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Increased P2X₇ Receptor Expression and Function in Thyroid Papillary Cancer: A New Potential Marker of the Disease?

Department of Internal Medicine (A.S., S.C., E.S., A.D., S.M., F.M.) and Department of Surgical Sciences, Section of Pathology (P.F.), University of Pisa, I-56100 Pisa, Italy; and Department of Experimental and Diagnostic Medicine (D.F., S.G., G.C., F.D.V.), Section of General Pathology and Interdisciplinary Centre for the Study of Inflammation, University of Ferrara, I-44100 Ferrara, Italy

Address all correspondence and requests for reprints to: Anna Solini, M.D., Ph.D., Department of Internal Medicine, University of Pisa, Via Roma 67, I-56100 Pisa, Italy. E-mail: a.solini{at}med.unipi.it.

Nucleotides are increasingly recognized as nonredundant extracellular signals for chemotaxis, cell growth, and cytokine release. Effects of extracellular nucleotides are mediated by P2 receptors, among which the P2X₇ subtype is attracting increasing attention for its involvement in apoptosis, cell growth, and cytokine release. Recent studies showed that P2X₇ is overexpressed in chronic lymphocytic leukemia and breast and prostate cancer. The aim of the present study was to better understand the clinical significance of P2X₇ receptor expression in normal and cancer human thyroid tissues. P2X₇ receptor message and protein expression and functional activity were tested in two cell lines (FB1 and FB2) established from either anaplastic or papillary primary thyroid cancer and in several histological samples of human papillary cancer. We show here that human thyroid papillary carcinoma, whether of the classical or follicular variant, expresses the P2X₇ receptor (P2X₇R) to a much higher level than normal thyroid tissue. The P2X₇R was similarly up-regulated in FB1 and FB2 cell lines. In contrast to normal thyroid cells, both cell lines responded to extracellular nucleotide stimulation with a large increase in intracellular Ca²⁺ and secretion of IL-6. Ca²⁺ increase was attenuated and release of IL-6 was fully blocked by P2X₇R inhibitors. Finally, the thyroid carcinoma cell lines had at least a 3-fold higher intracellular ATP concentration and maintained at least a 3-fold higher extracellular ATP level, compared with control cells. These data suggest that an enhanced P2X₇R function might be a feature of human thyroid cancer.