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Differential Expression of Parathyroid Hormone–Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells

¹ Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), ² INSERM U567, ³ Pôle Endocrinologie-Diabétologie Adultes-Enfants, Groupe Hospitalier Cochin-St-Vincent de Paul, Paris, France; ⁴ Institut National de la Recherche Agronomique, Nutrition et Régulation Lipidique des Fonctions Cérébrales, Jouy-en-Josas, France; and ⁵ Assistance Publique-Hôpitaux de Paris, Hôpital Antoine Béclère, Service de Biochimie, Hôpital Antoine Béclère, Clamart, France

Requests for reprints: Zhor Bouizar, Département d'Endocrinologie, Métabolisme and Cancer, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), INSERM, U567, Paris, France. Phone: 33-15373-2734; Fax: 33-15373-2703. E-mail: bouizar{at}cochin.inserm.fr

Adrenocortical tumors (ACT) are rare and heterogeneous, but their pathogenesis is unclear. The oncoprotein parathyroid hormone–related protein (PTHrP), found in many common tumors, can regulate their growth in an autocrine/paracrine fashion through the PTH-R1 receptor. Little is known about the role of PTHrP in ACT. We monitored the synthesis of PTHrP and PTH-R1 in a series of 25 ACT: 12 adrenocortical carcinomas (ACC) and 13 adrenocortical adenomas (ACA), and investigated the effects of PTHrP(1-34) on H295R cells derived from an ACC. PTH-R1 mRNA and proteins were detected by real-time PCR and Western blotting in all the ACT samples and in H295R cells. Their concentrations did not differ significantly from one ACT to another. PTHrP mRNA was assayed by quantitative real-time PCR. It was detected in 90% of ACC, and in 10% of ACA. There was a positive correlation with the prognostic factors, McFarlane stage and Weiss score. Tissue-specific PTHrP protein processing was shown by Western blotting. Immunohistochemical staining revealed numerous, dense foci of PTHrP-containing cells in ACC, but few positive cells in ACA or normal tissue. PTHrP stimulated the growth of H295R cells, whereas a specific anti-PTHrP antibody and a PTHrP-R1 antagonist both enhanced their apoptosis. PTHrP activated both adenylate cyclase/protein kinase A and the intracellular calcium/protein kinase C pathways via PTHrP-R1. The active synthesis of PTHrP is linked to poor prognosis in ACC, in which it may act as an autocrine/paracrine factor in tumor growth and malignancy. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2275–85)