The tumor suppressor PTEN inhibits EGF-induced TSP-1 and TIMP-1 expression in FTC-133 thyroid carcinoma cells

• Published in: Experimental cell research 2005-03, Vol.304 (1), p.187-201
• Main Authors: Soula-Rothhut, Mahdhia, Coissard, Cyrille, Sartelet, Hervé, Boudot, Cédric, Bellon, Georges, Martiny, Laurent, Rothhut, Bernard
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ANTIBODIES; APOPTOSIS; Carcinoma - metabolism; CARCINOMAS; Cell Line, Tumor; CELL PROLIFERATION; Epidermal growth factor; Epidermal Growth Factor - antagonists & inhibitors; Follicular thyroid carcinoma cell lines; GENE REGULATION; GROWTH FACTORS; Humans; LUNGS; MAP Kinase Kinase 1 - metabolism; METASTASES; MUTANTS; Phosphatidylinositol 3-Kinases - metabolism; Phosphoric Monoester Hydrolases - metabolism; PHOSPHORYLATION; PI3-kinase; Promoter Regions, Genetic; PROMOTERS; PTEN; PTEN Phosphohydrolase; Thrombospondin 1 - genetics; Thrombospondin 1 - metabolism; Thrombospondin-1; THYROID; Thyroid Neoplasms - metabolism; Tissue inhibitor of metalloproteinase; Tissue Inhibitor of Metalloproteinase-1 - metabolism; TOTAL SUSPENDED PARTICULATES; Tumor Suppressor Proteins - metabolism; Up-Regulation
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2004.10.026

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.