Abstract
Purpose
The clinical importance of cancer stem cells (CSCs) in head and neck squamous cell carcinoma (HNSCC) is well recognized. However, a reliable method for the detection of functioning CSC has not yet been established. We hypothesized that YAP1, a transcriptional coactivator, and SOX2, a master transcription factor of SCC, may cooperatively induce stemness through transcriptional reprogramming.
Methods
We immunohistochemically examined the expression of SOX2 and YAP1 in the CD44 variant 9 (CD44v9)-positive invasion front. A CSC-inducible module was identified through a combination of siRNAs and sphere formation assays. YAP1 and SOX2 interactions were analyzed in vitro.
Results
The triple overexpression of SOX2, YAP1, and CD44v9 was significantly associated with poor prognosis. TCGA data revealed that the CSC-inducible module, which was related to EMT and angiogenesis, was significantly correlated with poor prognosis. The KLF7 expression, representatively chosen from the module, also correlated with poor prognosis and was essential for sphere formation and CSC propagation. Sphere stress-activated YAP1 enhanced SOX2 activity.
Conclusions
The stress-triggered activation of YAP1/SOX2 transcriptionally reprograms HNSCC for the acquisition of stemness. Triple SOX2, YAP1, and CD44v9 immunostaining assays may be useful for the selection of high-risk patients with functioning CSCs, and YAP1 targeting may lead to the development of a CSC-targeting therapy.
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Abbreviations
- YAP1:
-
Yes-associated protein 1
- SOX2:
-
SRY (sex determining region Y)-box 2
- KLF:
-
Krüppel-like family of transcription factor
- OCT:
-
Octamer-binding Transcription Factor
- MMP:
-
Matrix metalloproteinase
- SLCO2A1:
-
Solute carrier organic anion transporter family, member 2A1
- SERPINB2:
-
Serpin family B member 2
- LEMD1:
-
LEM domain-containing 1
- DDX60:
-
DExD/H-box helicase 60
- BRD4:
-
Bromodomain containing 4
- TEAD:
-
TEA domain transcription factor
- FOXM1:
-
Forkhead box M1
- CYR61:
-
Cysteine-rich angiogenic inducer 61
- CTGF:
-
Connective Tissue Growth Factor
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Acknowledgements
We would like to thank J. S. Gutkind (University of California) for providing the Cal33 cells and Ms. Kimiko Baba for her excellent technical support.
Funding
We are grateful for the funding provided by the Japanese Society for the Promotion of Science (MEXT/JSPS KAKENHI Grant Number JP16K11255 to M.M., and JP16K11256 to T.W.).
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Conceptualization: HO, KS, TW, ST, MM; analysis: HO, KS, TN, KT, MM; data curation: HO, KS, TN; writing of the original draft: HO, MM; supervision: TW, ST, TN; project administration: MM; funding acquisition: TW, MM.
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All clinical samples were approved for analysis by the Ethics Committee at National Hospital Organization Kyushu Cancer Center (2015-43).
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Omori, H., Sato, K., Nakano, T. et al. Stress-triggered YAP1/SOX2 activation transcriptionally reprograms head and neck squamous cell carcinoma for the acquisition of stemness. J Cancer Res Clin Oncol 145, 2433–2444 (2019). https://doi.org/10.1007/s00432-019-02995-z
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DOI: https://doi.org/10.1007/s00432-019-02995-z