Downregulation of cell surface CA125/MUC16 induces epithelial-to-mesenchymal transition and restores EGFR signalling in NIH:OVCAR3 ovarian carcinoma cells.
Downregulation of cell surface CA125/MUC16 induces epithelial-to-mesenchymal transition and restores EGFR signalling in NIH:OVCAR3 ovarian carcinoma cells.
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DOI：
10.1038/bjc.2011.34
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发表时间：
2011-03-15
影响因子：
8.8
通讯作者：
Rancourt, C.
中科院分区：
文献类型：
--
作者：
Comamala, M.;Pinard, M.;Theriault, C.;Matte, I.;Albert, A.;Boivin, M.;Beaudin, J.;Piche, A.;Rancourt, C.
上皮性卵巢癌（EOC）细胞易于在整个腹膜腔内转移。上皮 - 间质转化（EMT）是转移性肿瘤进展的必要步骤。CA125/MUC16粘蛋白是一种高分子量糖蛋白，在大多数浆液性癌中过度表达，表明其在这些癌症的发病机制中可能起作用。
通过单链抗体介导的对过度表达的EOC NIH:OVCAR3细胞表面CA125/MUC16的敲低，研究了CA125/MUC16在上皮 - 间质转化中的作用。
CA125/MUC16的敲低与形态学改变相关，同时上皮标志物（E - 钙粘蛋白、细胞角蛋白 - 18）的表面表达降低，间质标志物（N - 钙粘蛋白、波形蛋白）的表达增加。免疫共沉淀实验表明，CA125/MUC16与E - 钙粘蛋白和β - 连环蛋白复合物结合。体外研究显示，CA125/MUC16敲低的细胞中细胞 - 细胞连接被破坏，运动性、迁移和侵袭性增强。在CA125/MUC16敲低的细胞中观察到表皮生长因子受体（EGFR）激活增强，同时Akt和ERK1/2磷酸化增加（它们是EGFR的下游效应物），以及基质金属蛋白酶 - 2（MMP - 2）和基质金属蛋白酶 - 9（MMP - 9）的表达和活性增加。表皮生长因子受体抑制强烈抑制了CA125/MUC16敲低细胞的运动性。
我们的研究结果表明，CA125/MUC16在上皮 - 间质转化中起作用，可能是通过其与E - 钙粘蛋白和β - 连环蛋白复合物的相互作用，以及调节NIH:OVCAR3细胞中的EGFR及其下游信号通路。
Epithelial ovarian cancer (EOC) cells are prone to metastasise throughout the peritoneal cavity. The epithelial-to-mesenchymal transition (EMT) is a necessary step towards metastatic tumour progression. CA125/MUC16 mucin is a high-molecular-weight glycoprotein overexpressed in the majority of serous carcinomas, suggesting a possible role in the pathogenesis of these cancers. The role of CA125/MUC16 in EMT was investigated using single-chain antibody-mediated knockdown of cell surface CA125/MUC16 in overexpressing EOC NIH:OVCAR3 cells. CA125/MUC16 knockdown was associated with morphological alterations along with decreased surface expression of epithelial markers (E-cadherin, cytokeratin-18) and increased expression of mesenchymal markers (N-cadherin, vimentin). Co-immunoprecipitation experiments revealed that CA125/MUC16 binds to E-cadherin and β-catenin complexes. The in vitro studies showed disruption of cell–cell junctions, enhanced motility, migration and invasiveness in CA125/MUC16 knockdown cells. Enhanced epidermal growth factor receptor (EGFR) activation was observed in CA125/MUC16 knockdown cells along with increased Akt and ERK1/2 phosphorylation, which are downstream effectors of EGFR, and increased MMP-2 and MMP-9 expression and activities. Epidermal growth factor receptor inhibition strongly inhibited the motility of CA125/MUC16 knockdown cells. Our findings suggest that CA125/MUC16 plays a role in EMT, presumably through its interaction with E-cadherin and β-catenin complexes and by modulating EGFR and its downstream signalling pathway in NIH:OVCAR3 cells.
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影响因子：
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作者：
Komatsu, M;Jepson, S;Carraway, KL
通讯作者：
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