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¹ Department of Biology, Åbo Akademi University, Tykistökatu 6A, 20520 Turku, Finland² Turku Graduate School of Biomedical Sciences³ Laboratory of Animal Physiology, Department of Biology, University of Turku, 20014 Turku, Finland⁴ Hospital for Children and Adolescents, Helsinki University Central Hospital, 00290 Helsinki, Finland⁵ Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, 00270 Helsinki, Finland

(Correspondence should be addressed to K Törnquist; Email: ktornqvi{at}abo.fi)

Sphingosine-1-phosphate (S1P) induces migration of human ML-1 thyroid follicular cancer cells and inhibits migration of human FRO anaplastic thyroid cancer cells. As tumour cells often secrete vascular endothelial growth factor (VEGF), we investigated a possible interaction between S1P and VEGF signalling in the regulation of thyroid tumour cell migration. We found that both ML-1 and FRO cells secreted VEGF-A (3.6 and <0.1 ng/10⁶ cells/day respectively) and VEGF-C (3.0 and 0.14 ng/10⁶ cells/day respectively). S1P stimulated VEGF-A secretion in both cell lines, and blocking S1P receptors 1, 2 and 3 attenuated the S1P-evoked secretion of VEGF-A. Neither TSH nor insulin affected the amount of secreted VEGF-A or -C in ML-1 cells, while simultaneous stimulation with insulin and S1P increased VEGF-C secretion in FRO cells. Both cell lines expressed VEGF receptor 2 (VEGFR-2) mRNA and proteins. Serum-evoked migration of both ML-1 and FRO cells was attenuated when VEGFR-2 was inhibited. Moreover, inhibiting VEGFR-2 in ML-1 cells resulted in a rapid downregulation of S1P₁ mRNA expression and S1P₁ protein levels, suppression of S1P-induced migration and a decrease in S1P-induced Akt phosphorylation. A VEGF-neutralizing antibody also reduced S1P-induced migration. In ML-1 cells, S1P phosphorylated VEGFR-2. In addition, VEGFR-2 inhibition resulted in the upregulation of S1P₃ mRNA within 24 h, but a significant increase in S1P₃ protein levels was not observed. VEGFR-2 inhibition, but not a VEGF-neutralizing antibody, reduced ML-1 cell proliferation independently of S1P stimulation. The results indicate a complex interaction between S1P and VEGFR-2 in ML-1 cells, particularly in regulating migratory responses.

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