SHH, WNT, and NOTCH pathways in medulloblastoma: when cancer stem cells maintain self-renewal and differentiation properties
SHH, WNT, and NOTCH pathways in medulloblastoma: when cancer stem cells maintain self-renewal and differentiation properties
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DOI：
10.1007/s00381-014-2403-x
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发表时间：
2014-07-01
影响因子：
1.4
通讯作者：
Caminada Toledo, Silvia Regina
中科院分区：
文献类型：
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作者：
Cordeiro, Bruna Mascaro;Oliveira, Indhira Dias;Caminada Toledo, Silvia Regina
婴儿髓母细胞瘤（MB）是一种发生在小脑的恶性神经上皮胚胎性肿瘤，被认为起源于具有干细胞或祖细胞外观的前体细胞颗粒细胞，由发育相关基因表达谱的改变引起。本工作旨在研究这些基因在MB肿瘤中的表达谱及其与临床病理特征的关系。我们在40个MB肿瘤样本中，通过qPCR量化了HH （PTCH1、PTCH2和GLI1）、WNT （APC、CTNNB1、WIF1和DKK2）和NOTCH通路（NOTCH2和HES1）的基因表达，以及MYCC、MYCN和TERT基因的表达，并将这一发现与患者的临床病理特征联系起来。以通用RNA作为对照样本，以对照样本中基因表达的中位数作为截止点，我们观察到HES1基因的表达较对照降低（p = 0.0059），但HES1过表达的患者与较短的生存期直接相关（p = 0.0165）。GLI1基因高表达个体的生存期明显较短（p = 0.0469），且高表达在5岁以下患者中普遍存在（p = 0.0479）。PTCH2高表达的患者生存期较差（p = 0.0426），与GLI1高表达相关（p = 0.0094）。我们还观察到，在MB样本的一个亚组中，WIF1和DKK2基因同时过表达（n = 11, p = 0.0118）。我们的研究结果表明，MB中存在激活的发育信号通路，这对细胞增殖和维持很重要，可能是新的治疗选择的目标。
Infant medulloblastoma (MB) is a malignant neuroepithelial embryonal tumor of the cerebellum, believed to derive from precursor granule cells with stem or progenitor cells appearance, and caused by a change in expression profile of genes related to the development. This work aims to study the expression profile of these genes in MB tumors, correlating with clinicopathological characteristics.We quantified, by qPCR in 40 MB tumor samples, the expression of genes in HH (PTCH1, PTCH2, and GLI1), WNT (APC, CTNNB1, WIF1, and DKK2), and NOTCH pathways (NOTCH2 and HES1), which have a crucial role in development, and genes as MYCC, MYCN, and TERT, correlating this findings to patient's clinicopathological characteristics.Considering the universal RNA as our control sample, and considering the median of gene expression in the control samples as our cutoff, we observed that HES1 gene showed decreased expression compared to control (p = 0.0059), but patients with HES1 overexpression were directly related to a shorter survival (p = 0.0165). Individuals with higher GLI1 gene expression had significant shorter survival (p = 0.0469), and high expression was prevalent in patients up to 5 years old (p = 0.0479). Patients showing high PTCH2 expression were related to worse survival (p = 0.0426), and it was correlated with GLI1 high expression (p = 0.0094). We also observed a concomitant overexpression of WIF1 and DKK2 genes in a subgroup of MB samples (n = 11, p = 0.0118).Our results suggest the presence of activated developmental signaling pathways in MB, which are important for cell proliferation and maintenance, and that may be targeted for novel therapeutic options.