Martins C S, Camargo R C, Saggioro F P, Neder L, Machado H R, Moreira A C, de Castro M
Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
Horm Metab Res. 2016 Dec;48(12):840-846. doi: 10.1055/s-0042-118613. Epub 2016 Nov 7.
In pituitary tumors, P27(CDKN1B) is underexpressed. We aimed to clarify whether translational regulation underlies this phenomenon. This study evaluated the expression of /, its targets (, ) and translational regulators (, , , ) and screened for variants in sporadic pituitary adenomas. Samples were obtained during transsphenoidal surgery from 48 patients with pituitary adenomas: 10 ACTH-, 17 GH-secreting, and 21 nonfunctioning (NFPA). The control group comprised 7 normal pituitaries (NP) obtained during autopsies. Gene expression was assessed by RT-PCR and protein expression by immunohistochemistry. The 15 exons of were sequenced. P27 protein underexpression was observed in all adenomas subtypes (p=0.001). mRNA (p=0.01) overexpression, but not protein, was observed in NFPA. No differential gene expression among groups was observed in regulators (p=0.23) and (p=0.34). The expression of and was similar among tumors and NP. Frequent variants (SNPs) were found in exon 14 and in the 3'-UTR in similar frequency to NCBI-dsSNP databases. We also observed rare variants in 11% of the studied tumor samples, indicating a high prevalence in pituitary adenomas, however, in silico studies failed to indicate deleterious effects. The high frequency of variants may influence, in some extent, pituitary tumors development, without clear role in its tumorigenesis. Our data reinforce the P27 underexpression in pituitary adenomas and provide further evidence of the post-translational machinery involvement, although this phenomenon cannot be explained either by mis-expression of P27 translational regulators - , , , - or directly by mutations.
在垂体肿瘤中，P27（CDKN1B）表达不足。我们旨在阐明翻译调控是否是这一现象的基础。本研究评估了[基因名称1]的表达、其靶标（[基因名称2]、[基因名称3]）和翻译调节因子（[基因名称4]、[基因名称5]、[基因名称6]、[基因名称7]），并在散发性垂体腺瘤中筛选[基因名称1]的变异体。在48例垂体腺瘤患者经蝶窦手术期间获取样本：10例促肾上腺皮质激素（ACTH）分泌型、17例生长激素（GH）分泌型和21例无功能型（NFPA）。对照组包括7例尸检时获得的正常垂体（NP）。通过逆转录聚合酶链反应（RT-PCR）评估基因表达，通过免疫组织化学评估蛋白质表达。对[基因名称1]的15个外显子进行测序。在所有腺瘤亚型中均观察到P27蛋白表达不足（p = 0.001）。在NFPA中观察到[基因名称1] mRNA（p = 0.01）过表达，但蛋白未过表达。在翻译调节因子[基因名称4]（p = 0.23）和[基因名称5]（p = 0.34）中未观察到各组间的差异基因表达。[基因名称6]和[基因名称7]在肿瘤和NP中的表达相似。在外显子14和3'-非翻译区（UTR）中发现了与美国国立生物技术信息中心（NCBI）单核苷酸多态性（SNP）数据库频率相似的常见[基因名称1]变异体。我们还在11%的研究肿瘤样本中观察到罕见的[基因名称1]变异体，表明其在垂体腺瘤中具有高患病率，然而，计算机模拟研究未能表明其有害影响。[基因名称1]变异体的高频率可能在一定程度上影响垂体肿瘤的发展，但在其肿瘤发生中没有明确作用。我们的数据强化了垂体腺瘤中P27表达不足，并提供了翻译后机制参与的进一步证据，尽管这一现象既不能通过P27翻译调节因子[基因名称4]、[基因名称5]、[基因名称6]、[基因名称7]的错误表达来解释，也不能直接由[基因名称1]突变来解释。
