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

口腔鳞癌(OSCC)是一种常见的侵袭性癌症。近年来，尽管有显著的 在努力了解这种疾病的病理生物学后，患者的病情只有轻微改善 预后。放射治疗是口腔鳞状细胞癌的主要治疗方式之一，但放射抵抗已导致口腔鳞癌患者 局部衰竭和肿瘤复发的发生率。辐射具有令人难以置信的细胞毒性，有可能 通过诱导DNA中致命的双链断裂(DSB)来完全消灭肿瘤。充分利用 放射治疗的益处和改善患者预后，透彻了解其分子机制 抗辐射能力是至关重要的。非同源末端连接(NHEJ)是辐射损伤的主要修复途径。 诱发DSB。放射治疗后局部衰竭和肿瘤复发的高发生率可能是一个反映 高效维修。因此，敏锐地了解NHEJ是如何发生的，对于制定新的战略来应对至关重要 提高辐射敏感性。本实验室鉴定出甲状腺激素受体相互作用蛋白13(TRIP13) 作为一种致癌的ATPase，在口腔鳞癌中促进NHEJ和辐射抵抗。这项研究的目标是 阐明TRIP13介导的NHEJ增强辐射抗性的分子机制。试点数据 结果表明，TRIP13的磷酸化是辐射抗性所必需的。此外，ATPase活性的丧失 TRIP13使口腔鳞状细胞癌对辐射敏感；ATPase经常参与生物复合体的组装。 因此，这项研究的中心假设是，磷酸化诱导的ATPase活性 TRIP13是NHEJ中DNA-PK复合体形成所必需的，从而提高了口腔鳞癌的辐射抗性。 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 通过诱导其ATPase活性来促进NHEJ；2)研究ATPase在多大程度上 TRIP13活性促进辐射抗性和3)验证pTRIP13作为辐射预测标志物 抵抗。为了达到这些目标，我们将设计转基因细胞系来剖析 体外和体内的抗辐射能力。这些目标将阐明TRIP13背后的分子机制- 介导的辐射抗性，并将研究磷酸化的TRIP13作为一种新的辐射预测标志 抵抗。

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.