Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma.
Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma.
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自分泌上皮调节蛋白通过 EMT 激活唾液腺样囊性癌肺转移的 EGFR 通路
DOI：
10.18632/oncotarget.7940
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发表时间：
2016-05-03
期刊：
影响因子：
--
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Liu S;Ye D;Xu D;Liao Y;Zhang L;Liu L;Yu W;Wang Y;He Y;Hu J;Guo W;Wang T;Sun B;Song H;Yin H;Liu J;Wu Y;Zhu H;Zhou BP;Deng J;Zhang Z
涎腺腺样囊性癌（SACC）以浸润性生长和高肺转移率为特征。肺转移患者预后差。转移性SACC的治疗一直不成功，主要是由于缺乏针对转移性细胞的特异性靶点。在这项研究中，我们发现，表皮生长因子受体（EGFR）组成性激活的转移性肺亚型的SACC细胞，这种激活是诱导自分泌表达的表皮调节蛋白（EREG），EGFR的配体。与非转移性亲本SACC细胞相比，转移性SACC-LM细胞中自分泌EREG表达增加。重要的是，EREG中和抗体，而不是正常的IgG，阻断自分泌EREG诱导的EGFR磷酸化和SACC细胞的迁移，这表明EREG诱导的EGFR活化是诱导细胞迁移和SACC细胞侵袭所必需的。此外，EREG激活的EGFR稳定了Snail和Slug，这促进了SACC细胞的EMT和转移特征。值得注意的是，用抑制剂靶向EGFR显著抑制了体外SACC细胞的运动性和体内肺转移。最后，EREG表达升高与头颈癌预后不良密切相关。因此，靶向EREG-EGFR-Snail/Slug轴代表了治疗转移性SACC的新策略，即使没有基因EGFR突变。
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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影响因子：
4
作者：
Bolós, V;Peinado, H;Cano, A
通讯作者：
Cano, A
影响因子：
45.3
作者：
Heinrich, MC;Corless, CL;Fletcher, JA
通讯作者：
Fletcher, JA
影响因子：
7.6
作者：
Dong, L.;Wang, Y. X.;Wang, C. Y.
通讯作者：
Wang, C. Y.
影响因子：
11.5
作者：
Bièche, I;Lerebours, F;Lidereau, R
通讯作者：
Lidereau, R
DOI：
10.1083/jcb.127.6.2021
发表时间：
1994-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Miettinen PJ;Ebner R;Lopez AR;Derynck R
通讯作者：
Derynck R