Hirofumi Omori1,2, Kuniaki Sato1, Takafumi Nakano1, Takahiro Wakasaki2, Satoshi Toh1, Kenichi Taguchi3, Takashi Nakagawa2, Muneyuki Masuda4. 1. Department of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minamiku, Fukuoka, Fukuoka, 811-1395, Japan. 2. Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, Fukuoka, 812-8582, Japan. 3. Department of Pathology, National Kyushu Cancer Center, 3-1-1 Notame, Minamiku, Fukuoka, Fukuoka, 811-1395, Japan. 4. Department of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minamiku, Fukuoka, Fukuoka, 811-1395, Japan. mmuneyuki@icloud.com.
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.
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.
Entities:
Keywords:
Cancer stem cell; Head and neck squamous cell carcinoma; KLF7; SOX2; YAP1
Authors: Hisham F Bahmad; Katia Cheaito; Reda M Chalhoub; Ola Hadadeh; Alissar Monzer; Farah Ballout; Albert El-Hajj; Deborah Mukherji; Yen-Nien Liu; Georges Daoud; Wassim Abou-Kheir Journal: Front Oncol Date: 2018-08-28 Impact factor: 6.244
Authors: Philipp Baumeister; Alessandra Hollmann; Julia Kitz; Artemis Afthonidou; Florian Simon; Julius Shakhtour; Brigitte Mack; Gisela Kranz; Darko Libl; Martin Leu; Markus A Schirmer; Martin Canis; Claus Belka; Horst Zitzelsberger; Ute Ganswindt; Julia Hess; Mark Jakob; Kristian Unger; Olivier Gires Journal: Sci Rep Date: 2018-10-01 Impact factor: 4.379