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: 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
• 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

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.

口腔鳞状细胞癌是一种常见的侵袭性癌症。近年来，尽管显著