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Substantial Production of Ghrelin by a Human Medullary Thyroid Carcinoma Cell Line

Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine (N.K., T.A., Y.H., H.A., K.T., K.H., M.S., K.M., K.N.), Kyoto 606-8507; Department of Biochemistry, National Cardiovascular Center Research Institute (H.H., M.K., K.K.), Osaka 565-8565; and Clinical Research Institute, Center for Endocrine and Metabolic Diseases, Kyoto National Hospital (A.S.), Kyoto 612-8555, Japan

Address all correspondence and requests for reprints to: Dr. Takashi Akamizu, Department of Medicine and Clinical Science, Kyoto University School of Medicine, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: akataka{at}kuhp.kyoto-u.ac.jp

Abstract

Ghrelin, an endogenous ligand for the GH secretagogue receptor, is a novel acylated peptide produced in the gastrointestinal endocrine cells as well as neuroendocrine cells in the hypothalamus. The Ser³ residue of ghrelin is modified by n-octanoic acid, a modification necessary for hormonal activity. Human medullary thyroid carcinoma is known to produce a variety of gastrointestinal and neuroendocrine peptides. In the present study we investigated ghrelin production in the thyroid gland, especially in human medullary thyroid carcinoma. PCR amplification demonstrated prepro-ghrelin gene transcripts in normal human thyroid tissue and two medullary thyroid carcinoma cell lines (human TT cells and rat 6-23 cells), but not in a rat thyroid follicular cell line. TT cells showed the expression of prepro-ghrelin mRNA of about 0.6 kb by Northern blot analysis. Furthermore, production of ghrelin in TT cells was demonstrated by RIA and immunocytochemistry. Accumulation of des-n-octanoyl ghrelin in the cultured medium of the cells was confirmed. Finally, human medullary thyroid carcinoma surgical specimens showed significantly higher des-n-octanoyl ghrelin contents than normal thyroid tissues. In conclusion, we revealed that ghrelin was produced by the human thyroid parafollicular carcinoma cell line, TT cells. These findings suggest that ghrelin is produced in the thyroid C cells as well as in medullary thyroid carcinoma and may provide opportunities to investigate its physiological role in the thyroid gland.

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