Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy, often diagnosed at advanced stages with poor survival outcomes. Homologous recombination (HR), a major DNA double-strand break (DSB) repair pathway, safeguards genomic stability via error-free repair. While HR deficiency has been well established as a driver of genomic instability and tumorigenesis in several cancer types, the role of HR in HNSCC remains relatively understudied. Methods: Here, we analyzed the expression patterns of key HR proteins in HNSCC and investigated their association with clinical parameters, DNA methylation, immune cell infiltration, and patient survival outcome. Results: Surprisingly, our results demonstrate that HR factors are consistently upregulated in HNSCC, in both HPV-positive and HPV-negative groups. Survival analysis identified many HR factors, including ATM, BRCA1, BRCA2, PALB2, LIG1, RPA1, and RPA2, as potential prognostic biomarkers for better overall survival. Interestingly, we observed a significant correlation between HR protein overexpression and immune cell infiltration in HNSCC, suggesting a potential immunomodulatory role of HR proteins. To experimentally validate this association in both HPV-positive and -negative cell lines, we showed that MRE11 and RAD51 overexpression in HNSCC cells led to increased phosphorylation of IRF3 and STAT1, indicating activation of the cGAS/STING-mediated innate immune signaling. Conclusion: Together, our findings provide a comprehensive overview of the HR pathway in HNSCC, highlighting the dual role of HR proteins in both genomic maintenance and immune regulation. The consistent upregulation of HR proteins, their association with disease progression, and potential immunogenic effects underscore their promise as diagnostic/prognostic biomarkers and therapeutic targets in HNSCC.
背景/目的：头颈部鳞状细胞癌（HNSCC）是一种侵袭性恶性肿瘤，常于晚期确诊且生存预后较差。同源重组（HR）作为DNA双链断裂（DSB）的主要修复途径，通过无差错修复机制维持基因组稳定性。尽管HR缺陷已被证实是多种癌症中基因组不稳定和肿瘤发生的重要驱动因素，但HR在HNSCC中的作用仍研究不足。方法：本研究系统分析了HNSCC中关键HR蛋白的表达模式，并探讨其与临床参数、DNA甲基化、免疫细胞浸润及患者生存结局的关联。结果：令人意外的是，我们的结果显示HR因子在HPV阳性和阴性HNSCC中均呈现一致性上调。生存分析发现ATM、BRCA1、BRCA2、PALB2、LIG1、RPA1和RPA2等多个HR因子可作为改善总生存期的潜在预后生物标志物。值得注意的是，我们观察到HR蛋白过表达与HNSCC免疫细胞浸润显著相关，提示HR蛋白可能具有免疫调节功能。通过在HPV阳性和阴性细胞系中的实验验证，我们发现HNSCC细胞中MRE11和RAD51的过表达可导致IRF3和STAT1磷酸化水平升高，表明cGAS/STING介导的先天免疫信号通路被激活。结论：本研究全面揭示了HR通路在HNSCC中的作用机制，强调了HR蛋白在基因组维持和免疫调控中的双重功能。HR蛋白的一致性上调、与疾病进展的关联及其潜在免疫原性效应，共同凸显了其作为HNSCC诊断/预后生物标志物和治疗靶标的重要价值。
肿瘤(癌症)患者之家