Institut National de la Santé et de la Recherche Médicale Unité 1016, 75014 Paris, France.
J Clin Endocrinol Metab. 2013 Jun;98(6):E1109-21. doi: 10.1210/jc.2012-4237. Epub 2013 Mar 28.
The cortisol secretion of adrenocortical adenomas can be either subtle or overt. The mechanisms leading to the autonomous hypersecretion of cortisol are unknown.
The objective of the study was to identify the gene expression profile associated with the autonomous and excessive cortisol secretion of adrenocortical adenomas.
The transcriptome of 22 unilateral adrenocortical adenomas (5 nonsecreting, 6 subclinical cortisol producing, 11 cortisol producing) was studied and correlated with cortisol secretion. Phosphodiesterase 8B (PDE8B) expression was measured by Western blot.
Unsupervised clustering identified 2 groups of adenomas with a difference in secretion level (P = .008). Cluster 1 included only cortisol-producing adenomas (8 of 11), whereas cluster 2 was an admixture of the nonsecreting, the subclinical cortisol-secreting, and 3 of the 11 cortisol-secreting adenomas (Fisher exact, P = .002). This cluster was driven by genes related to cortisol secretion and to extracellular matrix. More than 3000 genes correlated with cortisol secretion. Among the positively correlated were the steroidogenic enzymes, genes involved in cholesterol metabolism, and glutathione S-transferases. Among the negatively correlated genes were genes related to transcripts translation and the transcription factor GATA-6. The PDE8B, which inactivates the protein kinase A pathway, unexpectedly showed the strongest positive correlation with cortisol secretion, confirmed by Western blot. The protein kinase A-activity to cAMP ratio was increased in adenomas with high PDE8B levels, suggesting counterregulation to limit downstream activation of the pathway.
The transcriptome of adrenocortical adenomas reveals a major association with cortisol secretion and identifies specific groups of genes implicated in steroid secretion, suggesting that cAMP signaling alterations might be frequent in cortisol-secreting adenomas.
肾上腺皮质腺瘤的皮质醇分泌可以是微妙的，也可以是明显的。导致皮质醇自主分泌过多的机制尚不清楚。
本研究旨在确定与肾上腺皮质腺瘤自主和过度皮质醇分泌相关的基因表达谱。
研究了 22 例单侧肾上腺皮质腺瘤（5 例无分泌，6 例亚临床皮质醇产生，11 例皮质醇产生）的转录组，并与皮质醇分泌相关。通过 Western blot 测量磷酸二酯酶 8B（PDE8B）的表达。
无监督聚类确定了 2 组具有分泌水平差异的腺瘤（P =.008）。第 1 组仅包括皮质醇产生的腺瘤（11 例中的 8 例），而第 2 组是无分泌、亚临床皮质醇分泌和 11 例皮质醇分泌腺瘤中的 3 例的混合物（Fisher 确切检验，P =.002）。该聚类由与皮质醇分泌和细胞外基质相关的基因驱动。与皮质醇分泌相关的基因超过 3000 个。在正相关的基因中，有类固醇生成酶、参与胆固醇代谢的基因和谷胱甘肽 S-转移酶。在负相关的基因中，有与转录翻译和转录因子 GATA-6 相关的基因。出乎意料的是，磷酸二酯酶 8B（使蛋白激酶 A 途径失活）与皮质醇分泌呈最强的正相关，Western blot 验证了这一点。PDE8B 水平高的腺瘤中蛋白激酶 A-活性与 cAMP 的比值增加，表明存在代偿性调节以限制该途径下游的激活。
肾上腺皮质腺瘤的转录组与皮质醇分泌有很大的关联，并确定了与类固醇分泌相关的特定基因群，提示 cAMP 信号改变可能在皮质醇分泌腺瘤中频繁发生。
