NGAL Controls the Metastatic Potential of Anaplastic Thyroid Carcinoma Cells

• Published in: The journal of clinical endocrinology and metabolism 2013-01, Vol.98 (1), p.228-235
• Main Authors: Volpe, Vincenzo, Raia, Zelinda, Sanguigno, Luca, Somma, Domenico, Mastrovito, Paola, Moscato, Fortunato, Mellone, Stefano, Leonardi, Antonio, Pacifico, Francesco
• Format: Article
• Language: English
• Subjects: Acute-Phase Proteins - antagonists & inhibitors; Acute-Phase Proteins - genetics; Acute-Phase Proteins - metabolism; Acute-Phase Proteins - physiology; Animals; Biological and medical sciences; Endocrinopathies; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; HEK293 Cells; Humans; Lipocalin-2; Lipocalins - antagonists & inhibitors; Lipocalins - genetics; Lipocalins - metabolism; Lipocalins - physiology; Malignant tumors; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B - metabolism; NF-kappa B - physiology; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins - physiology; RNA, Small Interfering - pharmacology; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Thyroid. Thyroid axis (diseases); Tumor Cells, Cultured; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2012-2528

Context: We have previously identified neutrophil gelatinase-associated lipocalin (NGAL) as one of the genes mediating the oncogenic activity of nuclear factor-κB in human anaplastic thyroid carcinomas (ATCs). Objectives: To further investigate the role of NGAL in thyroid cancer, we established NGAL knocked-down and NGAL overexpressing ATC cell lines. Results: We found that the ability of NGAL knocked-down cells to degrade Matrigel in a transwell invasion assay and to form lung metastasis in nude mice was decreased. Because NGAL binds matrix metalloproteinase-9 (MMP-9), to form a macromolecular complex involved in the regulation of metastatic spread of cancer cells and given the strong expression of both genes in tissue specimens from human ATCs, we analyzed the MMP-9 enzymatic activity in NGAL-null ATC cells. Enzymatic immunoassays show that MMP-9 activity is reduced in NGAL-null ATC cells, even if its expression is not affected by NGAL inhibition. Ectopic expression of NGAL in an ATC cell line not expressing NGAL determines an increase of its metastatic property. The use of a mutated form of NGAL, unable to bind MMP-9, has no positive effect on the invasive potential of ATC cells and does not improve the MMP-9 enzymatic activity. Conclusions: Our results indicate NGAL as a novel target of nuclear factor-κB prometastatic activity in thyroid cancer through enhancement of MMP-9 enzymatic activity.