Functional screen analysis reveals miR-26b and miR-128 as central regulators of pituitary somatomammotrophic tumor growth through activation of the PTEN-AKT pathway.
Functional screen analysis reveals miR-26b and miR-128 as central regulators of pituitary somatomammotrophic tumor growth through activation of the PTEN-AKT pathway.
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DOI：
10.1038/onc.2012.190
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发表时间：
2013-03-28
期刊：
影响因子：
8
通讯作者：
Stratakis, C. A.
中科院分区：
文献类型：
--
作者：
Palumbo, T.;Faucz, F. R.;Azevedo, M.;Xekouki, P.;Iliopoulos, D.;Stratakis, C. A.
关键词：
microRNA参与了多种肿瘤的发病机制，但其在垂体肿瘤发生中的作用仍不清楚。环磷酸腺苷（cAMP）依赖性蛋白激酶（PKA）缺陷型垂体在PKA主要调节亚基PRKAR 1A单倍不足引起的增生背景下偶尔形成侵袭性生长激素（GH）分泌型垂体瘤。这种发展的分子基础仍然未知。我们已经确定了垂体瘤在增生背景下形成的17-microRNA特征（一半病例由PRKAR 1A突变引起）。通过功能筛选分析，我们筛选出两种microRNA：抑制miR-26 b表达和上调miR-128表达可抑制垂体瘤细胞殖民地形成能力和侵袭能力。此外，我们发现miR-26 b和miR-128分别通过调节其直接靶点PTEN和BMI 1影响垂体瘤细胞的行为。此外，我们发现miR-128通过BMI 1直接结合在PTEN启动子上影响垂体瘤细胞中的PTEN表达水平和AKT活性。综上所述，我们已经确定了产生GH的垂体肿瘤的microRNA特征，并发现miR-26 b和miR-128调节这些肿瘤中PTEN-AKT通路的活性。这是第一个提示，在增生或生殖系PRKAR 1A缺陷的背景下，调节PTEN-AKT通路的microRNA可能参与GH产生性垂体瘤的形成。
MicroRNAs have been involved in the pathogenesis of different types of cancer, however their function in pituitary tumorigenesis remains poorly understood. Cyclic-AMP (cAMP)-dependent protein kinase (PKA)-defective pituitaries occasionally form aggressive growth-hormone (GH)-producing pituitary tumors in the background of hyperplasia caused by haploinsufficiency of the PKA’s main regulatory subunit, PRKAR1A. The molecular basis for this development remains unknown. We have identified a 17-microRNA signature of pituitary tumors formed in the background of hyperplasia (caused in half of the cases by PRKAR1A-mutations). We selected two microRNAs on the basis of their functional screen analysis: inhibition of miR-26b expression and up-regulation of miR-128 suppressed the colony formation ability and invasiveness of pituitary tumor cells. Furthermore, we identified that miR-26b and miR-128 affected pituitary tumor cell behavior through regulation of their direct targets, PTEN and BMI1, respectively. In addition, we found that miR-128 through BMI1 direct binding on the PTEN promoter affected PTEN expression levels and AKT activity in the pituitary tumor cells. Taken together, we have identified a microRNA signature for GH-producing pituitary tumors and found that miR-26b and miR-128 regulate the activity of the PTEN-AKT pathway in these tumors. This is the first suggestion of the possible involvement of microRNAs regulating the PTEN-AKT pathway in GH-producing pituitary tumor formation in the context of hyperplasia or due to germline PRKAR1A defects.
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影响因子：
64.5
作者：
Hatziapostolou M;Polytarchou C;Aggelidou E;Drakaki A;Poultsides GA;Jaeger SA;Ogata H;Karin M;Struhl K;Hadzopoulou-Cladaras M;Iliopoulos D
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影响因子：
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作者：
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通讯作者：
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