Department of Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil.
Horm Cancer. 2010 Aug;1(4):187-96. doi: 10.1007/s12672-010-0041-7.
Genes involved in formation/development of the adenohypophysis, CTNNB1 gene, and microRNAs might be implicated in the craniopharyngioma pathogenesis. The objective of this study is to perform the molecular analysis of HESX1, PROP1, POU1F1, and CTNNB1 genes and evaluate a panel of miRNA expression in craniopharyngioma. We also verified whether the presence of CTNNB1 mutation is associated with clinical findings and miRNA expression. The study included 16 patients with adamantinomatous craniopharyngioma (nine children and seven adults; eight females and eight males; 6-55 years, median 15.5 years). DNA, RNA, and cDNA were obtained from craniopharyngioma and normal pituitaries. DNA was also extracted from peripheral blood of healthy subjects. All genes were amplified by polymerase chain reaction and direct sequenced. Relative quantification of miRNA expression was calculated using the 2(-ΔΔCt) method. We found no mutations in HESX1, PROP1, and POU1F1 genes and four polymorphisms in PROP1 gene which were in Hardy-Weinberg equilibrium and had similar allelic frequencies in craniopharyngioma and controls. We found seven different mutations in CTNNB1 in eight of 16 patients. Younger patients presented more frequently CTNNB1 mutation than adults. We observed hyperexpression of miR-150 (1.7-fold); no different expression of miR-16-1, miR-21, and miR23a; and an underexpression of miR-141, let-7a, miR-16, miR-449, miR-145, miR-143, miR-23b, miR-15a, and miR-24-2 (ranging from -7.5 to -2.5-fold; p = 0.02) in craniopharyngioma. There was no association between tumor size or the recurrence and the presence of CTNNB1mutations. miR-16 and miR-141 were underexpressed in craniopharyngioma presenting CTNNB1 mutations. miR-23a and miR24-2 were hyperexpressed in patients who underwent only one surgery. Mutations or polymorphisms in pituitary transcription factors are unlikely to contribute to the adamantinomatous craniopharyngioma pathogenesis, differently of CTNNB1 mutations. Our data suggest the potential involvement of the deregulation of miRNA expression in the craniopharyngioma pathogenesis and outcome and also that the miRNA could modulate the Wnt signaling pathway in craniopharyngioma tumorigenesis.
涉及腺垂体形成/发育的基因、CTNNB1 基因和 microRNAs 可能与颅咽管瘤的发病机制有关。本研究的目的是对 HESX1、PROP1、POU1F1 和 CTNNB1 基因进行分子分析，并评估颅咽管瘤中一组 microRNA 的表达。我们还验证了 CTNNB1 突变的存在是否与临床发现和 microRNA 表达相关。本研究纳入了 16 例造釉细胞瘤（9 例儿童和 7 例成人；8 例女性和 8 例男性；6-55 岁，中位年龄 15.5 岁）。从颅咽管瘤和正常垂体中提取 DNA、RNA 和 cDNA。还从健康受试者的外周血中提取 DNA。所有基因均通过聚合酶链反应扩增并直接测序。使用 2(-ΔΔCt)方法计算 microRNA 表达的相对定量。我们未发现 HESX1、PROP1 和 POU1F1 基因的突变，以及 PROP1 基因的四个多态性，这些多态性在颅咽管瘤和对照中均处于 Hardy-Weinberg 平衡状态，且等位基因频率相似。我们在 16 例患者中的 8 例中发现了 CTNNB1 的 7 种不同突变。年轻患者比成年患者更常出现 CTNNB1 突变。我们观察到 miR-150 的过度表达（1.7 倍）；miR-16-1、miR-21 和 miR23a 的表达无差异；miR-141、let-7a、miR-16、miR-449、miR-145、miR-143、miR-23b、miR-15a 和 miR-24-2 的表达下调（范围从 -7.5 到 -2.5 倍；p=0.02）在颅咽管瘤中。肿瘤大小或复发与 CTNNB1 突变之间无相关性。miR-16 和 miR-141 在存在 CTNNB1 突变的颅咽管瘤中表达下调。miR-23a 和 miR24-2 在仅接受一次手术的患者中过度表达。垂体转录因子的突变或多态性不太可能导致造釉细胞瘤的发病机制，而 CTNNB1 突变则不同。我们的数据表明，microRNA 表达的失调可能参与了颅咽管瘤的发病机制和结果，并且 microRNA 可能调节颅咽管瘤肿瘤发生中的 Wnt 信号通路。
