期刊
BRITISH JOURNAL OF CANCER
卷 104, 期 6, 页码 989-999出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2011.34
关键词
CA125; MUC16; mucins; ovarian cancer; EMT; EGFR
类别
资金
- Canadian Cancer Society [011225, 014363]
BACKGROUND: Epithelial ovarian cancer (EOC) cells are prone to metastasise throughout the peritoneal cavity. The epithelialto- mesenchymal transition (EMT) is a necessary step towards metastatic tumour progression. CA125/ MUC16 mucin is a highmolecular- weight glycoprotein overexpressed in the majority of serous carcinomas, suggesting a possible role in the pathogenesis of these cancers. METHODS: 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. RESULTS: 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 b-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. CONCLUSIONS: Our findings suggest that CA125/MUC16 plays a role in EMT, presumably through its interaction with E-cadherin and beta-catenin complexes and by modulating EGFR and its downstream signalling pathway in NIH: OVCAR3 cells. British Journal of Cancer (2011) 104, 989-999. doi: 10.1038/bjc. 2011.34 www. bjcancer. com
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