在头颈鳞状细胞癌（HNSCC）中，降低卡钙蛋白与预后不良和低生存率有关。卡钙蛋白（S100A8/A9）抑制癌细胞迁移和侵袭，并促进G2/M细胞周期停滞。我们研究了S100A8/A9是否调节了化疗放疗后HNSCC中的DNA损伤反应（DDR）和细胞凋亡。我们分析了TCGA中人类HNSCC案例中S100A8/A9与凋亡相关基因表达之间的关系。接着，将表达S100A8/A9和不表达S100A8/A9的癌肿细胞系（两种不同的系）暴露于基因毒性剂，并评估53BP1和γH2AX的表达以及活/死细胞的百分比。最后，用4-NQO处理S100A8/A9野生型和S100A8/A9null C57BL/6j小鼠，以诱导口腔发育不良和癌瘤病变，并比较53BP1水平。 在S100A8/A9高表达的HNSCC肿瘤中，基于TCGA分析，凋亡相关caspase家族成员基因上调，而限制凋亡的基因下调显著。在X-射线照射或紫杉醇处理后，表达S100A8/A9的癌肿细胞（即TR146和KB-S100A8/A9）显示出明显较高的53BP1和γH2AX表达、DNA断裂、死亡比例，以及对顺铂的更大敏感性，而野生型KB或TR146-S100A8/A9-KD细胞则不然。有趣的是，KB-S100A8/A9Δ113-114细胞显示出与S100A8/A9阴性KB和KB-EGFP细胞类似的53BP1和γH2AX水平。在4-NQO处理后，口腔病变中的53BP1表达在卡钙蛋白+/+小鼠中显著大于S100A8/A9null小鼠。在HNSCC细胞中，细胞内卡钙蛋白强烈暗示能增强DDR并促进对基因毒性剂的细胞凋亡。因此，具有S100A8/A9高表达的HNSCC患者可能会遇到更有利的疗效，因为更多的肿瘤细胞进入凋亡，并对化疗放疗治疗更敏感。 Copyright © 2022. Elsevier Ltd. 发布

In head and neck squamous cell carcinoma (HNSCC), poor prognosis and low survival rates are associated with downregulated calprotectin. Calprotectin (S100A8/A9) inhibits cancer cell migration and invasion and facilitates G2/M cell cycle arrest. We investigated whether S100A8/A9 regulates DNA damage responses (DDR) and apoptosis in HNSCC after chemoradiation.Human HNSCC cases in TCGA were analyzed for relationships between S100A8/A9 and expression of apoptosis-related genes. Next, S100A8/A9-expressing and non-expressing carcinoma lines (two different lineages) were exposed to genotoxic agents and assessed for 53BP1 and γH2AX expression and percent of viable/dead cells. Finally, S100A8/A9-wild-type and S100A8/A9null C57BL/6j mice were treated with 4-NQO to induce oral dysplastic and carcinomatous lesions, which were compared for levels of 53BP1.In S100A8/A9-high HNSCC tumors, apoptosis-related caspase family member genes were upregulated, whereas genes limiting apoptosis were significantly downregulated based on TCGA analyses. After X-irradiation or camptothecin treatment, S100A8/A9-expressing carcinoma cells (i.e., TR146 and KB-S100A8/A9) showed significantly higher 53BP1 and γH2AX expression, DNA fragmentation, proportions of dead cells, and greater sensitivity to cisplatin than wild-type KB or TR146-S100A8/A9-KD cells. Interestingly, KB-S100A8/A9Δ113-114 cells showed similar 53BP1 and γH2AX levels to S100A8/A9-negative KB and KB-EGFP cells. After 4-NQO treatment, 53BP1 expression in oral lesions was significantly greater in calprotectin+/+ than S100A8/A9null mice.In HNSCC cells, intracellular calprotectin is strongly suggested to potentiate DDR and promote apoptosis in response to genotoxic agents. Hence, patients with S100A8/A9-high HNSCC may encounter more favorable outcomes because more tumor cells enter apoptosis with increased sensitivity to chemoradiation therapy.Copyright © 2022. Published by Elsevier Ltd.