The NOTCH1-HEY1 pathway regulates self-renewal and epithelial-mesenchymal transition of salivary adenoid cystic carcinoma cells

• Published in: International journal of biological sciences Vol. 16; no. 4; pp. 598 - 610
• Main Authors: Xie, Jing, Lin, Li-Song, Huang, Xiao-Yu, Gan, Rui-Huan, Ding, Lin-Can, Su, Bo-Hua, Zhao, Yong, Lu, You-Guang, Zheng, Da-Li
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 2020; Ivyspring International Publisher
• Subjects: Adenoid; Antibodies; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Blood vessels; Cancer; Carcinoma, Adenoid Cystic - genetics; Carcinoma, Adenoid Cystic - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Cell proliferation; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Experiments; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Genes; Humans; Immunohistochemistry; Medical research; Mesenchyme; Metastases; Metastasis; Notch1 protein; Proteins; Reagents; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Research Paper; Salivary Glands - drug effects; Salivary Glands - pathology; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; Therapeutic applications; Thiazolidines - pharmacology; Tumorigenicity; Tumors; United Kingdom > UK; United States > US; China; Japan; NOTCH1; HEY1; invasion; proliferation; SACC; cancer stem cells; EMT
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.36407

Our previous study demonstrated a close relationship between the NOTCH signaling pathway and salivary adenoid cystic carcinoma (SACC). Its receptor gene, NOTCH1, and its downstream gene, HES1, contribute to the proliferation, invasion and metastasis of SACC. Accumulating evidence supports HEY1 as another effector of the signaling pathway. The purpose of this study was to explore the effects of the NOTCH1-HEY1 pathway on the proliferation, invasion and metastasis of SACC cells. Our results verified that HEY1 is a specific molecular target of the NOTCH signaling pathway in SACC cells and that its expression in carcinoma is much higher than that in paracarcinoma tissues. The expression of NOTCH1 and HEY1 are positively correlated in the salivary adenoid cystic carcinoma tissues. NOTCH1 is significantly related to the activation of HEY1 in SACC, and that HEY1 reciprocally regulates NOTCH1 expression in SACC. HEY1 promotes cell proliferation and spheroid formation and inhibits cell apoptosis
. In addition, HEY1 enhances the tumorigenicity of SACC
. Furthermore, HEY1 increases cell invasion and metastasis by driving the expression of epithelial-mesenchymal transition (EMT)-related genes and MMPs. The results of this study indicate that the NOTCH1-HEY1 pathway is specifically upregulated in SACC and promotes cell proliferation, self-renewal, invasion, metastasis and the expression of EMT-related genes and MMPs. Our findings suggest that a NOTCH1-HEY1 pathway inhibitor might therefore have potential therapeutic applications in treating SACC patients by inhibiting cancer cell growth and metastasis.