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Submitted on February 14, 2007
Accepted on May 31, 2007
Institut de Pharmacologie Moléculaire et Cellulaire CNRS UMR 6097 and Université de Nice Sophia Antipolis, Valbonne, France (M.D., M.A., G.R., J.D.M., E.L.); INSERM U515 - Hôpital St. Antoine, UPMC - Paris 6, Paris, France (H.T., M.L., C.M.); INSERM U526 - Faculté de Médecine, Nice, France (S.G., P.A.); Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, USA (A.N.W., G.P.Z.); Service de Pédiatrie (J.-C.M.) and Service de Gynécologie Obstétrique (A.B.) Hôpital de l'Archet, CHU Nice, France; Instituto de Pesquisa Pelé Pequeno Principe and Centro de Genética Molecular e Pesquisa do Câncer em Crianças (CEGEMPAC), Curitiba, Paraná, Brazil (B.C.F.)
* To whom correspondence should be addressed. E-mail: ninino{at}ipmc.cnrs.fr.
Context: Childhood adrenocortical tumors (ACT) have a fetal adrenal phenotype and overexpress Steroidogenic Factor-1 (SF-1). NOV/CCN3 mRNA is significantly downregulated in childhood ACT.
Objective: To measure NOV protein levels in childhood ACT and to characterize NOV expression regulation and biological function in human adrenocortical cells.
Design and Setting : Protein extracts from ACT and normal adrenal cortex samples, human adrenocortical carcinoma H295R, primary adrenocortical tumors and fetal adrenal cultures, tissue culture supernatants and cell lysates from H295R cells overexpressing SF-1 in an inducible fashion were used.
Main Outcome Measures: NOV protein levels were measured by EIA and immunoblot. Transient transfection assays were used to study the activity of NOV promoter. TUNEL, caspase assays and flow cytometry were used to assess the pro-apoptotic activity of NOV on cells in culture.
Results: NOV mRNA and protein expression is lower in childhood ACT than in normal adrenal cortex. No significant difference was observed between adenomas and carcinomas. SF-1 overexpression downregulates NOV at the transcriptional level. NOV has a selective pro-apoptotic activity towards human adrenocortical cells. The C-terminal domain of NOV is responsible for its pro-apoptotic effect. NOV protein is expressed in DAX-1 positive human fetal adrenal cells.
Conclusions: NOV is a selective pro-apoptotic factor for human adrenocortical cells. Reduced expression of NOV in ACT may play an important role in the process of childhood ACT tumorigenesis, accounting at least in part for the defect of apoptotic regression of the fetal adrenal that has been proposed to be responsible for tumor formation.
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