Possible Relevance between Prohormone Convertase 2 Expression and Tumor Growth in Human Adrenocorticotropin-Producing Pituitary Adenoma
Possible Relevance between Prohormone Convertase 2 Expression and Tumor Growth in Human Adrenocorticotropin-Producing Pituitary Adenoma
复制标题
DOI：
10.1210/jc.2009-2716
复制
发表时间：
2010-08-01
影响因子：
5.8
通讯作者：
Nakamura, Hirotoshi
中科院分区：
文献类型：
--
作者：
Iino, Kazumi;Oki, Yutaka;Nakamura, Hirotoshi
背景：前激素转换酶2(PC2)阳性的促肾上腺皮质激素释放激素(ACTH)腺瘤的术前诊断方法尚未建立。目的：研究PC2阳性APPAS患者血浆αMSH水平的意义及细胞增殖信号分子的作用。患者和主要观察指标：检测19例人APPAS中PC2、磷酸化ERK1/2、磷酸化Akt1/2/3(p-Akt)和受体酪氨酸激酶的表达。检测17例APPA患者和30例健康志愿者血浆中的α-MSH。结果：9例(47.4%)腺瘤PC2免疫阳性，肿瘤体积大，侵袭性强。在所有正常对照组和8例PC2阴性病例中，检测不到血浆αMSH，而在4例PC2阳性病例中，检测到异常高的水平。8个腺瘤(42.1%)同时表达PC2和p-Akt，7个腺瘤(36.8%)同时表达PC2和p-Akt，提示PC2和p-Akt在肿瘤中同时表达。定量RT-PCR显示PC2的表达与Akt的磷酸化有关，但与Akt的基因表达无关。结论：PC2的表达与Akt的磷酸化在分子水平上有关，导致细胞周期改变和腺瘤体积增大。血浆αMSH水平升高可推测PC2阳性APAs中磷脂酰肌醇3/Akt级联激活，并可能成为库欣病肿瘤生长的有价值的临床标志。(临床内分泌代谢酶95：4003-4011,2010)
Context: Methods for preoperative diagnosis of prohormone convertase 2 (PC2)-positive ACTH-producing pituitary adenomas(APPAs) have not been established. Also, their characteristics are not evident.Objective: This study was designed to understand the meaning of plasma alpha MSH levels and the role of cell proliferation-signaling molecules in PC2-positive APPAs.Patients and Main Outcome Measures: Nineteen human APPAs (four males and 15 females) were examined for the expression of PC2, phosphorylated ERK1/2, phosphorylated Akt1/2/3 (p-Akt) and receptor tyrosine kinases. alpha MSH was measured in extracted plasma from 17 APPA patients and 30 healthy volunteers.Results: Nine adenomas (47.4%) were immunopositive for PC2 and were large and invasive in nature. In all normal controls and eight PC2-negative cases, plasma alpha MSH was undetectable, whereas in four PC2-positive cases, it was detected at abnormally higher levels. Eight adenomas (42.1%) were immunopositive for both PC2 and p-Akt, and seven others (36.8%) were immunonegative for both, suggesting significant coexpression of PC2 and p-Akt in tumors. Quantitative RT-PCR revealed that PC2 expression is associated with phosphorylation of Akt but not with its gene expression. Most APPAs expressed receptor tyrosine kinases, but membrane-bound receptors could not be identified.Conclusions: Our study suggests that PC2 expression and Akt phosphorylation are related at the molecular level, resulting in a change in cell cycle and an increase in pituitary adenoma size. An elevation of plasma alpha MSH could conjecture the activation of the phosphatidylinositol 3/Akt cascade in PC2-positive APPAs and may become a valuable clinical marker of tumor growth in Cushing's disease. (J Clin Endocrinol Metab 95: 4003-4011, 2010)