Research Papers:

Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma

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

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Oncotarget. 2016; 7:25251-25263. https://doi.org/10.18632/oncotarget.7940

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Shuli Liu1,*, Dongxia Ye1,*, Dongliang Xu2,3, Yueling Liao2,3, Ling Zhang1, Liu Liu1, Wenwen Yu1, Yanan Wang1, Yue He1, Jingzhou Hu1, Wenzheng Guo2, Tong Wang2, Beibei Sun4, Hongyong Song2, Huijing Yin2, Jingyi Liu5, Yadi Wu5, Hanguang Zhu1, Binhua P. Zhou5, Jiong Deng2,3,4, Zhiyuan Zhang1

1Department of Oral and Maxillofacial–Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China

3Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China

4Translation Medicine Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China

5Department of Molecular and Cellular Biochemistry, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA

*These authors contributed equally to this work

Correspondence to:

Jiong Deng, email: [email protected]

Binhua P. Zhou, email: [email protected]

Zhiyuan Zhang, email: [email protected]

Keywords: SACC, lung metastasis, EREG, EGFR, EMT

Received: November 21, 2015     Accepted: February 11, 2016     Published: March 06, 2016


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.

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