Dissecting NF-kB pathway in HPV-associated head and neck cancer

项目总结 人乳头瘤病毒(HPV)相关性头颈部鳞状细胞癌(HNSCC)的发病率 在过去几十年里急剧增加，而且还在继续上升。尽管这场疫情的规模很大， HPV在HPV+HNSCC中的致癌机制尚未得到深入研究。相比较 对于与烟草相关的HNSCC患者，HPV+HNSCC患者的总生存率和 对治疗的反应较高，通常包括化疗和放射治疗；然而，幸存者 经常遭受治疗的毒副作用，如吞咽和言语障碍。此外, 大约25%的HPV+HNSCC患者发展为复发或转移性疾病，这些疾病的发生率有限 治疗方案。头颈肿瘤学的一个紧迫目标是降低HPV+治疗的发病率 HNSCC通过治疗降级。然而，识别预后良好的HPV+患者的生物标志物， 谁可能适合降级治疗，是缺乏的。使用三个独立的队列，我们发现 构成活性的核因子-κB(通常由核因子-κB调节因子的遗传缺陷引起，包括TRAF3和CyLD) HPV+HNSCC与生存相关，应作为预后生物标记物进行研究。我们的预赛 数据表明，肿瘤中存在过度激活的核因子-κB的患者的生存优势归因于更好的 肿瘤对治疗的反应以及两者，固有的NF-κB驱动的肿瘤特征(例如，下调 氧化应激反应的表达，NRF2靶基因)，以及不同的肿瘤微环境(例如， 肿瘤浸润性CD_4~+T细胞数量增加)，可能有助于提高对NF-κB活性的敏感性 肿瘤对辐射的影响。我们之前曾报道，TRAF3和CyLD的突变与缺乏 HPV整合，使我们假设，核因子-κB的激活可能使细胞维持HPVepisome。 由于典型的HPV致癌模型依赖于HPV的整合，我们还假设 核因子-κB的表达可能是HPV异体致癌的另一种机制的关键 维修。为了探索我们的假设，在特定的目标1中，我们将研究NF-κB信号对 人乳头瘤病毒基因表达与上体维持。在具体目标2中，我们将探讨核因子-κB的意义 人乳头瘤病毒对细胞增殖、存活和细胞转化的影响。最后，明确目标 3探讨NF-κB介导HPV+HNSCC辐射敏感性的机制。

Project summary The incidence of HPV-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) has dramatically increased over the last few decades and continues to rise. Despite the magnitude of this epidemic, mechanisms of HPV-driven carcinogenesis in HPV+ HNSCC have not been thoroughly investigated. Compared to patients with tobacco-associated HNSCC, those with HPV+ HNSCC have increased overall survival and higher response to treatment, which usually consists of chemo- and radiation therapy; however, survivors frequently suffer from treatment’s toxic side effects, such as swallowing and speech dysfunction. In addition, approximately 25% of HPV+ HNSCC patients develop recurrent or metastatic disease, for which there are limited treatment options. A pressing goal in head and neck oncology is to decrease the morbidity of therapy for HPV+ HNSCC through treatment de-escalation. However, biomarkers that identify HPV+ patients with good prognosis, who may be appropriate for de-escalation therapy, are lacking. Using three independent cohorts, we found that constitutively active NF-κB (usually arising from genetic defects in NF-κB regulators, including TRAF3 and CYLD) correlates with survival and should be explored as a prognostic biomarker in HPV+ HNSCC. Our preliminary data suggest that survival benefits of patients, whose tumors harbor overactive NF-κB, are attributed to better tumor response to therapy and that both, inherent NF-κB-driven tumor characteristics (e.g. downregulated expression of oxidative stress response, NRF2 target genes), as well as a distinct tumor microenvironment (e.g. elevated number of tumor infiltrating CD4+ T cells), may contribute to increased sensitivity of NF-κB active tumors to radiation. We previously reported that mutations in TRAF3 and CYLD were associated with a lack of HPV integration, leading us to hypothesize that NF-κB activation may enable cells to maintain HPV episomes. Since the canonical HPV carcinogenesis model depends on HPV integration, we also hypothesize that activation of NF-κB may be critical for an alternative mechanism of HPV carcinogenesis driven by HPV episomal maintenance. To explore our hypothesis, in Specific Aim 1, we will investigate the impact of NF-κB signaling on HPV gene expression and episomal maintenance. In Specific Aim 2, we will explore the significance of NF-κB pathway on cellular proliferation, survival, and cellular transformation in response to HPV. Finally, Specific Aim 3 will explore mechanisms of NF-κB mediated radiation sensitivity in HPV+ HNSCC.