Nephroblastoma overexpressed/cysteine-rich protein 61/connective tissue growth factor/nephroblastoma overexpressed gene-3 (NOV/CCN3), a selective adrenocortical cell proapoptotic factor, is down-regulated in childhood adrenocortical tumors

被引:53
作者
Doghman, Mabrouka
Arhatte, Malika
Thibout, Helene
Rodrigues, Giovanna
De Moura, Juliana
Grosso, Sebastien
West, Alina Nico
Laurent, Maryvonne
Mas, Jean-Christophe
Bongain, Andre
Zambetti, Gerard P.
Figueiredo, Bonald C.
Auberger, Patrick
Martinerie, Cecile
Lalli, Enzo [1 ]
机构
[1] CNRS, UMR 6097, Inst Pharmacol Mol & Cellulaire, F-06560 Valbonne, France
[2] Univ Nice Sophia Antipolis, F-06560 Valbonne, France
[3] Hop St Antoine, UPMC, U515, INSERM, F-75012 Paris, France
[4] INSERM, U526, Fac Med, F-06107 Nice, France
[5] St Jude Childrens Res Hosp, Dept Biochem, Memphis, TN USA
[6] Ctr Hosp Univ, Hop Archet, Serv Gynecol Obstet, F-06200 Nice, France
[7] Inst Pesquisa Pele Pequeno Principe, BR-80060110 Curitiba, Parana, Brazil
[8] Ctr Genet Mol & Pesquisa Canc & Criancas, BR-80060110 Curitiba, Parana, Brazil
关键词
D O I
10.1210/jc.2007-0342
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Context: Childhood adrenocortical tumors (ACTs) have a fetal adrenal phenotype and overexpress steroidogenic factor-1 (SF-1). Nephroblastoma overexpressed (NOV)/cysteine-rich protein 61/connective tissue growth factor/nephroblastoma overexpressed gene-3 mRNA is significantly down-regulated in childhood ACTs. Objective: The objective of the study was to measure NOV protein levels in childhood ACTs and 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 enzyme-linked immunoassay and immunoblot. Transient transfection deoxynucleotidyl transferase- mediated deoxyuridine triphosphate nick end labeling, caspase assays, and flow cytometry were used to assess the proapoptotic activity of NOV on cells in culture. Results: NOV mRNA and protein expression is lower in childhood ACTs than in normal adrenal cortex. No significant difference was observed between adenomas and carcinomas. SF-1 overexpression down-regulates NOV at the transcriptional level. NOV has a selective proapoptotic activity toward human adrenocortical cells. The C-terminal domain of NOV is responsible for its proapoptotic effect. NOV protein is expressed in DAX-1-positive human fetal adrenal cells. Conclusions: NOV is a selective proapoptotic factor for human adrenocortical cells. Reduced expression of NOV in ACTs 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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页码:3253 / 3260
页数:8
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