TY - JOUR
T1 - Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma
AU - Liu, Shuli
AU - Ye, Dongxia
AU - Xu, Dongliang
AU - Liao, Yueling
AU - Zhang, Ling
AU - Liu, Liu
AU - Yu, Wenwen
AU - Wang, Yanan
AU - He, Yue
AU - Hu, Jingzhou
AU - Guo, Wenzheng
AU - Wang, Tong
AU - Sun, Beibei
AU - Song, Hongyong
AU - Yin, Huijing
AU - Liu, Jingyi
AU - Wu, Yadi
AU - Zhu, Hanguang
AU - Zhou, Binhua P.
AU - Deng, Jiong
AU - Zhang, Zhiyuan
N1 - 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).
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
KW - EGFR
KW - EMT
KW - EREG
KW - Lung metastasis
KW - SACC
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U2 - 10.18632/oncotarget.7940
DO - 10.18632/oncotarget.7940
M3 - Article
C2 - 26958807
AN - SCOPUS:84966769727
SN - 1949-2553
VL - 7
SP - 25251
EP - 25263
JO - Oncotarget
JF - Oncotarget
IS - 18
ER -