Rationale: The oncogenesis of head and neck squamous cell carcinoma (HNSCC) is believed to result from oncogene activation and tumor suppressor inactivation. Here, we identified a new oncogenic role for the EREG gene in HNSCC./nMethods: The TCGA database and immunohistochemistry assay were used to analyze expression of EREG in HNSCC tissues. Immunoblotting was performed to identify the EGFR-mediated pathways altered by EREG. The role of EREG in oncogenesis was investigated in vivo and in vitro./nResults: Upregulated EREG expression predicted a poor prognosis and triggered HNSCC oncogenic transformation by activating the epidermal growth factor receptor (EGFR) signaling pathway. We also demonstrated the direct association of EREG with EGFR and that this binding required EGFR domains I and III and the N57 residue of EREG. Moreover, EREG overexpression was shown to promote HNSCC oncogenesis by inducing C-Myc expression, and the pharmacological inhibition of C-Myc rescued EREG-promoted HNSCC oncogenesis. Unlike other EGFR ligands, EREG could mimic EGFR mutations by sustaining the activation of the EGFR-Erk pathway, and high EREG expression was positively associated with the response to treatment with the EGFR inhibitor erlotinib. Furthermore, knockdown of EREG decreased sensitivity to erlotinib treatment in vitro and in vivo./nConclusions: These results identify the EREG-EGFR-C-Myc pathway as a crucial axis that drives HNSCC oncogenesis and show that EREG expression could be a predictive functional marker of sensitivity to erlotinib therapy in HNSCC.

中文翻译：

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EREG驱动的头颈部鳞状细胞癌的肿瘤发生对厄洛替尼疗法具有更高的敏感性。

原理：头颈部鳞状细胞癌（HNSCC）的癌变被认为是由癌基因激活和肿瘤抑制因子失活引起的。在这里，我们确定了EREG基因在HNSCC中的新致癌作用。/n方法：使用TCGA数据库和免疫组织化学分析法分析HNSCC组织中EREG的表达。进行了免疫印迹以鉴定由EREG改变的EGFR介导的途径。EREG的肿瘤发生中的作用进行了研究在体内和体外./n结果：EREG表达上调预示不良预后并通过激活表皮生长因子受体（EGFR）信号传导途径触发HNSCC致癌转化。我们还证明了EREG与EGFR的直接关联，并且这种结合需要EGFR域I和III和EREG的N57残基。此外，EREG过表达被证明通过诱导C-Myc表达来促进HNSCC肿瘤发生，并且C-Myc的药理抑制作用可以挽救EREG促进的HNSCC肿瘤发生。与其他EGFR配体不同，EREG可以通过维持EGFR-Erk途径的激活来模拟EGFR突变，并且高EREG表达与对EGFR抑制剂埃洛替尼的治疗反应呈正相关。此外，敲除EREG会降低体外对厄洛替尼治疗的敏感性和体内./n结论：这些结果识别EREG-EGFR-C-Myc的通路作为一个关键轴线驱动HNSCC肿瘤生成和显示，EREG的表达水平可以是敏感性的在HNSCC厄洛替尼治疗的预测性功能标记。