Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Theranostics. 2020 Aug 25;10(23):10589-10605. doi: 10.7150/thno.47176. eCollection 2020.
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. 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 and in . 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 and . 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.
头颈部鳞状细胞癌（HNSCC）的发生被认为是由于癌基因的激活和肿瘤抑制基因的失活。在这里，我们鉴定了 EREG 基因在 HNSCC 中的一个新的致癌作用。TCGA 数据库和免疫组织化学检测分析了 EREG 在 HNSCC 组织中的表达。免疫印迹法用于鉴定 EREG 改变的 EGFR 介导的途径。在 和 中研究了 EREG 在致癌中的作用。上调的 EREG 表达预示着预后不良，并通过激活表皮生长因子受体（EGFR）信号通路触发 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 结构域 I 和 III 以及 EREG 的 N57 残基。此外，过表达 EREG 通过诱导 C-Myc 表达促进 HNSCC 致癌，并且 C-Myc 的药理学抑制挽救了 EREG 促进的 HNSCC 致癌。与其他 EGFR 配体不同，EREG 可以通过维持 EGFR-Erk 通路的激活来模拟 EGFR 突变，并且高 EREG 表达与对 EGFR 抑制剂厄洛替尼治疗的反应呈正相关。此外，敲低 EREG 降低了对厄洛替尼治疗的敏感性 。这些结果确定了 EREG-EGFR-C-Myc 途径是驱动 HNSCC 致癌的关键轴，并表明 EREG 表达可能是 HNSCC 对厄洛替尼治疗敏感性的预测功能标志物。
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