miR-26a plays an important role in cell cycle regulation in ACTH-secreting pituitary adenomas by modulating protein kinase Cδ.
miR-26a plays an important role in cell cycle regulation in ACTH-secreting pituitary adenomas by modulating protein kinase Cδ.
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DOI：
10.1210/en.2012-2070
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发表时间：
2013-05
期刊：
影响因子：
4.8
通讯作者：
Zatelli MC
中科院分区：
文献类型：
--
作者：
Gentilin E;Tagliati F;Filieri C;Molè D;Minoia M;Rosaria Ambrosio M;Degli Uberti EC;Zatelli MC
分泌ACTH的垂体腺瘤中microRNA（miRNA）失调的功能后果尚未得到证实。miRNAs代表诊断和预后的生物标志物以及假定的治疗靶点;它们的研究可能揭示垂体腺瘤发展和进展的基础机制。药物与这些途径相互作用，可能有助于实现疾病控制，也在设置ACTH分泌垂体腺瘤。我们研究了在小鼠ACTH分泌型垂体腺瘤细胞系AtT 20/D16 v-F2中发现的人类垂体腺瘤组织中最失调的10种miRNAs的表达。在AtT 20/D16 v-F2细胞中进行进一步研究的所选miRNA代表了包括5种上调和5种下调的miRNA的表达组。其中，我们选择了最失调的小鼠miRNA，并寻找miRNA靶点及其生物学功能。我们发现AtT 20/D16 v-F2细胞具有特定的miRNA表达谱，并且miR-26 a是最失调的miRNA。后者在人垂体腺瘤中过表达，并且可以在体外模型中控制活细胞数，而不涉及半胱天冬酶3/7介导的凋亡。我们证明了蛋白激酶Cδ（PRKCD）是miR-26 a的直接靶点，并且miR-26 a的抑制使细胞周期延迟在G1期。这种效应涉及通过PRKCD调节下调细胞周期蛋白E和细胞周期蛋白A的表达。miR-26 a和相关通路，如PRKCD，在ACTH垂体细胞的细胞周期控制中发挥重要作用，为治疗持续性/复发性库欣病开辟了新的治疗可能性。
The functional aftermath of microRNA (miRNA) dysregulation in ACTH-secreting pituitary adenomas has not been demonstrated. miRNAs represent diagnostic and prognostic biomarkers as well as putative therapeutic targets; their investigation may shed light on the mechanisms that underpin pituitary adenoma development and progression. Drugs interacting with such pathways may help in achieving disease control also in the settings of ACTH-secreting pituitary adenomas. We investigated the expression of 10 miRNAs among those that were found as most dysregulated in human pituitary adenoma tissues in the settings of a murine ACTH-secreting pituitary adenoma cell line, AtT20/D16v-F2. The selected miRNAs to be submitted to further investigation in AtT20/D16v-F2 cells represent an expression panel including 5 up-regulated and 5 down-regulated miRNAs. Among these, we selected the most dysregulated mouse miRNA and searched for miRNA targets and their biological function. We found that AtT20/D16v-F2 cells have a specific miRNA expression profile and that miR-26a is the most dysregulated miRNA. The latter is overexpressed in human pituitary adenomas and can control viable cell number in the in vitro model without involving caspase 3/7-mediated apoptosis. We demonstrated that protein kinase Cδ (PRKCD) is a direct target of miR-26a and that miR26a inhibition delays the cell cycle in G1 phase. This effect involves down-regulation of cyclin E and cyclin A expression via PRKCD modulation. miR-26a and related pathways, such as PRKCD, play an important role in cell cycle control of ACTH pituitary cells, opening new therapeutic possibilities for the treatment of persistent/recurrent Cushing's disease.
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影响因子：
64.8
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影响因子：
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