Somatostatin Analogs Modulate AIP in Somatotroph Adenomas: The Role of the ZAC1 Pathway
Somatostatin Analogs Modulate AIP in Somatotroph Adenomas: The Role of the ZAC1 Pathway
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DOI：
10.1210/jc.2012-1111
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发表时间：
2012-08-01
影响因子：
5.8
通讯作者：
Korbonits, Marta
中科院分区：
文献类型：
--
作者：
Chahal, Harvinder S.;Trivellin, Giampaolo;Korbonits, Marta
内容：生长激素腺瘤窝藏芳烃受体相互作用蛋白（AIP）突变的反应不太好，生长抑素类似物，这表明生长抑素类似物的影响可能介导的AIP.Objective：调查的目的是研究AIP的参与生长抑素类似物的作用机制。设计：在人类研究中，16周的生长抑素类似物预处理相比，没有预处理。在体外细胞系研究中，研究了生长抑素类似物治疗或小干扰RNA（siRNA）/质粒转染的效果。设置：该研究在一所大学医院进行。患者：39名散发性和10名家族性肢端肥大症患者参与了该研究。干预：干预包括术前兰瑞肽治疗和垂体手术。结果：对于人体研究，测量GH和IGF-I水平、AIP和生长抑素受体染色。结果：兰瑞肽预处理可降低GH和IGF-I水平及肿瘤体积（P均< 0.0001）;兰瑞肽预处理组的AIP免疫染色强于单纯手术组（P < 0.001）。兰瑞肽预处理后，女性AIP评分与IGF-I变化相关（R = 0.68，P < 0.05）。在AIP突变的样本中，生长抑素受体染色没有减少。在GH 3细胞中，1 nM奥曲肽可增加AIP mRNA和蛋白表达（均P < 0.01）及ZAC 1 mRNA表达（P < 0.05）。野生型AIP的过表达增加了ZAC 1 mRNA的表达，而AIP siRNA敲低则降低了ZAC 1 mRNA的表达（均P < 0.05）。结论：AIP基因可能通过ZAC 1在生长抑素类似物治疗散发性生长激素肿瘤的作用机制中发挥作用，这可能解释了生长抑素类似物对AIP基因突变患者无效的原因。（临床内分泌代谢杂志97：E1411-E1420，2012）
Context: Somatotroph adenomas harboring aryl hydrocarbon receptor interacting protein (AIP) mutations respond less well to somatostatin analogs, suggesting that the effects of somatostatin analogs may be mediated by AIP.Objective: The objective of the investigation was to study the involvement of AIP in the mechanism of effect of somatostatin analogs.Design: In the human study, a 16-wk somatostatin analog pretreatment compared with no pretreatment. In the in vitro cell line study, the effect of somatostatin analog treatment or small interfering RNA (siRNA)/plasmid transfection were studied.Setting: The study was conducted at a university hospital.Patients: Thirty-nine sporadic and 10 familial acromegaly patients participated in the study.Intervention: Interventions included preoperative lanreotide treatment and pituitary surgery.Outcome: For the human study, GH and IGF-I levels, AIP, and somatostatin receptor staining were measured. For the cell line, AIP and ZAC1 (zinc finger regulator of apoptosis and cell cycle arrest) expression, metabolic activity, and clone formation were measured.Results: Lanreotide pretreatment reduced GH and IGF-I levels and tumor volume (all P < 0.0001). AIP immunostaining was stronger in the lanreotide-pretreated group vs. the surgery-only group (P < 0.001). After lanreotide pretreatment, the AIP score correlated to IGF-I changes in females (R = 0.68, P < 0.05). Somatostatin receptor staining was not reduced in samples with AIP mutations. In GH3 cells, 1 nM octreotide increased AIP mRNA and protein (both P < 0.01) and ZAC1 mRNA expression (P < 0.05). Overexpression of wild-type (but not mutant) AIP increased ZAC1 mRNA expression, whereas AIP siRNA knockdown reduced ZAC1 mRNA (both P < 0.05). The siRNA-mediated knockdown of AIP led to an increased metabolic activity and clonogenic ability of GH3 cells compared with cells transfected with a nontargeting control (both P < 0.001).Conclusion: These results suggest that AIP may play a role in the mechanism of action of somatostatin analogs via ZAC1 in sporadic somatotroph tumors and may explain their lack of effectiveness in patients with AIP mutations. (J Clin Endocrinol Metab 97: E1411-E1420, 2012)