The cholecystokinin2-receptor mediates calcitonin secretion, gene expression, and proliferation in the human medullary thyroid carcinoma cell line, TT

Gastrin-induced release of calcitonin from medullary thyroid carcinomas (MTC) is based on the expression of the cholecystokinin(2)-receptor (CCK2R) in these tumors. Recently, we have shown that the CCK2R is expressed not only in MTC but also in C-cells within the normal thyroid gland. The functions of the CCK2R in MTC and C-cells are largely unknown. We therefore explored the effects of gastrin-induced CCK2R stimulation in the highly differentiated MTC cell line, TT. CCK2R expression in TT-cells is detectable by RT-PCR as well as immunocytochemistry. Stimulation of the CCK2R by gastrin induces immediate release of calcitonin from TT-cells. Moreover, quantitative (LightCycler) RT-PCR demonstrates that gastrin stimulates transcription of the calcitonin and chromogranin A genes in TT-cells. TT-cell proliferation, assessed by counting of viable cells and H-3-thymidine uptake, is markedly increased by gastrin. This effect is inhibited by the CCK2R-specific antagonist L-365,260. Our findings suggest physiological functions for the CCK2R in calcitonin-secretion and gene expression as well as a pathophysiological role in MTC proliferation. CCK2R antagonists might have therapeutic potential in these tumors. (C) 2004 Elsevier B.V All rights reserved.