Int J Biol Sci 2020; 16(4):598-610. doi:10.7150/ijbs.36407

Research Paper

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

Jing Xie1,3,4*, Li-song Lin2*, Xiao-yu Huang1,3,4*, Rui-huan Gan1,3, Lin-can Ding1, Bo-hua Su1, Yong Zhao3,5, You-guang Lu1,3✉, Da-li Zheng3✉

1. Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou 350000, China
2. Department of Oral and Maxillofacial Surgery, Affiliated First Hospital of Fujian Medical University, 20 Cha Zhong Road, Fuzhou 350005, China
3. Key laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, 88 Jiaotong Rd, Fuzhou 350004, China
4. Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou 350122, China
5. Department of pathology, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou 350000, China
* These authors contributed equally to this paper

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Citation:
Xie J, Lin Ls, Huang Xy, Gan Rh, Ding Lc, Su Bh, Zhao Y, Lu Yg, Zheng Dl. The NOTCH1-HEY1 pathway regulates self-renewal and epithelial-mesenchymal transition of salivary adenoid cystic carcinoma cells. Int J Biol Sci 2020; 16(4):598-610. doi:10.7150/ijbs.36407. Available from http://www.ijbs.com/v16p0598.htm

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Abstract

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 vitro. In addition, HEY1 enhances the tumorigenicity of SACC in vivo. 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.

Keywords: SACC, NOTCH1, HEY1, cancer stem cells, proliferation, invasion, EMT