ERK1/2-Nanog signaling pathway enhances CD44(+) cancer stem-like cell phenotypes and epithelial-to-mesenchymal transition in head and neck squamous cell carcinomasopen access
- Authors
- Huang, Chuang; Yoon, Changhwan; Zhou, Xiao-Hong; Zhou, Ying-Chun; Zhou, Wen-Wen; Liu, Hong; Yang, Xin; Lu, Jun; Lee, Sei Young; Huang, Kun
- Issue Date
- Apr-2020
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- CELL DEATH & DISEASE, v.11, no.4
- Journal Title
- CELL DEATH & DISEASE
- Volume
- 11
- Number
- 4
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/42849
- DOI
- 10.1038/s41419-020-2448-6
- ISSN
- 2041-4889
- Abstract
- Head and neck squamous cell carcinomas (HNSCCs) harbor a subset of cells that are CD44(+) and present with malignancy and radiotherapy resistance. As a key regulator of self-renewal, Nanog expression not only determines cell fate in pluripotent cells but also mediates tumorigenesis in cancer cells; thus, we examined the role of Nanog in CD44(+) HNSCC. Three HNSCC cell lines, tumor xenografts, and patient tumors were examined. Nanog levels were significantly higher in CD44(+) HNSCC spheroids than in CD44(-) spheroids, and further increased when grown as spheroids to enrich for CSCs. CD44(+) spheroids showed a 3.4-7.5-fold increase in migration and invasion compared with CD44(-) spheroids and were resistant to radiation therapy, which was reversed by inhibiting Nanog. Nanog knockdown also decreased spheroid formation by 66.5-68.8%. Moreover, a phosphokinase array identified upregulated ERK1/2 signaling in CD44(+) HNSCC cells compared with that in CD44(-) cells. ERK1/2 signaling was found to regulate Nanog expression, aiding tumor progression, metastasis, and radiotherapy resistance. In xenograft models, the combination of radiation and Nanog or ERK1/2 inhibition inhibited tumor growth by 75.6% and 79.1%, respectively. In lung metastasis models, CD44(+) cells injected into the tail vein of mice led to significantly more lung metastases and higher Nanog expression level compared with that by ERK1/2-knockdown CD44(+) cells. Finally, in tumor tissues, CD44 and Nanog expression levels were correlated with tumorigenesis in HNSCC patients. Thus, targeting Nanog and the ERK1/2 signaling pathway may prevent or reverse CSC phenotypes and epithelial-mesenchymal transition that drive tumor progression, metastasis, and radiotherapy resistance in HNSCC.
- Files in This Item
-
- Appears in
Collections - College of Medicine > College of Medicine > 1. Journal Articles
![qrcode](https://api.qrserver.com/v1/create-qr-code/?size=55x55&data=https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/42849)
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.