Radiotherapy (RT) plus the anti-EGFR monoclonal antibody Cetuximab (CTX) is an effective combination therapy for a subset of head and neck squamous cell carcinoma (HNSCC) patients. However, predictive markers of efficacy are missing, resulting in many patients treated with disappointing results and unnecessary toxicities. Here, we report that activation of EGFR upregulates miR-9 expression, which sustains the aggressiveness of HNSCC cells and protects from RT-induced cell death. Mechanistically, by targeting KLF5, miR-9 regulates the expression of the transcription factor Sp1 that, in turn, stimulates tumor growth and confers resistance to RT+CTX in vitro and in vivo. Intriguingly, high miR-9 levels have no effect on the sensitivity of HNSCC cells to cisplatin. In primary HNSCC, miR-9 expression correlated with Sp1 mRNA levels and high miR-9 expression predicted poor prognosis in patients treated with RT+CTX. Overall, we have discovered a new signaling axis linking EGFR activation to Sp1 expression that dictates the response to combination treatments in HNSCC. We propose that miR-9 may represent a valuable biomarker to select which HNSCC patients might benefit from RT+CTX therapy.

中文翻译：

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miR-9 调节和预测 HNSCC 放疗和 EGFR 抑制的反应

放射治疗 (RT)加抗 EGFR 单克隆抗体西妥昔单抗 (CTX) 是针对部分头颈鳞状细胞癌 (HNSCC) 患者的有效联合疗法。然而，疗效的预测标志物缺失，导致许多患者的治疗结果令人失望，并出现不必要的毒性。在此，我们报告 EGFR 的激活上调 miR-9 表达，从而维持 HNSCC 细胞的侵袭性并防止 RT 诱导的细胞死亡。从机制上讲，通过靶向 KLF5，miR-9 调节转录因子 Sp1 的表达，进而刺激肿瘤生长并在体外和体内赋予 RT+CTX 抗性。有趣的是，高 miR-9 水平对 HNSCC 细胞对顺铂的敏感性没有影响。在原发性 HNSCC 中，miR-9 表达与 Sp1 mRNA 水平相关，并且高 miR-9 表达预示着接受 RT+CTX 治疗的患者预后不良。总的来说，我们发现了一个将 EGFR 激活与 Sp1 表达联系起来的新信号轴，它决定了 HNSCC 联合治疗的反应。我们认为 miR-9 可能是一个有价值的生物标志物，用于选择哪些 HNSCC 患者可能从 RT+CTX 治疗中受益。