimulated the secretion of MMP2 and the invasive behavior, and MMP inhibitor abrogated such effect of TGFβ1. This indicates that TGFβ1 may act partly through stimulating the secretion of MMP in promoting ovarian cancer cell invasion. Additionally, TGFβ1 stimulated ILK kinase activity in SKOV3 cells. And knockdown of ILK using specific siRNA suppressed the basal and TGFβ1-stimulated invasion/migration, and reduced the secretion of uPA and increased the secretion of its inhibitor (PAI-1). Conversely, knockdown of ILK did not affect TGFβ1-stimulated secretion of MMP2 and its cell-associated activator MT1-MMP. Collectively, this study suggests that TGF��1 promotes invasion/migration in ovarian cancer cells, and both MMP and uPA systems are involved in the process. Furthermore, ILK serves as a key mediator in TGFβ1 regulation of uPA/PAI-1 system critical for the invasiveness of human ovarian cancer cells. Thus, therapeutic strategies target to blockade the upregulated MMP or uPA/PAI-1 system, as well as ILK may be of potential for cancer treatment.