Target Gene Activation of the Wnt Signaling Pathway in Nuclear β-Catenin Accumulating Cells of Adamantinomatous Craniopharyngiomas
Target Gene Activation of the Wnt Signaling Pathway in Nuclear β-Catenin Accumulating Cells of Adamantinomatous Craniopharyngiomas
复制标题
釉质瘤型颅咽管瘤核内β-连环蛋白积聚细胞中Wnt信号通路的靶基因激活
DOI：
10.1111/j.1750-3639.2008.00180.x
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发表时间：
2009-07-01
期刊：
影响因子：
6.4
通讯作者：
Buslei, Rolf
中科院分区：
文献类型：
--
作者：
Hoelsken, Annett;Kreutzer, Juergen;Buslei, Rolf
在大多数成釉细胞瘤性颅咽管瘤（adaCP）中可以发现激活β-连环蛋白（CTNNB 1）突变，这表明在这种组织病理学特有的肿瘤实体中存在异常的Wnt信号通路。然而，没有证据表明β-连环蛋白的核转位与CTNNB 1突变和靶基因激活相关。我们进行了一项基于激光显微切割的研究，比较了β-连环蛋白积聚与非积聚的肿瘤细胞。在造釉细胞瘤和乳头状肿瘤标本中进行突变分析和基因表达谱分析。在adaCP中可以检测到靶基因激活，即Axin 2的过表达，特别是在具有核β-连环蛋白积累的肿瘤细胞中。此外，在积聚的细胞群中鉴定了BMP 4的表达增加，这支持了口腔外胚层起源的假设。有趣的是，蓄积和非蓄积肿瘤细胞群在外显子3内携带CTNNB 1突变。因此，我们将分析扩展到编码膜连接和主动/被动核转运机制的遗传区域（外显子4和外显子8-13），但未检测到任何改变。这是第一份证明核β-连环蛋白积累与adaCP中靶基因激活之间存在关联的报告。结果证实了Wnt信号通路是adaCP独特且具有挑战性的临床和形态学表型的分子基础。
Activating beta-catenin (CTNNB1) mutations can be identified in the majority of adamantinomatous craniopharyngiomas (adaCP), suggesting an aberrant Wnt signaling pathway in this histopathologically peculiar tumor entity. However, there is no proven evidence that nuclear translocation of beta-catenin is associated with CTNNB1 mutations and target gene activation. We performed a laser-microdissection-based study comparing beta-catenin accumulating vs. non-accumulating tumor cells. Mutational analysis and gene expression profiling using real-time polymerase chain reaction were conducted in adamantinomatous and papillary tumor specimens. Target gene activation, that is, over-expression of Axin2 could be detected in adaCP, especially in tumor cells with nuclear beta-catenin accumulation. In addition, increased expression of BMP4 was identified in the accumulating cell population, which supports the hypothesis of an oral ectodermal origin. Interestingly, accumulating and non-accumulating tumor cell populations carried CTNNB1 mutations within exon 3. We extended the analysis, therefore, towards genetic regions encoding for membrane linkage and active/passive nuclear transport mechanisms (exon 4 and exon 8-13), but could not detect any alteration. This is the first report demonstrating an association between nuclear beta-catenin accumulation and target gene activation in adaCP. The results confirm the Wnt signaling pathway as molecular basis of the distinct and challenging clinical and morphological phenotype of adaCP.