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

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.

• Authors: 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, Zhiyuan Zhang
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 18 Pg. 25251-63 (May 03 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26958807 (Publication Type: Journal Article)

Chemical References

• EREG protein, human
• Epiregulin
• EGFR protein, human
• ErbB Receptors

Topics

• Animals
• Carcinoma, Adenoid Cystic (metabolism, secondary)
• Cell Line, Tumor
• Epiregulin (metabolism)
• Epithelial-Mesenchymal Transition (physiology)
• ErbB Receptors (metabolism)
• Gene Expression Regulation, Neoplastic (physiology)
• Heterografts
• Humans
• Lung Neoplasms (metabolism, secondary)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Salivary Gland Neoplasms (metabolism, pathology)
• Signal Transduction (physiology)