EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers.
EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers.
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DOI：
10.1371/journal.pbio.2006624
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发表时间：
2018-09
期刊：
影响因子：
9.8
通讯作者：
Gires O
中科院分区：
文献类型：
--
作者：
Pan M;Schinke H;Luxenburger E;Kranz G;Shakhtour J;Libl D;Huang Y;Gaber A;Pavšič M;Lenarčič B;Kitz J;Jakob M;Schwenk-Zieger S;Canis M;Hess J;Unger K;Baumeister P;Gires O
头颈部鳞状细胞癌（HNSCC）的特征在于突出的分子异质性，导致严重的治疗抗性和不良的临床结果。最近发现，上皮间质转化（EMT）的肿瘤间和肿瘤内异质性是临床预后不良的主要参数。在这里，我们探讨了HNSCC临床样本和体外模型中治疗靶点表皮生长因子受体（EGFR）和上皮分化上皮细胞粘附分子（EpCAM）的主要决定因素的表达和功能。我们描述了EGFR低/EpCAM高HNSCC患者（n = 180）的生存率改善，并为观察到的临床结果差异提供了分子基础。EGF/EGFR具有作为增殖和EMT诱导剂的浓度依赖性双重能力，其通过中央分子开关磷酸化细胞外信号调节激酶1/2（pERK 1/2）和EMT转录因子（EMT-TF）Snail、锌指E-box结合同源框1（Zeb 1）和Slug的差异活化。此外，可溶性EpCAM胞外域（EpEX）被鉴定为EGFR的配体，其激活pERK 1/2和磷酸化AKT（pAKT）并诱导EGFR依赖性增殖，但抑制EGF介导的EMT、Snail、Zeb 1和Slug激活和细胞迁移。EpEX通过竞争性调节pERK 1/2激活强度和抑制EMT-TF来实现EMT抑制，这反映在临床样品中pERK 1/2及其靶Slug的水平上。因此，pERK 1/2和/或Slug的高表达预示着HNSCC的不良结局。因此，EpEX是EGFR的配体，其诱导增殖但抵消由EGF/EGFR/pERK 1/2轴介导的EMT。因此，新出现的EGFR/EpCAM分子串扰代表了改善HNSCC的患者定制辅助治疗的有希望的靶点。头颈部鳞状细胞癌（HNSCC）的生存率很低，死亡率超过55%。影响生存的主要因素是转移瘤的形成和治疗抵抗。部分上皮-间质转化（EMT）过程中的表型变化为肿瘤细胞提供了增加的迁移、侵袭和治疗抗性。因此，了解EMT的分子机制是重要的，EMT是转移级联反应和耐药发展的中心过程。在目前的工作中，我们确定了表皮生长因子受体（EGFR）和上皮细胞粘附分子（EpCAM）之间的分子串扰作为一种新的决定因素的临床结果在HNSCCs。低水平EGFR但高水平EpCAM（EGFR低/EpCAM高）与预后良好相关，生存率高于90%，而EGFR高/EpCAM低与生存率差相关，低于10%。EGFR显示具有诱导增殖和EMT的浓度依赖性能力。EpCAM（EpEX）细胞外结构域的蛋白水解切割产生EGFR的配体，其诱导EGFR依赖性增殖但抵消EGF诱导的EMT。我们描绘了EGFR/细胞外信号调节激酶1/2（ERK 1/2）/EpCAM信号转导轴，这可能是一个有前途的HNSCC治疗靶点。
Head and neck squamous cell carcinomas (HNSCCs) are characterized by outstanding molecular heterogeneity that results in severe therapy resistance and poor clinical outcome. Inter- and intratumoral heterogeneity in epithelial-mesenchymal transition (EMT) was recently revealed as a major parameter of poor clinical outcome. Here, we addressed the expression and function of the therapeutic target epidermal growth factor receptor (EGFR) and of the major determinant of epithelial differentiation epithelial cell adhesion molecule (EpCAM) in clinical samples and in vitro models of HNSCCs. We describe improved survival of EGFRlow/EpCAMhigh HNSCC patients (n = 180) and provide a molecular basis for the observed disparities in clinical outcome. EGF/EGFR have concentration-dependent dual capacities as inducers of proliferation and EMT through differential activation of the central molecular switch phosphorylated extracellular signal–regulated kinase 1/2 (pERK1/2) and EMT transcription factors (EMT-TFs) Snail, zinc finger E-box-binding homeobox 1 (Zeb1), and Slug. Furthermore, soluble ectodomain of EpCAM (EpEX) was identified as a ligand of EGFR that activates pERK1/2 and phosphorylated AKT (pAKT) and induces EGFR-dependent proliferation but represses EGF-mediated EMT, Snail, Zeb1, and Slug activation and cell migration. EMT repression by EpEX is realized through competitive modulation of pERK1/2 activation strength and inhibition of EMT-TFs, which is reflected in levels of pERK1/2 and its target Slug in clinical samples. Accordingly, high expression of pERK1/2 and/or Slug predicted poor outcome of HNSCCs. Hence, EpEX is a ligand of EGFR that induces proliferation but counteracts EMT mediated by the EGF/EGFR/pERK1/2 axis. Therefore, the emerging EGFR/EpCAM molecular cross talk represents a promising target to improve patient-tailored adjuvant treatment of HNSCCs. Head and neck squamous cell carcinomas (HNSCCs) display poor survival, with death rates above 55%. Major factors affecting survival are metastases’ formation and therapy resistance. Phenotypic changes during partial epithelial-mesenchymal transition (EMT) provide tumor cells with increased migration, invasion, and therapy resistance. Understanding molecular mechanisms of EMT, as a central process of the metastatic cascade and the development of therapy resistance, is therefore important. In the present work, we identified molecular cross talk between epidermal growth factor receptor (EGFR) and epithelial cell adhesion molecule (EpCAM) as a novel determinant of clinical outcome in HNSCCs. Low levels of EGFR but high levels of EpCAM (EGFRlow/EpCAMhigh) were associated with favorable prognosis, with survival rates above 90%, whereas EGFRhigh/EpCAMlow correlated with poor survival, below 10%. EGFR was shown to have a concentration-dependent capacity to induce proliferation and EMT. Proteolytic cleavage of the extracellular domain of EpCAM (EpEX) produces a ligand of EGFR that induces EGFR-dependent proliferation but counteracts EGF-induced EMT. We delineate an EGFR/extracellular signal–regulated kinase 1/2 (ERK1/2)/EpCAM signaling axis that may be a promising therapeutic target for HNSCCs.
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