Department of Neuropathology, Otto- von-Guericke University, Magdeburg, Germany.
Department of Neurosurgery, Otto- von-Guericke University, Magdeburg, Germany.
J Neurol Sci. 2017 Sep 15;380:112-121. doi: 10.1016/j.jns.2017.07.009. Epub 2017 Jul 8.
E-Cadherin has been suggested to be involved in meningioma progression but is also known as a key player of epithelial to mesenchymal transition (EMT). We wondered whether the adherens junction protein E-Cadherin, the tight junction protein Zo-1, and transcription factors suppressing E-Cadherin expression (Slug, Snail, Twist, Zeb-1) are differentially expressed between histopathological subtypes of meningioma, and if the expression of these factors is related to biological features of meningiomas. Analyzing 85 meningiomas of various histopathological subtypes and grades of malignancy by immunohistochemistry and 50 of them in addition by real-Time-PCR, we observed significantly reduced expression of Zeb-1, Twist and Slug, together with slightly increased expression levels for E-Cadherin and Zo- 1 in fibroblastic WHO-grade I tumors compared to meningothelial WHO grade I tumors, contradicting the hypothesis of EMT in the fibroblastic meningiomas characterized by mesenchymal appearance. However, comparing aggressive WHO grade II or III meningiomas with WHO-grade I tumors, we observed altered expression levels (loss of E-Cadherin and Zo-1, increased expression of Zeb-1 and Slug) indicating molecular features of EMT in aggressive meningiomas. This was supported by reduced E-Cadherin and increased Slug levels in recurrent compared to non-recurrent meningiomas. The expression levels of E-cadherin and Zo-1 were positively correlated with expression of NF2 mRNA. In primary meningioma cultures and IOMM-Lee meningioma cells, EMT induction by TGF-ß resulted in altered morphology and increased expression of EMT associated transcription factors. Meningioma cells with allelic losses of NF2 showed generally higher levels of various EMT relevant proteins, but were unresponsive to TGF-ß treatment. Our data indicate that aggressive meningiomas of WHO grade II/III are characterized by molecular alterations indicating partial EMT. This might contribute to the aggressive biology of these tumors.
E-钙黏蛋白已被认为参与脑膜瘤的进展，但也被认为是上皮间质转化（EMT）的关键参与者。我们想知道黏着连接蛋白 E-钙黏蛋白、紧密连接蛋白 Zo-1 和抑制 E-钙黏蛋白表达的转录因子（Slug、Snail、Twist、Zeb-1）在脑膜瘤的组织病理学亚型之间是否存在差异表达，以及这些因子的表达是否与脑膜瘤的生物学特征有关。通过免疫组织化学分析 85 例不同组织病理学亚型和恶性程度的脑膜瘤，其中 50 例采用实时 PCR 分析，我们观察到纤维母细胞瘤 WHO 分级 I 肿瘤中 Zeb-1、Twist 和 Slug 的表达明显降低，E-钙黏蛋白和 Zo-1 的表达水平略有升高，与脑膜瘤 WHO 分级 I 肿瘤相比，这与纤维母细胞瘤中 EMT 的假说相矛盾，纤维母细胞瘤表现为间充质外观。然而，与 WHO 分级 I 肿瘤相比，侵袭性 WHO 分级 II 或 III 脑膜瘤观察到表达水平的改变（E-钙黏蛋白和 Zo-1 的丢失，Zeb-1 和 Slug 的表达增加），表明侵袭性脑膜瘤中 EMT 的分子特征。这一结果得到了复发脑膜瘤中 E-钙黏蛋白和 Slug 水平降低的支持，而非复发脑膜瘤中 E-钙黏蛋白和 Slug 水平降低。E-钙黏蛋白和 Zo-1 的表达水平与 NF2 mRNA 的表达呈正相关。在原发性脑膜瘤培养物和 IOMM-Lee 脑膜瘤细胞中，TGF-β诱导的 EMT 导致形态改变和 EMT 相关转录因子表达增加。NF2 等位基因缺失的脑膜瘤细胞通常表现出更高水平的各种 EMT 相关蛋白，但对 TGF-β治疗无反应。我们的数据表明，WHO 分级 II/III 的侵袭性脑膜瘤具有分子改变，表明部分 EMT。这可能有助于这些肿瘤的侵袭性生物学。
