Elucidating the Molecular Mechanism of TRIP13-mediated Radiation Resistance in Oral Squamous Cell Carcinoma

阐明 TRIP13 介导的口腔鳞状细胞癌放射抗性的分子机制

基本信息

批准号：
10480747
负责人：
Marsha-Kay Norissa Deanna Hutchinson
金额：
$ 5.26万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10480747
关键词：
ATP phosphohydrolase ATPase Domain Address Antibodies Attenuated Binding Biological Cell Line Cell Survival Cells Cetuximab Complex Custom DNA DNA Damage DNA-dependent protein kinase Data Disease Double Strand Break Repair Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Exposure to FDA approved Failure Genetic Engineering Goals Human Cell Line Hydrolysis Immunohistochemistry Impairment In Vitro Incidence Investigation Knowledge Laboratories Malignant Epithelial Cell Malignant Neoplasms Mediating Modality Molecular Mus Mutation Nonhomologous DNA End Joining Oncogenic Pathway interactions Patient-Focused Outcomes Patients Peptides Phosphorylation Pilot Projects Proteins RIPK1 gene Radiation Radiation Induced DNA Damage Radiation Tolerance Radiation induced double strand break Radiation therapy Radiation-Sensitizing Agents Recurrence Role Site Survival Rate Testing Thyroid Hormone Receptor Western Blotting Work advanced disease aggressive therapy base cytotoxic genetically modified cells improved in vivo insight irradiation mouth squamous cell carcinoma neoplastic cell novel novel strategies overexpression patient prognosis predictive marker radiation resistance radiation response radioresistant repaired tumor

项目摘要

Oral squamous cell carcinoma (OSCC) is a common and aggressive cancer. In recent years, despite significant effort to understand the pathobiology of the disease, there has been only marginal improvement in patient prognosis. Radiation is one of the chief treatment modalities for OSCC, but radiation resistance has led to a high incidence of locoregional failure and tumor recurrence. Radiation is incredibly cytotoxic and has the potential to completely annihilate tumors via induction of lethal double strand breaks (DSBs) in DNA. To adequately exploit the benefits of radiation and improve patient outcomes, a thorough understanding of the molecular mechanisms of radiation resistance is essential. Non-homologous end joining (NHEJ) is the main repair pathway for radiation- induced DSBs. The high incidence of locoregional failure and tumor recurrence after radiation is likely a reflection of efficient repair. Therefore, a keen understanding of how NHEJ occurs is vital to developing novel strategies to increase radiation sensitivity. Our laboratory identified thyroid hormone receptor interacting protein 13 (TRIP13) as an oncogenic ATPase that promotes NHEJ and radiation resistance in OSCC. The goal of this study is to delineate the molecular mechanism of TRIP13-mediated NHEJ that enhances radiation resistance. Pilot data show that phosphorylation of TRIP13 is essential for radioresistance. Moreover, loss of the ATPase activity of TRIP13 sensitizes OSCC to radiation; ATPases are frequently involved in assembly of biological complexes. Therefore, the central hypothesis of the proposed study is that phosphorylation-induced ATPase activity of TRIP13 is necessary for DNA-PK complex formation in NHEJ, thereby promoting radiation resistance in OSCC. To test this hypothesis, we propose the following specific aims: 1) to explore the extent to which phosphorylation of TRIP13 promotes NHEJ via induction of its ATPase activity; 2) to investigate the extent to which the ATPase activity of TRIP13 promotes radiation resistance and 3) to validate pTRIP13 as a predictive marker of radiation resistance. To address these aims, we will engineer genetically modified cell lines to dissect the mechanism of radiation resistance in vitro and in in vivo. These aims will elucidate the molecular mechanism behind TRIP13- mediated radiation resistance and will investigate phospho-TRIP13 as a novel predictive marker of radiation resistance.

口腔鳞状细胞癌（OSCC）是一种常见的侵袭性癌症。近年来，尽管显着尽管努力了解该疾病的病理学，但患者的病情仅略有改善预后。放射治疗是 OSCC 的主要治疗方式之一，但放射抵抗导致了较高的治疗率。局部区域失败和肿瘤复发的发生率。辐射具有令人难以置信的细胞毒性，并有可能通过诱导 DNA 中的致命双链断裂 (DSB) 来彻底消灭肿瘤。为充分利用放疗的好处和改善患者的治疗效果，全面了解分子机制抗辐射能力至关重要。非同源末端连接（NHEJ）是辐射修复的主要途径诱导 DSB。放疗后局部区域失败和肿瘤复发的高发生率可能是一种反映的高效修复。因此，深入了解 NHEJ 如何发生对于制定新策略至关重要增加辐射敏感性。我们的实验室鉴定出甲状腺激素受体相互作用蛋白 13 (TRIP13) 作为一种致癌 ATP 酶，可促进 OSCC 中的 NHEJ 和辐射耐受性。这项研究的目标是描述 TRIP13 介导的 NHEJ 增强辐射抗性的分子机制。试点数据表明 TRIP13 的磷酸化对于放射抗性至关重要。此外，ATP酶活性的丧失 TRIP13 使 OSCC 对辐射敏感； ATP酶经常参与生物复合物的组装。因此，本研究的中心假设是磷酸化诱导的 ATPase 活性 TRIP13 对于 NHEJ 中 DNA-PK 复合物的形成是必需的，从而促进 OSCC 的辐射耐受性。为了检验这一假设，我们提出以下具体目标：1）探索磷酸化的程度 TRIP13 通过诱导其 ATP 酶活性来促进 NHEJ； 2）研究ATP酶的作用程度 TRIP13 的活性可促进辐射抗性，3) 验证 pTRIP13 作为辐射的预测标记物反抗。为了实现这些目标，我们将设计转基因细胞系来剖析其机制体外和体内的辐射抗性。这些目标将阐明 TRIP13- 背后的分子机制介导的辐射抗性，并将研究磷酸-TRIP13作为新型辐射预测标记物反抗。