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

• 批准号: 10649402
• 负责人: Marsha-Kay Norissa Deanna Hutchinson
• 金额: $ 5.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649402
• 关键词: ATP phosphohydrolase; ATPase Domain; Address; Antibodies; Attenuated; Binding; Biological; Cell Line; Cell Survival; Cetuximab; Complex; 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; Recurrent tumor; Role; Site; Survival Rate; Testing; Thyroid Hormone Receptor; Western Blotting; Work; advanced disease; aggressive therapy; 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

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（Oral squamous cell carcinoma，OSCC）是一种常见的恶性肿瘤。近年来，尽管 尽管我们努力了解这种疾病的病理生物学，但患者的病情只有轻微的改善。 预后放射治疗是口腔鳞状细胞癌的主要治疗方式之一，但放射抵抗导致了高放射性。 局部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， 通过诱导DNA中的致死性双链断裂（DSB）完全消灭肿瘤。充分利用 辐射的好处和改善患者的结果，对分子机制的透彻理解 抗辐射能力是必不可少的。非同源末端连接（NHEJ）是辐射的主要修复途径- 诱导DSB。放射治疗后局部失败和肿瘤复发的高发生率可能反映了 有效的修复。因此，深入了解NHEJ是如何发生的，对于开发新的策略至关重要， 增加辐射敏感性。本实验室鉴定出甲状腺激素受体相互作用蛋白13（TRIP 13） 作为一种致癌ATP酶，促进NHEJ和放射抵抗OSCC。本研究的目的是 描绘TRIP 13介导的NHEJ增强辐射抵抗力的分子机制。导频数据 显示TRIP 13磷酸化对于辐射抗性是必需的。此外，ATP酶活性的丧失， TRIP 13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ATP酶活性 TRIP 13是NHEJ中DNA-PK复合物形成所必需的，从而促进OSCC的辐射抗性。 为了验证这一假设，我们提出了以下具体目标：1）探索磷酸化的程度， TRIP 13通过诱导其ATP酶活性来促进NHEJ; 2）研究ATP酶活性在多大程度上影响NHEJ的活性。 TRIP 13的活性促进辐射抗性和3）验证pTRIP 13作为辐射的预测标志物 阻力为了实现这些目标，我们将设计转基因细胞系，以剖析 体外和体内的抗辐射性。这些目标将阐明TRIP 13背后的分子机制。 介导的辐射抗性，并将研究磷酸TRIP 13作为辐射的新的预测标志物 阻力