TGF-β1-induced CK17 enhances cancer stem cell-like properties rather than EMT in promoting cervical cancer metastasis via the ERK1/2- MZF1 signaling pathway.

Tumor metastasis remains a major obstacle for improving overall cancer survival in cervical cancer ( CC), which may be due to the existence of tumor microenvironment-related cancer stem cells ( CSCs) and epithelial-mesenchymal transition ( EMT). The mechanism underlying these processes needs to be further elucidated. Here, we report that TGF-β1, one of the key microenvironmental stimuli, can enhance CSC characteristics, facilitate the EMT, and induce CK17. Silencing CK17 expression attenuated CSC-like properties without affecting the EMT markers induced by TGF-β1, whereas forced overexpression of CK17 promoted lymphatic metastasis in vivo even without EMT inducement. Inhibitors of ERK1/2 signaling drastically decreased the induction of CK17 mediated by TGF-β1. By combined computational and experimental approaches, we identified and validated that MZF1 was a key transcription factor binding to the promoter of CK17. Taken together, these results demonstrate that CK17 induced by the TGF-β1- ERK1/2- MZF1 signaling pathway facilitates metastasis by promoting the acquisition of CSC properties rather than by inducing the EMT process in CC, suggesting that this CK17-related signaling pathway might be a suitable target for the development of therapy for CC metastasis. [ABSTRACT FROM AUTHOR]