Sonic Hedgehog pathway is upregulated in adamantinomatous craniopharyngiomas
Sonic Hedgehog pathway is upregulated in adamantinomatous craniopharyngiomas
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DOI：
10.1530/eje-14-0934
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发表时间：
2015-05-01
影响因子：
5.8
通讯作者：
Antonini, S. R.
中科院分区：
文献类型：
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作者：
Gomes, D. C.;Jamra, S. A.;Antonini, S. R.
目的：骨髓间充质干细胞在人成釉细胞瘤样颅咽管瘤（aCP）的发生发展中起重要作用。我们假设Wnt/β-catenin和Sonic Hedgehog（SHH）通路之间的相互作用（这两者在正常垂体发育中都很重要）将有助于aCPs.Design的发病机制：探索aCPs中SHH信号通路组分的mRNA和蛋白表达及其与CTNNB 1/β-catenin突变鉴定和患者预后的关系。在18份aCP样本中，对CTNNB 1进行了测序，并分别通过实时定量PCR和免疫组织化学方法评估了SHH途径成员（SHH、PTCH 1、SMO、GLI 1、GLI 2、GLI 3和SUFU）以及SMO、GLI 1、GLI 3、SUFU、β-连环蛋白和Ki 67蛋白的mRNA表达水平。正常垂体前叶作为对照。结果：与正常垂体前叶相比，aCPs中SHH（+400倍变化（FC）; P < 0.01）、GLI 1（+102-FC; P< 0.001）和GLI 3（+5.1-FC; P < 0.01）的mRNA表达均显著增加。SMO和SUFU mRNA的低表达与无病生存期的延长有关（P分别< 0.01和P=0.02）。在47%的样本中发现CTNNB 1/β-连环蛋白突变。具有确定突变的aCP呈现出SMO和GLI 1的较高mRNA表达（分别为+4.3-FC; P=0.02和+10.2-FC; P=0.03）。SMO、GLI 1、GLI 3和SUFU染色分别见于85%、67%、93%和64%的样本。在栅栏细胞中检测到强烈的GLI 1和GLI 3染色，其还标记细胞增殖的标志物Ki 67。因此，Wnt/β-连环蛋白和SHH通路的激活，这两个都是重要的垂体胚胎发生，似乎有助于aCP的发病机制。
Objectives: Pituitary stem cells play a role in the oncogenesis of human adamantinomatous craniopharyngiomas (aCPs). We hypothesized that crosstalk between the Wnt/beta-catenin and Sonic Hedgehog (SHH) pathways, both of which are important in normal pituitary development, would contribute to the pathogenesis of aCPs.Design: To explore the mRNA and protein expression of components of the SHH signaling pathway in aCPs and their relationship with the identification of CTNNB1/beta-catenin mutations and patients outcomes.Patients and methods: 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, beta-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.Results: 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/beta-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.Conclusions: The upregulation of SHH signaling occurs in aCPs. Thus, activation of Wnt/beta-catenin and SHH pathways, both of which are important in pituitary embryogenesis, appears to contribute to the pathogenesis of aCP.