American Association for Cancer Research
10780432ccr171366-sup-182889_2_supp_4340256_cy1xgc.pdf (800.11 kB)

Figure S5 from The NOTCH4HEY1 Pathway Induces Epithelial–Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma

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journal contribution
posted on 2023-03-31, 19:40 authored by Takahito Fukusumi, Theresa W. Guo, Akihiro Sakai, Mizuo Ando, Shuling Ren, Sunny Haft, Chao Liu, Panomwat Amornphimoltham, J. Silvio Gutkind, Joseph A. Califano

Figure S5. Comparison of HNSCC CSCs marker genes between NOTCH4, HEY1 high and low groups using the TCGA data set. ALDH1 expression in si-NOTCH4 and si-HEY1 cells.


National Institute of Dental and Craniofacial Research



Purpose: Recently, several comprehensive genomic analyses demonstrated NOTCH1 and NOTCH3 mutations in head and neck squamous cell carcinoma (HNSCC) in approximately 20% of cases. Similar to other types of cancers, these studies also indicate that the NOTCH pathway is closely related to HNSCC progression. However, the role of NOTCH4 in HNSCC is less well understood.Experimental Design: We analyzed NOTCH4 pathway and downstream gene expression in the TCGA data set. To explore the functional role of NOTCH4, we performed in vitro proliferation, cisplatin viability, apoptosis, and cell-cycle assays. We also compared the relationships among NOTCH4, HEY1, and epithelial–mesenchymal transition (EMT)-related genes using the TCGA data set and in vitro assays.Results: HEY1 is specifically upregulated in HNSCC compared with normal tissues in the TCGA data set. NOTCH4 is more significantly related to HEY1 activation in HNSCC in comparison with other NOTCH receptors. NOTCH4 promotes cell proliferation, cisplatin resistance, inhibition of apoptosis, and cell-cycle dysregulation. Furthermore, NOTCH4 and HEY1 upregulation resulted in decreased E-cadherin expression and increased Vimentin, Fibronectin, TWIST1, and SOX2 expression. NOTCH4 and HEY1 expression was associated with an EMT phenotype as well as increased invasion and cell migration.Conclusions: In HNSCC, the NOTCH4–HEY1 pathway is specifically upregulated, induces proliferation and cisplatin resistance, and promotes EMT. Clin Cancer Res; 24(3); 619–33. ©2017 AACR.

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