The tumor suppressor PTEN inhibits EGF-induced TSP-1 and TIMP-1 expression in FTC-133 thyroid carcinoma cells.
Thrombospondin-1 (TSP-1) is a multidomain extracellular macromolecule that was first identified as natural modulator of angiogenesis and tumor growth. In the present study, we found that epidermal growth factor (EGF) up-regulated TSP-1 expression in FTC-133 (primary tumor) but not in FTC-238 (lung metastasis) thyroid cancer cells. Both EGF and TSP-1 induced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. In FTC-133 cells, EGF induced proliferation in a TSP-1- and TIMP-1-dependent manner. In addition, we determined that re-expression of the tumor suppressor protein PTEN induced cell death, an effect that correlated with a block of Akt kinase phosphorylation. EGF-induced TSP-1 and TIMP-1 promoter activity and protein expression were inhibited in FTC-133 cells stably expressing wtPTEN but not in cells expressing mutant PTEN. Furthermore, we found that wtPTEN inhibited EGF--but not TSP-1--stimulated FTC-133 cell migration and also inhibited invasion induced by EGF and by TSP-1. Finally, an antibody against TSP-1 reversed EGF-stimulated FTC-133 cell invasion as well as the constitutive invasive potential of FTC-238 cells. Overall, our results suggest that PTEN can function as an important modulator of extracellular matrix proteins in thyroid cancer. Therefore, analyzing differential regulation of TSP-1 by growth factors such as EGF can be helpful in understanding thyroid cancer development.
Soula-Rothhut
Mahdhia
M
Unité Matrice Extracellulaire et Régulations Cellulaires, CNRS UMR 6198, Laboratory of Biochemistry, University of Reims Champagne-Ardenne, Moulin de la Housse, 51687 Reims Cedex 2, France.
Coissard
Cyrille
C
Sartelet
Hervé
H
Boudot
Cédric
C
Bellon
Georges
G
Martiny
Laurent
L
Rothhut
Bernard
B
D017209:Apoptosis; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation
D019700:Thrombospondin 1; D019715:Tissue Inhibitor of Metalloproteinase-1; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D048369:MAP Kinase Kinase 1; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human