Autocrine Epiregulin Activates EGFR Pathway for Lung Metastasis Via EMT in Salivary Adenoid Cystic Carcinoma

Authors

Shuli Liu, Shanghai Jiao Tong University, China
Dongxia Ye, Shanghai Jiao Tong University, China
Dongliang Xu, Shanghai Jiao Tong University, China
Yueling Liao, Shanghai Jiao Tong University, China
Ling Zhang, Shanghai Jiao Tong University, China
Liu Liu, Shanghai Jiao Tong University, China
Wenwen Yu, Shanghai Jiao Tong University, China
Yanan Wang, Shanghai Jiao Tong University, China
Yue He, Shanghai Jiao Tong University, China
Jingzhou Hu, Shanghai Jiao Tong University, China
Wenzheng Guo, Shanghai Jiao Tong University, China
Tong Wang, Shanghai Jiao Tong University, China
Beibei Sun, Shanghai Jiao Tong University, China
Hongyong Song, Shanghai Jiao Tong University, China
Huijing Yin, Shanghai Jiao Tong University, China
Jingyi Liu, University of KentuckyFollow
Yadi Wu, University of KentuckyFollow
Hanguang Zhu, Shanghai Jiao Tong University, China
Binhua P. Zhou, University of KentuckyFollow
Jiong Deng, Shanghai Jiao Tong University, China
Zhiyuan Zhang, Shanghai Jiao Tong University, China

Abstract

Salivary adenoid cystic carcinoma (SACC) is characterized by invasive local growth and a high incidence of lung metastasis. Patients with lung metastasis have a poor prognosis. Treatment of metastatic SACC has been unsuccessful, largely due to a lack of specific targets for the metastatic cells. In this study, we showed that epidermal growth factor receptors (EGFR) were constitutively activated in metastatic lung subtypes of SACC cells, and that this activation was induced by autocrine expression of epiregulin (EREG), a ligand of EGFR. Autocrine EREG expression was increased in metastatic SACC-LM cells compared to that in non-metastatic parental SACC cells. Importantly, EREG-neutralizing antibody, but not normal IgG, blocked the autocrine EREG-induced EGFR phosphorylation and the migration of SACC cells, suggesting that EREG-induced EGFR activation is essential for induction of cell migration and invasion by SACC cells. Moreover, EREG-activated EGFR stabilized Snail and Slug, which promoted EMT and metastatic features in SACC cells. Of note, targeting EGFR with inhibitors significantly suppressed both the motility of SACC cells in vitro and lung metastasis in vivo. Finally, elevated EREG expression showed a strong correlation with poor prognosis in head and neck cancer. Thus, targeting the EREG-EGFR-Snail/Slug axis represents a novel strategy for the treatment of metastatic SACC even no genetic EGFR mutation.

Document Type

Article

Publication Date

3-6-2016

Notes/Citation Information

Published in Oncotarget, v. 7, no. 18, p. 25251-25263.

Licensed under a Creative Commons Attribution 3.0 License.

Digital Object Identifier (DOI)

https://doi.org/10.18632/oncotarget.7940

Funding Information

This work was supported by grants National Nature Science Foundation of China 81202132, 91129303, 81541041, 81172104, 81572759, 81572693, 81430061, 91413115, Shanghai Municipal Health Bureau 2012173, Ministry of Science and Technology No. 2013CB910901, 2015CB910403. This work was also supported by grants from NIH (CA125454 and CA188118)(to BPZ).

Repository Citation

Liu, Shuli; Ye, Dongxia; Xu, Dongliang; Liao, Yueling; Zhang, Ling; Liu, Liu; Yu, Wenwen; Wang, Yanan; He, Yue; Hu, Jingzhou; Guo, Wenzheng; Wang, Tong; Sun, Beibei; Song, Hongyong; Yin, Huijing; Liu, Jingyi; Wu, Yadi; Zhu, Hanguang; Zhou, Binhua P.; Deng, Jiong; and Zhang, Zhiyuan, "Autocrine Epiregulin Activates EGFR Pathway for Lung Metastasis Via EMT in Salivary Adenoid Cystic Carcinoma" (2016). Markey Cancer Center Faculty Publications. 64.
https://uknowledge.uky.edu/markey_facpub/64