Thymosin beta4 regulates migration of colon cancer cells by a pathway involving interaction with Ku80.
Aberrant expression of thymosin beta4 (Tbeta4) has recently been found to be associated with colorectal carcinoma (CRC) progression evidently due to an increase of the motility and invasion of tumor cells and the induction of a proangiogenic phenotype of endothelial cells. Both mechanisms depend upon matrix-degrading proteases, particularly plasmin and matrix metalloproteinases (MMPs) that are responsible for extensive tissue remodeling. Cleavage of ECM macromolecules weakens the structural integrity of tissues and exposes cryptic domains of extracellular components, which elicit biological responses distinct from intact molecules. Interestingly, signaling via integrins (alphaVbeta3, alpha5beta1) in CRC cells (HT29, CX1.1) is induced by Tbeta4 and VEGF-A only when they grow in 3D fibrin gels but not in 2D ones. The cells growing in 3D fibrin gels release upon Tbeta4 significant amounts of active MMPs (MMP-2, MMP-9, and MMP-7) that cause extensive proteolysis in their close vicinity. As evidenced by a variety of approaches (transfection experiments, coimmunoprecipitation, gene silencing with siRNA), we found that this involves interaction of Tbeta4 with Ku80, which has recently been described by us to mediate Tbeta4 intracellular activity.
Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland. cciern@zdn.am.lodz.pl
Czeslaw S
CS
Cierniewski
Izabela
I
Papiewska-Pajak
Mariusz
M
Malinowski
Izabela
I
Sacewicz-Hofman
Magdalena
M
Wiktorska
Jakub
J
Kryczka
Tomasz
T
Wysocki
Jolanta
J
Niewiarowska
Radoslaw
R
Bednarek
D002465:Cell Movement / Q000235:genetics; D002477:Cells / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013947:Thymosin / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000099201:Thymosin beta(4)
D016023:Integrins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020782:Matrix Metalloproteinases; D034741:RNA, Small Interfering; D013947:Thymosin; D042461:Vascular Endothelial Growth Factor A; D000099201:Thymosin beta(4)