Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Croatia.
J Cancer Res Clin Oncol. 2010 May;136(5):695-702. doi: 10.1007/s00432-009-0708-z. Epub 2009 Nov 12.
The molecular mechanisms and candidate genes involved in development of meningiomas still needs investigation and elucidation.
In the present study 60 meningiomas were analyzed regarding changes of tumor suppressor gene E-cadherin (CDH1), a component of adherens junction and an indirect modulator of the wnt signaling. Gene instability was tested by polymerase chain reaction/loss of heterozygosity (LOH) method. Protein expression was analyzed by immunohistochemistry.
The results of our analysis showed altogether 32% of samples with LOH of the CDH1 gene. Interestingly, another type of genomic instability was detected; replication error-positive samples (RER+). Three out of 28 heterozygous samples were RER+ (11%). The instability is the result of impaired cellular mismatch repair. Fibrous and angiomatous cases showed higher percent of genetic changes, 67 and 75%, respectively. Immunostaining showed that overall 73% of samples had downregulation of E-cadherin expression. Intense downregulation of E-cadherin was noticed in tumors with grades II and III. Five out of nine samples with LOH were accompanied with the downregulation of E-cadherin protein expression (56%). One RER+ sample had lower expression of E-cadherin. We noticed that 36.4% of samples with lower E-cadherin expression had beta-catenin located in the nucleus. Also, 75% of samples with genomic instabilities had beta-catenin in the nucleus. Our findings demonstrated that there is significant association between the genetic changes of CDH1 and the nuclear localization of beta-catenin protein (chi(2) = 5.25, df = 1, P < 0.022). Beta-catenin was progressively upregulated from meningothelial to atypical, while 60% of anaplastic showed upregulation and nuclear localization of the protein.
Our results suggest that genetic instabilities of the E-cadherin gene have a role in meningioma development and progression. Detected microsatellite instability indicates that mismatch repair may also be targeted in meningioma.
涉及脑膜瘤发生的分子机制和候选基因仍需要研究和阐明。
本研究分析了 60 例脑膜瘤，研究了肿瘤抑制基因 E-钙黏蛋白（CDH1）的变化，E-钙黏蛋白是黏着连接的组成部分，也是 Wnt 信号的间接调节剂。通过聚合酶链反应/杂合性丢失（LOH）方法检测基因不稳定性。采用免疫组织化学法分析蛋白表达。
我们的分析结果显示，共有 32%的样本存在 CDH1 基因的 LOH。有趣的是，还检测到另一种类型的基因组不稳定性；复制错误阳性样本（RER+）。在 28 个杂合样本中，有 3 个为 RER+（11%）。这种不稳定性是细胞错配修复受损的结果。纤维状和血管性病例的遗传变化比例较高，分别为 67%和 75%。免疫组化显示，总体上有 73%的样本 E-钙黏蛋白表达下调。II 级和 III 级肿瘤中 E-钙黏蛋白的下调更为明显。在 9 个存在 LOH 的样本中，有 5 个伴有 E-钙黏蛋白蛋白表达的下调（56%）。一个 RER+样本的 E-钙黏蛋白表达较低。我们注意到，有 36.4%的 E-钙黏蛋白表达较低的样本中β-连环蛋白位于细胞核内。此外，有 75%的基因组不稳定样本中β-连环蛋白位于细胞核内。我们的研究结果表明，CDH1 基因的遗传变化与β-连环蛋白蛋白的核定位之间存在显著相关性（χ 2 = 5.25，df = 1，P < 0.022）。β-连环蛋白从脑膜内皮细胞逐渐上调至非典型，而 60%的间变性表现出蛋白的上调和核定位。
我们的研究结果表明，E-钙黏蛋白基因的遗传不稳定性在脑膜瘤的发生和发展中起作用。检测到的微卫星不稳定性表明错配修复也可能成为脑膜瘤的靶点。
