CXCR4 expression in papillary thyroid carcinoma: induction by nitric oxide and correlation with lymph node metastasis.
BACKGROUND
Metastasis to regional lymph nodes is a common step in the progression of cancer. Recent evidence suggests that tumor production of CXCR4 promotes lymph node metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers.


METHODS
Nitrite/nitrate levels and functional CXCR4 expression were assessed in K1 and B-CPAP papillary thyroid carcinoma (PTC) cells after induction and/or inhibition of NO synthesis. CXCR4 expression was also analyzed in primary human PTC. The relationship between nitrotyrosine levels, which are a biomarker for peroxynitrate formation from NO in vivo, CXCR4 expression, and lymph node status was also analyzed.


RESULTS
Production of nitrite/nitrate and functional CXCR4 expression in both cell lines was increased by treatment with the NO donor DETA NONOate. The NOS inhibitor L-NAME eliminated this increase. Positive CXCR4 immunostaining was observed in 60.7% (34/56) of PTCs. CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis in human PTC.


CONCLUSIONS
Our data indicate that NO stimulates CXCR4 expression in vitro. Formation of the NO biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in human PTC. NO may induce lymph node metastasis via CXCR4 induction in papillary thyroid carcinoma.
Yasuoka
Hironao
H
Department of Clinical Laboratory Medicine, Wakayama Medical University, Wakayama, Japan. hyasuoka@mail.wakayama-med.ac.jp
Kodama
Rieko
R
Hirokawa
Mitsuyoshi
M
Takamura
Yuuki
Y
Miyauchi
Akira
A
Sanke
Tokio
T
Nakamura
Yasushi
Y
D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D004791:Enzyme Inhibitors; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D009603:Nitroso Compounds; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D019331:NG-Nitroarginine Methyl Ester