Responsiveness to DDAVP in Cushing’s disease is associated with USP8 mutations through enhancing AVPR1B promoter activity
Responsiveness to DDAVP in Cushing’s disease is associated with USP8 mutations through enhancing AVPR1B promoter activity
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DOI：
10.1007/s11102-022-01220-4
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发表时间：
2022-04
期刊：
影响因子：
3.8
通讯作者：
Hiroki Shichi;H. Fukuoka;Maki Kanzawa;Masaaki Yamamoto;Naoki Yamamoto;Masaki Suzuki;Shin Urai;R. Matsumoto;Keitaro Kanie;Y. Fujita;H. Bando;G. Iguchi;N. Inoshita;S. Yamada;Yutaka Takahashi;Wataru Ogawa
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文献类型：
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作者：
Hiroki Shichi;H. Fukuoka;Maki Kanzawa;Masaaki Yamamoto;Naoki Yamamoto;Masaki Suzuki;Shin Urai;R. Matsumoto;Keitaro Kanie;Y. Fujita;H. Bando;G. Iguchi;N. Inoshita;S. Yamada;Yutaka Takahashi;Wataru Ogawa
目的探讨库欣病（CD）患者对去氨加压素（DDAVP）试验反应的特点及其机制。患者分为两组：DDAVP试验（+）（DDAVP试验期间促肾上腺皮质激素[ACTH]水平增加≥ 1.5倍）和DDAVP试验（-）（ACTH水平增加< 1.5倍）。采用定量RT-PCR和免疫组织化学方法对这些肿瘤中AVP受体的表达水平进行定量。AVP受体启动子活性进行了分析，使用双荧光素酶报告分析system.ResultsFemales（96.9%）和USP 8突变体（85.7%）是更普遍的DDAVP测试（+）比在DDAVP测试（-）。事实上，与USP 8野生型肿瘤相比，USP 8突变阳性肿瘤中ACTH和皮质醇对DDAVP的反应性更高（分别为3.0倍vs.1.3倍，1.6倍vs.1.1倍）。DDAVP的疗效与AVPR 1B的表达水平相关，而与AVPR 2的表达水平无关。Comparatively，Avpr 1b启动子活性增强的过度表达的muscle USP 8相比，野生型。ConclusionsWe发现，在CD的ACTH DDAVP的反应是更大的肿瘤与USP 8突变。目前的数据表明USP 8突变上调AVPR 1B启动子活性。此外，我们还发现DDAVP检测可以预测USP 8突变的存在。
PurposeTo clarify the characteristics of Cushing’s disease (CD) patients who respond to the desmopressin (DDAVP) test and its underlying mechanisms.MethodsForty-seven patients with CD who underwent DDAVP testing were included. Patients were divided into two groups: DDAVP test (+) (adrenocorticotropic hormone [ACTH] levels increased by ≥ 1.5-fold during the DDAVP test) and DDAVP test (−) (ACTH levels increased by < 1.5-fold). AVP receptor expression levels in these tumors were quantified using quantitative RT-PCR and immunohistochemistry. AVP receptor promoter activity was analyzed using a dual-luciferase reporter assay system.ResultsFemales (96.9%) andUSP8mutants (85.7%) were more prevalent in the DDAVP test (+) than in the DDAVP test (−). Indeed, the ACTH and cortisol responsiveness to DDAVP was greater inUSP8mutation positive tumors than that inUSP8wild type tumors (3.0-fold vs. 1.3-fold, 1.6-fold vs. 1.1-fold, respectively). Responsiveness to DDAVP was correlated with the expression levels ofAVPR1B,but not with those ofAVPR2. Comparably,Avpr1bpromoter activity was enhanced by the overexpression of mutantUSP8compared to the wild type.ConclusionsWe found that the responsiveness of ACTH to DDAVP in CD was greater in tumors withUSP8mutations. The present data suggest thatUSP8mutations upregulate theAVPR1Bpromoter activity. Additionally, we showed that the DDAVP test can predict the presence ofUSP8mutations.