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

Abstract

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.

Proteomic analysis revealed the altered kidney protein profile of a Cyld knockout mouse model

“…AKR1B3, which is downregulated in adrenal tumors (Lefrançois-Martinez et al, 2004), is downregulated after Cyld knockout (fold change: 0.12), indicating that deletion of Cyld may increase the risk of adrenal tumor formation. It is also reported that the polymorphism of AKR1B1 (the human equivalent of AKR1B3) is closely associated with diabetic autonomic neuropathy (Donaghue et al, 2005), which suggests that AKR1B1 could be used as an early biomarker of autonomic neuropathy.…”

Cellular senescence bypass screen identifies new putative tumor suppressor genes

“…There is some evidence that expression of AKR1B1 is decreased in adrenocortical cancer (Lefrancois-Martinez et al, 2004).…”

Adrenocortical development and cancer: focus on SF-1

“…While some studies reported similar SF-1 levels in normal adrenal compared to cortisol-producing adenomas (Sasano et al 1995, Shibata et al 2001 and in adrenocortical adenomas and carcinomas (Kiiveri et al 2005), others described increased SF-1 mRNA expression in aldosterone-and cortisol-producing adenomas (Bassett et al 2005), and in adenomas relative to carcinomas (Lefrançois- Martinez et al 2004). Possible explanations for these discrepancies are differences between the methods used to measure SF-1 expression at the mRNA or protein level.…”