Yu Chih-Chia, Chan Michael W Y, Lin Hon-Yi, Chiou Wen-Yen, Lin Ru-Inn, Chen Chien-An, Lee Moon-Sing, Chi Chen-Lin, Chen Liang-Cheng, Huang Li-Wen, Chew Chia-Hui, Hsu Feng-Chun, Yang Hsuan-Ju, Hung Shih-Kai
Department of Medical Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan.
Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan.
Front Oncol. 2021 Jun 23;11:647175. doi: 10.3389/fonc.2021.647175. eCollection 2021.
Predicting and overcoming radioresistance are crucial in radiation oncology, including in managing oral squamous cell carcinoma (OSCC). First, we used RNA-sequence to compare expression profiles of parent OML1 and radioresistant OML1-R OSCC cells in order to select candidate genes responsible for radiation sensitivity. We identified IRAK2, a key immune mediator of the IL-1R/TLR signaling, as a potential target in investigating radiosensitivity. In four OSCC cell lines, we observed that intrinsically low IRAK2 expression demonstrated a radioresistant phenotype (i.e., OML1-R and SCC4), and vice versa (i.e., OML1 and SCC25). Next, we overexpressed IRAK2 in low IRAK2-expression OSCC cells and knocked it down in high IRAK2-expression cells to examine changes of irradiation response. After ionizing radiation (IR) exposure, IRAK2 overexpression enhanced the radiosensitivity of radioresistant cells and synergistically suppressed OSCC cell growth both and , and vice versa. We found that IRAK2 overexpression restored and enhanced radiosensitivity by enhancing IR-induced cell killing caspase-8/3-dependent apoptosis. OSCC patients with high IRAK2 expression had better post-irradiation local control than those with low expression (i.e., 87.4% 60.0% at five years, P = 0.055), showing that IRAK2 expression was associated with post-radiation recurrence. Multivariate analysis confirmed high IRAK2 expression as an independent predictor for local control (HR, 0.11; 95% CI, 0.016 - 0.760; P = 0.025). In conclusion, IRAK2 enhances radiosensitivity, modulating caspase 8/3-medicated apoptosis, potentially playing double roles as a predictive biomarker and a novel therapeutic target in OSCC.
预测并克服放射抗性在放射肿瘤学中至关重要，在口腔鳞状细胞癌（OSCC）的治疗中亦是如此。首先，我们使用RNA测序来比较亲本OML1和放射抗性OML1-R OSCC细胞的表达谱，以筛选出与放射敏感性相关的候选基因。我们鉴定出IRAK2，一种IL-1R/TLR信号传导的关键免疫介质，作为研究放射敏感性的潜在靶点。在四种OSCC细胞系中，我们观察到内源性低IRAK2表达表现出放射抗性表型（即OML1-R和SCC4），反之亦然（即OML1和SCC25）。接下来，我们在低IRAK2表达的OSCC细胞中过表达IRAK2，并在高IRAK2表达的细胞中敲低它，以检测辐射反应的变化。在电离辐射（IR）暴露后，IRAK2过表达增强了放射抗性细胞的放射敏感性，并协同抑制了OSCC细胞的生长，反之亦然。我们发现IRAK2过表达通过增强IR诱导的细胞杀伤和caspase-8/3依赖性凋亡来恢复并增强放射敏感性。IRAK2高表达的OSCC患者放疗后的局部控制情况优于低表达患者（即五年时分别为87.4%和60.0%，P = 0.055），表明IRAK2表达与放疗后复发相关。多变量分析证实高IRAK2表达是局部控制的独立预测因子（HR，0.11；95% CI，0.016 - 0.760；P = 0.025）。总之，IRAK2通过调节caspase 8/3介导的凋亡增强放射敏感性，在OSCC中可能作为预测生物标志物和新型治疗靶点发挥双重作用。
