title: Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival.
abstract: Pheochromocytomas are catecholamine-producing tumors which are generally benign, but which can also present as or develop into malignancy. Molecular pathways of malignant transformation remain poorly understood. Pheochromocytomas express various trophic peptides which may influence tumoral cell behavior. Here, we investigated the expression of trophic amidated peptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), neuropeptide Y (NPY), and adrenomedullin (AM), and their receptors in benign and malignant pheochromocytomas in order to assess their potential role in chromaffin cell tumorigenesis and malignant transformation. PACAP, NPY, and AM are expressed in the majority of pheochromocytomas studied; NPY exhibiting the highest mRNA levels relative to reference genes. Although median gene expression or peptide levels were systematically lower in malignant compared to benign tumors, no statistically significant difference was found. Among all the receptors of these peptides that were analyzed, only the AM receptor RDC1 displayed a differential expression between benign and malignant pheochromocytomas. This receptor exhibited a fourfold higher expression in malignant than in benign tumors. AM and stromal cell-derived factor 1, which has also been described as a ligand for RDC1, increased the number of human pheochromocytoma cells in primary culture and exerted anti-apoptotic activity on rat pheochromocytoma PC12 cells. In addition, RDC1 gene silencing decreased the number of viable PC12 cells. This study shows the expression of several trophic peptides and their receptors in benign and malignant pheochromocytomas, and suggests that AM and its RDC1 receptor could be involved in chromaffin cell tumorigenesis through pro-survival effects. Therefore, AM and RDC1 may represent valuable targets for the treatment of malignant pheochromocytomas.
authors.affiliation: INSERM, U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N), IFRMP23, University of Rouen, 76821 Mont-Saint-Aignan, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Thouënnon
authors.forename: Alice
authors.initials: A
authors.lastname: Pierre
authors.forename: Yannick
authors.initials: Y
authors.lastname: Tanguy
authors.forename: Johann
authors.initials: J
authors.lastname: Guillemot
authors.forename: Destiny-Love
authors.initials: DL
authors.lastname: Manecka
authors.forename: Marlène
authors.initials: M
authors.lastname: Guérin
authors.forename: L'houcine
authors.initials: L
authors.lastname: Ouafik
authors.forename: Mihaela
authors.initials: M
authors.lastname: Muresan
authors.forename: Marc
authors.initials: M
authors.lastname: Klein
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Hervé
authors.initials: H
authors.lastname: Lefebvre
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Plouin
authors.forename: Laurent
authors.initials: L
authors.lastname: Yon
authors.forename: Youssef
authors.initials: Y
authors.lastname: Anouar
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism*; D053607:Adrenomedullin / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology; D005562:Formazans / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D009478:Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000235:genetics / Q000378:metabolism*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D058265:Receptors, Adrenomedullin; D017476:Receptors, Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics; D018000:Receptors, Peptide / Q000096:biosynthesis* / Q000235:genetics; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts / Q000737:chemistry
chemical_list: D005562:Formazans; D009478:Neuropeptide Y; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D058265:Receptors, Adrenomedullin; D017476:Receptors, Neuropeptide Y; D018000:Receptors, Peptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D013778:Tetrazolium Salts; D053607:Adrenomedullin; C079782:MTT formazan