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Decreased Expression of Cyclic Adenosine Monophosphate-Regulated Aldose Reductase (AKR1B1) Is Associated with Malignancy in Human Sporadic Adrenocortical Tumors

Unité Mixte de Recherche 6547 CNRS-Université Blaise Pascal Clermont II (A.-M.L.-M., P.V., C.T., G.V., C.J., A.M.), Génétique des Eucaryotes et Endocrinologie Moléculaire, Complexe Universitaire des Cézeaux, 63177 Aubière, France; Institut National de la Santé et de la Recherche Médicale U-576, Département d’Endocrinologie (J.B., X.B.), Institut Cochin, Université René Descartes-Paris V, 75014 Paris, France; Department of Endocrinology (N.G.-P.), Faculty of Medicine, University of Sherbrooke, Québec J1H 5N4, Canada; and Protein Function Discovery Facility (D.H.), Queen’s University, Ontario K7L 3N6, Kingston, Canada

Address all correspondence and requests for reprints to: Dr. A. Martinez, UMR6547 CNRS-Université Blaise Pascal Clermont II, Génétique des Eucaryotes et Endocrinologie Moléculaire, Complexe Universitaire des Cézeaux, 24 avenue des Landais, 63177 Aubière Cedex, France. E-mail: antoine.martinez{at}univ-bpclermont.fr.

The human aldose reductase, AKR1B1, participates in glucose metabolism and osmoregulation and is supposed to play a protective role against toxic aldehydes derived from lipid peroxidation and steroidogenesis that could affect cell growth/differentiation when accumulated. Adrenal gland is a major site of expression of AKR1B1, and we asked whether changes in its expression could be associated with adrenal disorders. Therefore, we examined AKR1B1 gene expression in human fetal adrenals, adrenocortical cell line, and tumors and compared the results with the expression of steroidogenic genes (StAR and CYP11A) and regulators of adrenal cortex development [steroidogenic factor-1 (SF-1) and dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX1)]. Using specific antibodies, Northern blotting, and enzymatic assays, we present evidences that AKR1B1 detectable in 15-wk-old fetal glands is regulated by cAMP in NCI-H295 cells and thus that AKR1B1 is functionally related to the ACTH-responsive murine akr1b7/mvdp gene rather than to its direct ortholog, the mouse aldose reductase akr1b3 gene. Although low DAX1 expression in aldosterone-producing adenomas (n = 5) was confirmed (P < 0.05), no correlation was found between the expression of all other genes and the tumors endocrine activity. In contrast, relative abundance of AKR1B1 mRNA was decreased in adrenocortical carcinomas (n = 5; mean ± SEM, 0.95 ± 0.2) when compared with adenomas (n = 12; 9.29 ± 3.05; P < 0.001). Most (seven of eight) adrenocortical carcinomas (19.0 ± 5.4) had very low relative AKR1B1 protein levels when compared with benign tumors (cortisol-producing adenomas, n = 5, 63.0 ± 9.8; nonfunctional adenomas, n = 5, 58.0 ± 10.4; aldosterone-producing adenomas, n = 4, 65.3 ± 7.7; P < 0.001), Cushing’s hyperplasia (n = 5, 54.6 ± 5.3; P < 0.01), or normal adrenals (n = 4; 37.1 ± 5.3; P < 0.001). These properties provide the first evidence that expression of cAMP-regulated AKR1B1 is decreased in adrenocortical cancer. This might take part in adrenal tumorigenesis and could be investigated as a marker of malignancy for the diagnosis of adrenal tumors.

This work was supported by the Centre National de la Recherche Scientifique, Université Blaise Pascal, Association de la Recherche contre le Cancer (Grant ARC 4471), and Cortico et Medullosurrénale: Etude des Tumeurs Endocrines network.

Abbreviations: ACC, Adrenocortical carcinoma; APA, aldosterone-producing adenoma; CPA, cortisol-producing adenoma; DAX1, dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1; HNE, 4-hydroxynonenal; MVDP, mouse vas deferens protein; NADPH, nicotinamide adenine dinucleotide phosphate reduced; NFA, nonfunctional adenoma; PKA, protein kinase A; SF, steroidogenic factor; StAR, steroidogenic acute regulatory protein.

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