PDF(Pubmed)
Abstract：
Pituitary neuroendocrine corticotroph tumors commonly cause Cushing\'s disease (CD) that results from increased adrenocorticotropic hormone (ACTH) secretion by the pituitary tumor and consequent increase of cortisol levels in blood. However, in some patients, corticotroph tumors remain clinically non-functioning. Cortisol secretion is regulated by the hypothalamic-pituitary-adrenal axis and includes a negative feedback between cortisol and ACTH secretion. Glucocorticoids reduce ACTH level both by hypothalamic regulation and acting on corticotrophs via glucocorticoid (GR) and mineralocorticoid (MR) receptors. The aim of the study was to determine the role of GR and MR expression at mRNA and protein levels in both functioning and silent corticotroph tumors.
Ninety-five patients were enrolled, including 70 with CD and 25 with silent corticotroph tumors. Gene expression levels of NR3C1 and NR3C2 coding for GR and MR, respectively, were determined with qRT-PCR in the two tumor types. GR and MR protein abundance was assessed with immunohistochemistry.
Both GR and MR were expressed in corticotroph tumors. Correlation between NR3C1 and NR3C2 expression levels was observed. NR3C1 expression was higher in silent than in functioning tumors. In CD patients NR3C1 and NR3C2 levels were negatively correlated with morning plasma ACTH levels and tumor size. Higher NR3C2 was confirmed in patients with remission after surgery and in densely granulated tumors. Expression of both genes and GR protein was higher in USP8-mutated tumors. Similar relationship between USP8 mutations and expression levels were observed in analysis of silent tumors that also revealed a negative correlation between GR and tumor size and higher NR3C1 expression in densely granulated tumors.
Although the associations between gene/protein expression and patients clinical features are not strong, they consistently show an evident trend in which higher receptor expression corresponds to more favorable clinical characteristics.
Ninety-five patients were enrolled, including 70 with CD and 25 with silent corticotroph tumors. Gene expression levels of NR3C1 and NR3C2 coding for GR and MR, respectively, were determined with qRT-PCR in the two tumor types. GR and MR protein abundance was assessed with immunohistochemistry.
Both GR and MR were expressed in corticotroph tumors. Correlation between NR3C1 and NR3C2 expression levels was observed. NR3C1 expression was higher in silent than in functioning tumors. In CD patients NR3C1 and NR3C2 levels were negatively correlated with morning plasma ACTH levels and tumor size. Higher NR3C2 was confirmed in patients with remission after surgery and in densely granulated tumors. Expression of both genes and GR protein was higher in USP8-mutated tumors. Similar relationship between USP8 mutations and expression levels were observed in analysis of silent tumors that also revealed a negative correlation between GR and tumor size and higher NR3C1 expression in densely granulated tumors.
Although the associations between gene/protein expression and patients clinical features are not strong, they consistently show an evident trend in which higher receptor expression corresponds to more favorable clinical characteristics.
摘要：
垂体神经内分泌促肾上腺皮质激素肿瘤通常由垂体肿瘤分泌促肾上腺皮质激素（ACTH）增加和血液中皮质醇水平升高引起库欣病（CD）。然而,在一些患者中，促肾上腺皮质激素肿瘤在临床上仍无功能。皮质醇分泌受下丘脑-垂体-肾上腺轴调节，包括皮质醇和ACTH分泌之间的负反馈。糖皮质激素通过下丘脑调节和通过糖皮质激素（GR）和盐皮质激素（MR）受体作用于促肾上腺皮质激素降低ACTH水平。该研究的目的是确定GR和MR在mRNA和蛋白质水平上的表达在功能性和沉默的促肾上腺皮质激素肿瘤中的作用。
■纳入95名患者，包括70例CD和25例无症状促肾上腺皮质激素肿瘤。NR3C1和NR3C2编码GR和MR的基因表达水平，分别,用qRT-PCR测定两种肿瘤类型。用免疫组织化学评估GR和MR蛋白丰度。
■GR和MR均在促肾上腺皮质激素肿瘤中表达。观察NR3C1和NR3C2表达水平之间的相关性。NR3C1在沉默中的表达高于在功能性肿瘤中的表达。在CD患者中，NR3C1和NR3C2水平与早晨血浆ACTH水平和肿瘤大小呈负相关。在手术后缓解的患者和浓密的颗粒状肿瘤中证实了较高的NR3C2。在USP8突变的肿瘤中，两种基因和GR蛋白的表达均较高。在沉默肿瘤的分析中观察到USP8突变与表达水平之间的类似关系，这也揭示了GR与肿瘤大小之间的负相关以及在密集颗粒肿瘤中更高的NR3C1表达。
■尽管基因/蛋白质表达与患者临床特征之间的关联不强，它们始终显示出明显的趋势，其中较高的受体表达对应于更有利的临床特征。
■纳入95名患者，包括70例CD和25例无症状促肾上腺皮质激素肿瘤。NR3C1和NR3C2编码GR和MR的基因表达水平，分别,用qRT-PCR测定两种肿瘤类型。用免疫组织化学评估GR和MR蛋白丰度。
■GR和MR均在促肾上腺皮质激素肿瘤中表达。观察NR3C1和NR3C2表达水平之间的相关性。NR3C1在沉默中的表达高于在功能性肿瘤中的表达。在CD患者中，NR3C1和NR3C2水平与早晨血浆ACTH水平和肿瘤大小呈负相关。在手术后缓解的患者和浓密的颗粒状肿瘤中证实了较高的NR3C2。在USP8突变的肿瘤中，两种基因和GR蛋白的表达均较高。在沉默肿瘤的分析中观察到USP8突变与表达水平之间的类似关系，这也揭示了GR与肿瘤大小之间的负相关以及在密集颗粒肿瘤中更高的NR3C1表达。
■尽管基因/蛋白质表达与患者临床特征之间的关联不强，它们始终显示出明显的趋势，其中较高的受体表达对应于更有利的临床特征。
