Gomes D C, Jamra S A, Leal L F, Colli L M, Campanini M L, Oliveira R S, Martinelli C E, Elias P C L, Moreira A C, Machado H R, Saggioro F, Neder L, Castro M, Antonini S R
School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
School of Medicine of Ribeirao PretoUniversity of Sao Paulo, Avenida Bandeirantes, 3900 - Monte Alegre, CEP 14049-900, Ribeirao Preto, Sao Paulo, BrazilFederal University of UberlandiaUberlandia, Minas Gerais, Brazil.
Eur J Endocrinol. 2015 May;172(5):603-8. doi: 10.1530/EJE-14-0934. Epub 2015 Feb 18.
Pituitary stem cells play a role in the oncogenesis of human adamantinomatous craniopharyngiomas (aCPs). We hypothesized that crosstalk between the Wnt/β-catenin and Sonic Hedgehog (SHH) pathways, both of which are important in normal pituitary development, would contribute to the pathogenesis of aCPs.
To explore the mRNA and protein expression of components of the SHH signaling pathway in aCPs and their relationship with the identification of CTNNB1/β-catenin mutations and patients outcomes.
In 18 aCP samples, CTNNB1 was sequenced, and the mRNA expression levels of SHH pathway members (SHH, PTCH1, SMO, GLI1, GLI2, GLI3, and SUFU) and SMO, GLI1, GLI3, SUFU, β-catenin, and Ki67 proteins were evaluated by quantitative real-time PCR and immunohistochemistry respectively. Anterior normal pituitaries were used as controls. Associations between molecular findings and clinical data were analyzed.
The aCPs presented higher mRNA expression of SHH (+400-fold change (FC); P<0.01), GLI1 (+102-FC; P<0.001), and GLI3 (+5.1-FC; P<0.01) than normal anterior pituitaries. Longer disease-free survival was associated with low SMO and SUFU mRNA expression (P<0.01 and P=0.02 respectively). CTNNB1/β-catenin mutations were found in 47% of the samples. aCPs with identified mutations presented with higher mRNA expression of SMO and GLI1 (+4.3-FC; P=0.02 and +10.2-FC; P=0.03 respectively). SMO, GLI1, GLI3, and SUFU staining was found in 85, 67, 93, and 64% of the samples respectively. Strong GLI1 and GLI3 staining was detected in palisade cells, which also labeled Ki67, a marker of cell proliferation.
The upregulation of SHH signaling occurs in aCPs. Thus, activation of Wnt/β-catenin and SHH pathways, both of which are important in pituitary embryogenesis, appears to contribute to the pathogenesis of aCP.
垂体干细胞在人类造釉细胞瘤型颅咽管瘤（aCPs）的肿瘤发生中起作用。我们推测，在正常垂体发育中起重要作用的Wnt/β-连环蛋白和音猬因子（SHH）信号通路之间的相互作用，可能有助于aCPs的发病机制。
探讨aCPs中SHH信号通路成分的mRNA和蛋白表达，及其与CTNNB1/β-连环蛋白突变鉴定和患者预后的关系。
对18例aCP样本进行CTNNB1测序，分别通过定量实时PCR和免疫组化评估SHH信号通路成员（SHH、PTCH1、SMO、GLI1、GLI2、GLI3和SUFU）以及SMO、GLI1、GLI3、SUFU、β-连环蛋白和Ki67蛋白的mRNA表达水平。以前的正常垂体作为对照。分析分子研究结果与临床数据之间的关联。
与正常垂体前叶相比，aCPs中SHH（变化400倍；P<0.01）、GLI1（变化102倍；P<0.001）和GLI3（变化5.1倍；P<0.01）的mRNA表达更高。无病生存期延长与SMO和SUFU mRNA低表达相关（分别为P<0.01和P=0.02）。47%的样本中发现CTNNB1/β-连环蛋白突变。发现有突变的aCPs中SMO和GLI1的mRNA表达更高（分别为变化4.3倍；P=0.02和变化10.2倍；P=0.03）。分别在85%、67%、93%和64%的样本中发现SMO、GLI1、GLI3和SUFU染色。在栅栏状细胞中检测到强GLI1和GLI3染色，这些细胞也标记了细胞增殖标志物Ki67。
aCPs中发生SHH信号上调。因此，在垂体胚胎发育中起重要作用的Wnt/β-连环蛋白和SHH信号通路的激活，似乎有助于aCP的发病机制。
