Department of Diagnostic Medical Sciences and Special Therapies, Surgical Pathology and Cytopathology Unit, University of Padova, Padova, Italy.
Mod Pathol. 2012 Jan;25(1):86-99. doi: 10.1038/modpathol.2011.144. Epub 2011 Oct 7.
Epithelial-mesenchymal transition is a physiopathological process by which epithelial cells acquire mesenchymal shape and properties. Malignant mesothelioma is histologically characterized by the concomitant presence of epithelioid and sarcomatoid features, the latter being associated to worse prognosis, thus suggesting a role of epithelial-mesenchymal transition in this dual phenotype. We studied 109 malignant mesotheliomas (58 epithelioid, 26 sarcomatoid, and 25 biphasic) by immunohistochemistry and qRT-PCR analysis, and demonstrated a substantial switch from epithelial markers (E-cadherin, β-catenin, and cytokeratins 5/6) to mesenchymal markers (N-cadherin, vimentin, α-smooth muscle actin, Snail, Slug, Twist, ZEB1, ZEB2, S100A4, MMP2, and MMP9) through epithelioid to biphasic and sarcomatoid histotypes. In agreement with these findings, the ectopic expression of miR-205 (a repressor of ZEB1 and ZEB2 expression) in MeT-5A (mesothelial cell line), H2452 (an epithelioid malignant mesothelioma cell line) and MSTO-211H (a biphasic malignant mesothelioma cell line) not only induced a significant reduction of ZEB1 and ZEB2 and a consequent up-regulation of E-cadherin gene expression, but also inhibited migration and invasion. Moreover, miR-205 was significantly down-regulated in biphasic and sarcomatoid histotypes (qRT-PCR and in situ hybridization analyses). Collectively, our findings indicate that epithelial-mesenchymal transition has a significant part in the morphological features of malignant mesothelioma. In particular, miR-205 down-regulation correlated significantly with both a mesenchymal phenotype and a more aggressive behavior.
上皮-间充质转化是上皮细胞获得间充质形态和特性的一种生理病理过程。恶性间皮瘤在组织学上的特征是同时存在上皮样和肉瘤样特征，后者与预后较差相关，因此提示上皮-间充质转化在这种双重表型中起作用。我们通过免疫组织化学和 qRT-PCR 分析研究了 109 例恶性间皮瘤（58 例上皮样，26 例肉瘤样，25 例双相型），并证实了从上皮标志物（E-钙黏蛋白、β-连环蛋白和细胞角蛋白 5/6）到间充质标志物（N-钙黏蛋白、波形蛋白、α-平滑肌肌动蛋白、Snail、Slug、Twist、ZEB1、ZEB2、S100A4、MMP2 和 MMP9）的实质性转变，通过上皮样到双相型和肉瘤样组织型。与这些发现一致的是，miR-205（ZEB1 和 ZEB2 表达的抑制剂）在 MeT-5A（间皮细胞系）、H2452（上皮样恶性间皮瘤细胞系）和 MSTO-211H（双相恶性间皮瘤细胞系）中的异位表达不仅显著降低了 ZEB1 和 ZEB2 的表达，并且随后上调了 E-钙黏蛋白基因的表达，还抑制了迁移和侵袭。此外，双相型和肉瘤样组织型中 miR-205 的表达显著下调（qRT-PCR 和原位杂交分析）。总之，我们的研究结果表明，上皮-间充质转化在恶性间皮瘤的形态特征中起重要作用。特别是，miR-205 的下调与间充质表型和更具侵袭性的行为显著相关。
