Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada.
Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada.
Oral Oncol. 2024 Dec;159:107061. doi: 10.1016/j.oraloncology.2024.107061. Epub 2024 Oct 1.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide. In recent years, there has been an increase in the rate of HNSCC cases attributed to the infection of the oropharynx by the human papillomavirus (HPV). Given the significant treatment-related toxicities of the current standard of care for HPV-positive HNSCC, there is an urgent need for the development of precision patient stratification and treatment strategies to improve patients' quality of life while maintaining excellent survival rates. We have previously carried out whole genome sequencing of HPV+ HNSCC tumors that failed concurrent cisplatin and radiation treatment and discovered that MACROD2 deletion is enriched among these tumors. In the current study, we sought to investigate the mechanistic role of MACROD2 in HPV+ HNSCC treatment resistance. Our results indicate that MACROD2 depletion in HNSCC cell lines leads to increased cell viability and colony formation capacity. Interestingly, MACROD2 depletion did not alter cisplatin sensitivity but led to an increase in radiation resistance of HPV+ HNSCC cell lines. RNA sequencing and immunofluorescence microscopy demonstrated that MACROD2-depleted HPV+ HNSCC cells displayed elevated levels of hypoxia and an altered DNA damage response. Taken together, this study establishes and characterizes the role of MACROD2 in HPV+ HNSCC radioresistance. Further work is needed to validate MACROD2 as a biomarker of treatment failure and to understand how to overcome the identified molecular mechanisms of resistance.
头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症类型。近年来，由于人乳头瘤病毒（HPV）感染口咽部，HNSCC 病例的发病率有所上升。鉴于 HPV 阳性 HNSCC 目前标准治疗相关的毒性作用显著，迫切需要开发精准的患者分层和治疗策略，在保持优异生存率的同时提高患者的生活质量。我们之前对接受顺铂和放疗联合治疗失败的 HPV+ HNSCC 肿瘤进行了全基因组测序，发现这些肿瘤中 MACROD2 缺失富集。在本研究中，我们试图研究 MACROD2 在 HPV+ HNSCC 治疗耐药中的机制作用。我们的结果表明，在 HNSCC 细胞系中敲除 MACROD2 会导致细胞活力和集落形成能力增加。有趣的是，MACROD2 缺失并未改变顺铂敏感性，但导致 HPV+ HNSCC 细胞系对辐射的抵抗力增强。RNA 测序和免疫荧光显微镜显示，MACROD2 敲除的 HPV+ HNSCC 细胞显示出高水平的缺氧和改变的 DNA 损伤反应。综上所述，本研究确立并描述了 MACROD2 在 HPV+ HNSCC 放射抵抗中的作用。需要进一步的工作来验证 MACROD2 是否可以作为治疗失败的生物标志物，并了解如何克服已确定的耐药分子机制。
