Expression Profiles of COUP–TF, DAX-1, and SF-1 in the Human Adrenal Gland and Adrenocortical Tumors: Possible Implications in Steroidogenesis

Abstract

Chicken ovalbumin upstream promoter–transcription factor (COUP–TF), DAX-1, and steroidogenic factor-1 (SF-1) are orphan members of the nuclear hormone receptor superfamily. COUP–TF and DAX-1 have been shown to negatively regulate the transcriptional activity of SF-1, a steroidogenic cell-specific activator of various steroidogenic cytochrome P450 genes. We therefore examined the expression levels and immunolocalization of COUP–TF, DAX-1, and SF-1 in human adrenal gland (NL) and adrenocortical adenomas, and compared the results with CYP17 expression levels and its enzyme activities to study their potential correlation with adrenocortical steroidogenesis. In NL (n = 10), expressions of COUP–TF, DAX-1, and SF-1 were detected in the nuclei of adrenocortical cells, but not in the medulla. In cortisol-producing adenomas causing Cushing syndrome (CS, n = 20), CYP17 expression was upregulated (298 ± 2% vs NL 98 ± 4%), whereas expression levels of both COUP–TFs (COUP–TFI, 52 ± 5% vs NL 98 ± 4%; COUP–TFII, 18 ± 4% vs NL 98 ± 4%) and DAX-1 (42 ± 4% vs NL 100 ± 4%) were reduced. In deoxycorticosterone-producing adenomas (DOC, n = 2), on the other hand, CYP17 expression was extremely reduced (8 and 12% vs NL 98 ± 4%), whereas DAX-1 expression increased markedly (350 and 360% vs NL 100 ± 4%). Expression levels of SF-1 did not differ between NL (100 ± 8%) and CS (106 ± 10%), but its expression appeared to be decreased in DOC (25 and 20%). These results showed CYP17 expression to be upregulated and downregulated in CS and DOC, respectively, in a manner reciprocal to that of its repressors, COUP–TF and/or DAX-1. In summary, the results indicate that co-localization of COUP–TF, DAX-1, and SF-1 in NL was lost in adrenocortical tumors and that these orphan receptors play an important role in the regulation of steroidogenesis in human adrenals.