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

摘要 主要研究者，特拉维斯施兰克博士，医学博士，博士，是一个一年级的教员在大学 来自北卡罗来纳州耳鼻喉科。他被聘为外科医生科学家，目前 有75%的时间用于研究他过去在计算生物物理学和实验方面的训练 生物化学激励并装备了他在计算领域从事独立的研究生涯 基因组学和头颈癌分子生物学。提出的研究目标是一个副产品的 PI正在努力改进基于RNA的方法，用于鉴定NRF 2活性头颈部鳞状细胞 癌（HNSCC）肿瘤。 NRF 2是细胞氧化应激反应的关键转录调节因子， 在多种癌症类型中，患者预后和放射反应较差。NRF 2的突变激活是 在8%的HPV阴性（HPV-）HNSCC中观察到。然而，我们基于RNA转录的估计表明， NRF 2在24%的HPV-HNSCC中异常激活。这项工作已经确定了非典型的NRF 2和CUL 3 与NRF 2激活相关的变体。这些变体的功能后果将是 研究（目标1）。我们还发现激素原神经降压素在NRF 2活性的HNSCC中高度表达， 没有NRF 2通路突变的肿瘤。我们的初步数据表明，前神经降压素可能激活NRF 2， 通过与KEAP 1（NRF 2稳定性的调节剂）的先前未报道的相互作用。这种新的功能， 原神经降压素将在目标2中研究。众所周知，NRF 2活性的抑制可使放射增敏 癌细胞我们还发现，在HPV相关性宫颈癌中，NRF 2靶向表达部分受到抑制， (HPV+）HNSCC肿瘤，其对辐射高度敏感。p14 ARF在HPV+中也高度表达。 HNSCC结合NRF 2，并抑制一些NRF 2靶标的反式激活。目标3将探讨假设 由于高水平的p14 ARF，NRF 2靶向抑制有助于这些肿瘤的放射敏感性。 由于以下几个原因，拟议的工作将是有影响力的：1）开发的肿瘤子分类方法 解决肿瘤RNA表达数据的不完善的临床/基因组注释的非常常见的问题，2） 将探索神经降压素的激素原形式的第一个已知/报道的信号传导作用，以及3） 与辐射反应相关的NRF 2靶点的鉴定可能提示新的治疗方法。 生物技术研究所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。的 导师委员会还在NRF 2生物学、计算基因组学、p14 ARF 和神经降压素。总的来说，导师团队之前已经培训了四名K奖获得者，包括 两个外科医生兼科学家能提供重要的职业指导

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.