Nitric Oxide in Papillary Thyroid Carcinoma: Induction of Vascular Endothelial Growth Factor D and Correlation with Lymph Node Metastasis

• Published in: The journal of clinical endocrinology and metabolism 2006-04, Vol.91 (4), p.1582-1585
• Main Authors: Nakamura, Yasushi, Yasuoka, Hironao, Zuo, Hui, Takamura, Yuuki, Miyauchi, Akira, Nakamura, Misa, Kakudo, Kennichi
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Carcinoma, Papillary - blood; Carcinoma, Papillary - pathology; Cell Line, Tumor; Endocrinopathies; Enzyme Inhibitors - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Humans; Immunohistochemistry; Lymphatic Metastasis - pathology; Male; Malignant tumors; Medical sciences; Middle Aged; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - physiology; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase - antagonists & inhibitors; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Thyroid Neoplasms - blood; Thyroid Neoplasms - pathology; Thyroid. Thyroid axis (diseases); Tyrosine - analogs & derivatives; Tyrosine - biosynthesis; Vascular Endothelial Growth Factor D - biosynthesis; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2005-1790

Purpose: Vascular endothelial growth factor-D (VEGF-D) plays an important role in lymph node metastasis via lymphangiogenesis in papillary thyroid carcinoma (PTC). Although PTC metastasizes to regional lymph nodes at a high frequency, the regulation of VEGF-D expression is largely unknown. Experimental Design: Nitrite/nitrate levels and VEGF-D production were assessed in K1 papillary thyroid carcinoma cells after induction and/or inhibition of nitric oxide (NO) synthesis. Formation of nitrotyrosine, a biomarker for peroxynitrate formation from NO in vivo, was analyzed in primary human PTC. Results: The production of nitrite/nitrate and VEGF-D in K1 cells was increased by treatment with the NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA NONOate). The NO synthase inhibitor NG-nitro-l-arginine methyl ester inhibited the increase in nitrate/nitrite and eliminated the increase in VEGF-D. High-grade nitrotyrosine staining was observed in 51.8% (29 of 56) of PTCs. Nitrotyrosine levels were significantly correlated with VEGF-D immunoreactivity and lymph node metastasis. Conclusions: Our data showed a role for NO in stimulating VEGF-D expression in vitro. The formation of its biomarker, nitrotyrosine, was also correlated with VEGF-D expression in human PTC. NO may induce lymph node metastasis via VEGF-D stimulation in PTC.