MiR-9 modulates and predicts the response to radiotherapy and EGFR-inhibition in HNSCC

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.

放射治疗（Radiotherapy, RT）联合抗表皮生长因子受体（EGFR）单克隆抗体西妥昔单抗（Cetuximab, CTX）是针对部分头颈部鳞状细胞癌（Head and Neck Squamous Cell Carcinoma, HNSCC）患者的有效联合治疗方案。然而目前仍缺乏疗效预测标志物，导致诸多患者接受该治疗后疗效欠佳，并承受不必要的毒副反应。本研究证实，EGFR激活可上调微小RNA-9（miR-9）的表达，该miR-9可维持头颈部鳞状细胞癌细胞的侵袭性，并拮抗放射治疗诱导的细胞死亡。机制层面，miR-9通过靶向KLF5调控转录因子Sp1的表达，而Sp1可进一步刺激肿瘤生长，并在体内外实验中赋予肿瘤细胞对RT+CTX联合治疗的耐药性。值得注意的是，高表达miR-9并不会对头颈部鳞状细胞癌细胞对顺铂的敏感性产生影响。在原发性头颈部鳞状细胞癌样本中，miR-9的表达水平与Sp1的mRNA水平呈显著正相关，且高表达miR-9可预测接受RT+CTX治疗患者的不良预后。综上，本研究发现了一条全新的信号轴，其将EGFR激活与Sp1表达相关联，可决定头颈部鳞状细胞癌患者对联合治疗的应答效果。我们认为，miR-9可作为潜在的有效生物标志物，用于筛选能够从RT+CTX联合治疗中获益的头颈部鳞状细胞癌患者。