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 DengZhiyuan Zhang

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish
Pages (from-to)25251-25263
Number of pages13
JournalOncotarget
Volume7
Issue number18
DOIs
StatePublished - May 1 2016

Bibliographical note

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).

Keywords

  • EGFR
  • EMT
  • EREG
  • Lung metastasis
  • SACC

ASJC Scopus subject areas

  • Oncology

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