Ephrin A4-ephrin receptor A10 signaling promotes cell migration and spheroid formation by upregulating NANOG expression in oral squamous cell carcinoma cells

• Published in: Scientific reports Vol. 11; no. 1; pp. 644 - 17
• Main Authors: Chen, Yu-Lin, Yen, Yi-Chen, Jang, Chuan-Wei, Wang, Ssu-Han, Huang, Hsin-Ting, Chen, Chung-Hsing, Hsiao, Jenn-Ren, Chang, Jang-Yang, Chen, Ya-Wen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/532/71; 631/67; 631/67/1665; 631/80; 631/80/84; 631/80/86; 692/4028; 692/4028/67; Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast cancer; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell adhesion & migration; Cell migration; Cell Movement; Cell Proliferation; DNA microarrays; Ephrin-A4 - genetics; Ephrin-A4 - metabolism; Epithelial-Mesenchymal Transition; Extracellular signal-regulated kinase; Gene expression; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Kinases; Male; Mesenchyme; Metastases; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms - genetics; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; multidisciplinary; Nanog Homeobox Protein - genetics; Nanog Homeobox Protein - metabolism; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oct-4 protein; Oral cancer; Oral squamous cell carcinoma; Prognosis; Prostate cancer; Receptors, Eph Family - genetics; Receptors, Eph Family - metabolism; Science; Science (multidisciplinary); Spheroids, Cellular - metabolism; Spheroids, Cellular - pathology; Squamous cell carcinoma; Survival; Survival Rate; Transcription factors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-80060-3

Ephrin type-A receptor 10 (EPHA10) has been implicated as a potential target for breast and prostate cancer therapy. However, its involvement in oral squamous cell carcinoma (OSCC) remains unclear. We demonstrated that EPHA10 supports in vivo tumor growth and lymphatic metastasis of OSCC cells. OSCC cell migration, epithelial mesenchymal transition (EMT), and sphere formation were found to be regulated by EPHA10, and EPHA10 was found to drive expression of some EMT- and stemness-associated transcription factors. Among EPHA10 ligands, exogenous ephrin A4 (EFNA4) induced the most OSCC cell migration and sphere formation, as well as up-regulation of SNAIL , NANOG , and OCT4 . These effects were abolished by extracellular signal-regulated kinase (ERK) inhibition and NANOG knockdown. Also, EPHA10 was required for EFNA4-induced cell migration, sphere formation, and expression of NANOG and OCT4 mRNA. Our microarray dataset revealed that EFNA4 mRNA expression was associated with expression of NANOG and OCT4 mRNA, and OSCC patients showing high co-expression of EFNA4 with NANOG or OCT4 mRNA demonstrated poor recurrence-free survival rates. Targeting forward signaling of the EFNA4-EPHA10 axis may be a promising therapeutic approach for oral malignancies, and the combination of EFNA4 mRNA and downstream gene expression may be a useful prognostic biomarker for OSCC.