NF-κB over-activation portends improved outcomes in HPV-associated head and neck cancer.
NF-κB over-activation portends improved outcomes in HPV-associated head and neck cancer.
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DOI：
10.18632/oncotarget.28232
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Issaeva, Natalia
中科院分区：
文献类型：
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作者：
Schrank, Travis P;Prince, Andrew C;Sathe, Tejas;Wang, Xiaowei;Liu, Xinyi;Alzhanov, Damir T;Burtness, Barbara;Baldwin, Albert S;Yarbrough, Wendell G;Issaeva, Natalia
对头颈鳞状细胞癌 (HNSCC) 的了解不断发展，导致更具体的诊断疾病分类。在由人乳头瘤病毒 (HPV) 引起的 HNSCC 中，含有 TRAF3 或 CYLD 缺陷的肿瘤与临床结果的改善和游离型 HPV 的维持相关。 TRAF3 和 CYLD 是 NF-κB 的负调节因子，其中任一者的失活突变都会导致 NF-κB 过度活跃。在这里，我们开发并验证了一种基于 NF-κB 活性分离 HPV+ HNSCC 的基因表达分类器。正如预期的那样，新型分类器在 NF-κB 靶标中大量富集，因此我们将其命名为 NF-κB 活性分类器 (NAC)。在两个独立队列中，高 NF-κB 活性与生存率改善相关。使用 NAC，鉴定出具有高 NF-κB 活性但缺乏 TRAF3 或 CYLD 缺陷的肿瘤；因此，虽然 TRAF3 或 CYLD 基因缺陷识别出大多数具有 NF-κB 激活的肿瘤，但导致 NF-κB 活性的未知机制也存在。 NAC 正确分类了两种新型 CYLD 错义突变的功能后果。使用报告基因检测，我们测试了这些 CYLD 突变，结果表明它们抑制 NF-kB 的活性与野生型蛋白相当。 NF-κB 活性分类器的未来应用可能是识别 HPV+ HNSCC 患者的生存情况更好或更差，并对治疗策略产生影响。
Evolving understanding of head and neck squamous cell carcinoma (HNSCC) is leading to more specific diagnostic disease classifications. Among HNSCC caused by the human papilloma virus (HPV), tumors harboring defects in TRAF3 or CYLD are associated with improved clinical outcomes and maintenance of episomal HPV. TRAF3 and CYLD are negative regulators of NF-κB and inactivating mutations of either leads to NF-κB overactivity. Here, we developed and validated a gene expression classifier separating HPV+ HNSCCs based on NF-κB activity. As expected, the novel classifier is strongly enriched in NF-κB targets leading us to name it the NF-κB Activity Classifier (NAC). High NF-κB activity correlated with improved survival in two independent cohorts. Using NAC, tumors with high NF-κB activity but lacking defects in TRAF3 or CYLD were identified; thus, while TRAF3 or CYLD gene defects identify the majority of tumors with NF-κB activation, unknown mechanisms leading to NF-kB activity also exist. The NAC correctly classified the functional consequences of two novel CYLD missense mutations. Using a reporter assay, we tested these CYLD mutations revealing that their activity to inhibit NF-kB was equivalent to the wild-type protein. Future applications of the NF-κB Activity Classifier may be to identify HPV+ HNSCC patients with better or worse survival with implications for treatment strategies.