Differential gene expression in ACTH -secreting and non-functioning pituitary tumors

Abstract

Objective: Differential expression of several genes between ACTH-secreting pituitary tumors causing Cushing' disease (CD), silent corticotroph adenoma (SCA), and non-functioning pituitary tumors (NFT) was investigated. Design and methods: We used tissue specimens from 35 pituitary tumors (12 CD, 8 SCA, and 15 NFT). Steady-state mRNA levels of the genes related to proopiomelanocortin (POMC) transcription, synthesis, processing, and secretion, such as neurogenic differentiation 1 (NeuroD1), T-box 19 (Tpit), corticotropin releasing hormone receptor (CRHR), vasopressin receptor 1b (V1bR), prohormone convertase (PC) 1/3 and PC2, 11b-hydroxysteroid dehydrogenase (11b-HSD) type 1 and type 2, glucocorticoid receptor a (GRa), annexin A1, histone deacetylase 2 (HDAC2), and BRM/SWI2-related gene 1, were determined by real-time RT-PCR. Results and conclusion: POMC and Tpit mRNA levels were greater in CD and SCA than those in NFT. NeuroD1 mRNA levels were less in CD than those in NFT, but almost comparable between SCA and NFT. PC1/3 mRNA levels were greater in CD, but less in SCA than those in NFT. PC2 mRNA levels in CD and SCA were less than those in NFT. CRHR, V1bR, and 11b-HSD2 mRNA levels in CD were greater than those in SCA and NFT. HDAC2 mRNA levels in CD and SCA were lower than those in NFT. In conclusion, our study demonstrated that the genes related to transcription, synthesis, processing, and secretion of POMC are differentially regulated in ACTH-secreting pituitary tumors causing CD and SCA compared with those in NFT. This may partly explain the development of clinically active and inactive CD.European Journal of Endocrinology 157 717-724

Nur77 gene expression levels were involved in different ACTH-secretion autonomy between Cushing’s disease and subclinical Cushing’s disease

“…POMC mRNA levels were significantly higher in CD than in NFT, a finding consistent with that of a previous study by Tateno et al [8]. In the anterior lobe of the pituitary gland, POMC gene is expressed in ACTH-producing cells, and its expression is regulated by various transcription factors, such as Tpit and Nur77.…”

“…Tateno et al [8] showed that POMC and Tpit mRNA levels were higher in CD than in non-functioning pituitary tumors (NFTs). PC1/3 mRNA levels were also higher in CD than in NFT.…”

Silent corticotroph adenomas

“…DAX-1, an orphan nuclear receptor, is also a cell-specific factor for gonadotroph cell differentiation [23] and is expressed in nonfunctioning adenomas [18]. SCAs have been shown by some groups to have similar Tpit expression to CD [20,58] while others demonstrate lower expression [10,52]. In one series, despite variable expression, POMC and TPIT mRNA levels correlated positively in SCAs, similar to the pattern in Cushing macroadenomas [43].…”

Pathophysiology and treatment of subclinical Cushing’s disease and pituitary silent corticotroph adenomas [Review]

“…It has been reported that ACTH-secreting pituitary tumors show enhanced 11β-HSD2 gene expression but suppressed 11β-HSD1 gene expression [44,45]. Expression levels of 11β-HSD2 mRNA in the ACTH-secreting pituitary tumors that cause Cushing's disease were greater than those in SCAs [46], suggesting a partial or weak resistance by glucocorticoids in SCAs.…”