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

Department of Pathology, Wakayama Medical University (Y.N., H.Y., H.Z., M.N., K.K.), 641-8509 Wakayama City, Japan; and Department of Surgery (Y.T., A.M.), Kuma Hospital, 650-0011 Kobe, Japan

Address all correspondence and requests for reprints to: Dr. Yasushi Nakamura, Department of Pathology, Wakayama Medical University, 811-1 Kimiidera, 641-8509 Wakayama City, Japan. E-mail: ynakamur{at}wakayama-med.ac.jp.

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 N^G-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.

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