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

• Published in: The FEBS journal 2017-09, Vol.284 (18), p.3000-3017
• Main Authors: Wu, Lanfang, Han, Lingfei, Zhou, Chenfei, Wei, Wenfei, Chen, Xiaojing, Yi, Hongyan, Wu, Xiangguang, Bai, Xiangyang, Guo, Suiqun, Yu, Yanhong, Liang, Li, Wang, Wei
• Format: Article
• Language: English
• Subjects: Adult; Animals; cancer stem cell; Cell Line, Tumor; cervical cancer metastasis; CK17; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Keratin-17 - antagonists & inhibitors; Keratin-17 - genetics; Keratin-17 - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Lymphatic Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Neoplasm Transplantation; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Promoter Regions, Genetic; Protein Binding; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; TGF‐β1; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.14162

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. We demonstrated that CK17 induced by the TGF‐β1‐ERK1/2‐MZF1 signaling pathway facilitates metastasis by promoting the acquisition of cancer stem cell properties rather than by inducing the EMT process in cervical cancer, which suggested that this CK17‐related signaling pathway might be a suitable target for the development of therapy for cervical cancer metastasis.