Downregulation of cytokeratin 18 induces cellular partial EMT and stemness through increasing EpCAM expression in breast cancer |
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| Institution: | 1. Bezmialem Vakif University, Faculty of Medicine, Department of Medical Oncology, Fatih/Istanbul, Turkey;2. Bezmialem Vakif University, Faculty of Medicine, Department of Internal Medicine, Fatih/Istanbul, Turkey;3. Bezmialem Vakif University, Faculty of Medicine, Department of Biochemistry, Fatih/Istanbul, Turkey;1. Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil;2. Laboratory of Nanobiotechnology, Institute of Biotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil;3. University of California Davis, Dept. of Medical Microbiology and Immunology, Davis, CA, USA;1. Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy;2. Unit of Cellular Networks and Therapeutic Targets, Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute – IRCCS, Rome, Italy;3. Applied Research on Cancer Centre (ARC-Net) and Department of Diagnostics and Public Health, University of Verona, Verona, Italy |
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| Abstract: | Induction of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) characteristics underlie the development of metastasis, chemoresistance, and tumor recurrence in breast cancer. Downregulation of cytokeratin 18 (CK18) is a critical molecular event of EMT; however, its importance in the induction of EMT and CSC features has not been defined to date. This study aimed to investigate the biological significance and underlying molecular mechanisms of CK18 in inducing EMT phenotype and stemness properties of breast cancer cells. Three breast cancer cell lines (i.e., non-metastatic MCF-7, highly metastatic MDA-MB-231, and mitoxantrone (MX)-selected resistant MCF-7/MX cells) and two CK18-knockdown stable cell clones (MCF-7-shCK18-7D and  3C) were used to determine the association between CK18 and EMT and stemness. CK18 expression was extremely low in highly metastatic, resistant, and transforming growth factor (TGF)-β1/tumor necrosis factor (TNF)-α-treated breast cancer cells with mesenchymal phenotype and increased expression of CSC markers. Depletion of CK18 promoted partial EMT and the acquisition of stemness properties in breast cancer MCF-7 cells. Mechanistically, CK18 interference in MCF-7 cells activated the Wnt/β-catenin signaling, resulting in the up-regulation of epithelial cell adhesion molecule (EpCAM). Consistently, the stemness properties and metastasis can be attenuated by further knockdown of EpCAM in CK18-depleted cells. In conclusion, downregulation of CK18 promotes partial EMT and enhances breast cancer stemness by increasing EpCAM expression partly via the Wnt/β-catenin pathway. These findings indicate that CK18 may serve as a potential treatment target for advanced breast cancer. |
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