Mechanisms Determining Dysregulation of the NRF2 Oxidative Stress Response in Head and Neck Squamous Cell Carcinoma

头颈鳞状细胞癌中 NRF2 氧化应激反应失调的机制

• 批准号: 10672189
• 负责人: Travis P. Schrank
• 金额: $ 17.4万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672189
• 关键词: Address; Binding; Biochemical; Biochemistry; Bioinformatics; Biology; Biophysics; CDKN2A gene; CUL3 gene; Cells; Classification; Clinical; Complex; DNA Sequence Alteration; Data; Development; Diagnosis; Doctor of Philosophy; Faculty; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Genomics; Goals; HPV-negative head and neck cancer; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Institution; K-Series Research Career Programs; Knowledge; Label; MDM2 gene; Machine Learning; Mediating; Mentorship; Methods; Molecular Biology; Mutation; Neurotensin; Neurotensin Receptors; North Carolina; Otolaryngology; Oxidative Stress; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Phenotype; Prognosis; Proteins; Proteomics; RNA; Radiation; Radiation Tolerance; Radiosensitization; Reading Frames; Reporting; Repression; Research; Research Personnel; Resources; Role; Scientist; Signal Transduction; Site; Somatic Mutation; Surgeon; TP53 gene; Time; Training; Transactivation; Transcriptional Activation; Treatment Failure; Universities; Variant; Vocational Guidance; Work; autocrine; biological adaptation to stress; cancer cell; cancer genomics; cancer type; career; genetic signature; genetic variant; improved; machine learning classification; member; novel; novel strategies; overexpression; programs; prohormone; radiation resistance; radiation response; targeted treatment; tool; transcription factor; translational genomics; treatment risk; tumor

ABSTRACT The principle investigator, Dr. Travis Schrank, MD, PhD, is a first-year faculty member in the University of North Carolina Department of Otolaryngology. He has been hired in a surgeon-scientist role and presently has 75% protected time for research. His past training in computational biophysics and experimental biochemistry have motivated and equipped him pursue an independent research career in computational genomics and head and neck cancer molecular biology. The presented research aims are an outgrowth of the PI's ongoing efforts to improve RNA based methods for identifying NRF2 active head and neck squamous cell carcinoma (HNSCC) tumors. NRF2 is the key transcriptional regulator of the cellular oxidative stress response, and has been related to poor patient outcome and radiation response in multiple cancer types. Mutational activation of NRF2 is observed in 8% of HPV negative (HPV-) HNSCC. However, our estimates based on RNA transcription suggest that NRF2 is aberrantly activated in 24% of HPV- HNSCC. This work has identified atypical NRF2 and CUL3 variants which are associated with NRF2 activation. The functional consequences of these variants will be investigated (Aim 1). We also find that the prohormone Neurotensin is highly expressed in NRF2 active HNSCC tumors without NRF2 pathway mutations. Our preliminary data suggest that pro-Neurotensin may activate NRF2, through a previously unreported interaction with KEAP1 (a regulator of NRF2 stability). This novel function of pro-Neurotensin will be investigated in Aim 2. Suppression of NRF2 activity is well known to radio-sensitize cancer cells. We have also identified a partially suppressed pattern of NRF2 target expression in HPV associated (HPV+) HNSCC tumors, which are highly sensitive to radiation. p14ARF is also highly expressed in HPV+ HNSCC, binds NRF2, and suppresses transactivation of some NRF2 targets. Aim 3 will explore the hypothesis that NRF2 target suppression due to high levels of p14ARF, contributes to the radio-sensitivity of these tumors. The proposed work will be impactful for several reasons, 1) the tumor subclassification method developed address the very common problem of imperfect clinical/genomic annotations of tumor RNA expression data, 2) the first known/reported signaling role for the prohormone form of Neurotensin will be explored, and 3) identification of NRF2 targets associated with radiation response may suggest novel approaches to treatment. UNC has exceptionally strong institutional expertise and resources related to cancer genomics. The mentorship committee also has key project specific expertise in NRF2 biology, computational genomics, p14ARF and Neurotensin. Collectively the mentorship team has previously trained four K award recipients and includes two surgeon-scientists who can provide critical career guidance.

抽象的 首席研究员 Travis Schrank 博士（医学博士、哲学博士）是大学一年级教员 北卡罗来纳州耳鼻喉科系。他已被聘为外科医生科学家，目前 有 75% 的受保护时间用于研究。他过去接受过计算生物物理学和实验方面的培训 生物化学激励并装备了他在计算领域追求独立的研究生涯 基因组学和头颈癌分子生物学。所提出的研究目标是以下研究的产物 PI 不断努力改进基于 RNA 的方法来识别 NRF2 活性头颈鳞状细胞 癌（HNSCC）肿瘤。 NRF2 是细胞氧化应激反应的关键转录调节因子，与 多种癌症类型的患者预后不佳和放射反应不佳。 NRF2 的突变激活是 在 8% HPV 阴性 (HPV-) HNSCC 中观察到。然而，我们基于 RNA 转录的估计表明 NRF2 在 24% 的 HPV-HNSCC 中异常激活。这项工作已鉴定出非典型 NRF2 和 CUL3 与 NRF2 激活相关的变体。这些变体的功能后果将是 进行调查（目标 1）。我们还发现激素原神经降压素在 NRF2 活跃的 HNSCC 中高表达 没有 NRF2 通路突变的肿瘤。我们的初步数据表明神经降压素原可能激活 NRF2， 通过之前未报道的与 KEAP1（NRF2 稳定性调节因子）的相互作用。这个新颖的功能 目标 2 将研究神经降压素原。众所周知，抑制 NRF2 活性可提高放射敏感性 癌细胞。我们还发现了 HPV 相关 NRF2 靶标表达的部分抑制模式。 (HPV+) HNSCC 肿瘤，对辐射高度敏感。 p14ARF 在 HPV+ 中也高表达 HNSCC 结合 NRF2，并抑制一些 NRF2 靶标的反式激活。目标 3 将探索假设 高水平的 p14ARF 导致 NRF2 靶点抑制，导致这些肿瘤的放射敏感性。 拟议的工作将产生影响有几个原因，1）开发的肿瘤亚分类方法 解决肿瘤 RNA 表达数据不完善的临床/基因组注释这一非常常见的问题，2) 将探索第一个已知/报道的神经降压素激素原形式的信号传导作用，以及 3) 与辐射反应相关的 NRF2 靶标的识别可能会提出新的治疗方法。 北卡罗来纳大学拥有与癌症基因组学相关的非常强大的机构专业知识和资源。这 指导委员会还拥有 NRF2 生物学、计算基因组学、p14ARF 等关键项目特定专业知识 和神经降压素。导师团队之前总共培训了四名 K 奖获得者，其中包括 两名可以提供关键职业指导的外科医生科学家。