Nitric oxide in papillary thyroid carcinoma: induction of vascular endothelial growth factor D and correlation with lymph node metastasis.
OBJECTIVE
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.


METHODS
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.
Nakamura
Yasushi
Y
Department of Pathology, Wakayama Medical University, 811-1 Kimiidera, 641-8509 Wakayama City, Japan. ynakamur@wakayama-med.ac.jp
Yasuoka
Hironao
H
Zuo
Hui
H
Takamura
Yuuki
Y
Miyauchi
Akira
A
Nakamura
Misa
M
Kakudo
Kennichi
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D002291:Carcinoma, Papillary / Q000097:blood* / Q000473:pathology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013964:Thyroid Neoplasms / Q000097:blood* / Q000473:pathology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis*
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D042643:Vascular Endothelial Growth Factor D; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester