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FEBS J. 2017 Sep;284(18):3000-3017. doi: 10.1111/febs.14162. Epub 2017 Jul 31.

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.

Author information

1
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
2
Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.
3
Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
4
Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
5
Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Abstract

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.

KEYWORDS:

CK17; TGF-β1; cancer stem cell; cervical cancer metastasis; epithelial-mesenchymal transition

PMID:
28703907
DOI:
10.1111/febs.14162
[Indexed for MEDLINE]
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