甲状腺激素受体交互子13（TRIP13）诱导三阴型乳腺癌放疗抵抗的分子机制

Triple negative breast cancer (TNBC) shows the worst prognosis among all subtypes of breast cancer. Previous data have revealed a relative radioresistance for TNBC, which is a very important cause of the high loco-regional relapse rate of TNBC. Thus, it is very urgent to identify the radioresistant subgroup of TNBC and to find some effective targeted radio-sensitizers for those patients. Several studies have showed that Thyroid Hormone Receptor Interactor 13 (TRIP13) is overexpressed in certain malignancies. One study demonstrated that overexpression of TRIP13 in squamous cell carcinoma of the head and neck (SCCHN) lead to aggressive, treatment-resistant tumors and enhanced repair of DNA damage. They also identified proteins, such as Ku70, Ku80 and DNA-PKcs, that mediate nonhomologous end joining (NHEJ), as TRIP13-binding partners, suggesting TRIP13 promote NHEJ. Recently, we found that TRIP13 was amplified and overexpressed in TNBC and the overexpression of TRIP13 in TNBC might lead to radioresistance and poor prognosis. The potential mechanisms includes: ① TRIP13 activates NHEJ to enhance DNA damage repair; ② TRIP13 promotes anti-apoptosis and stemness of TNBC via NF-κB signaling pathway. However, the exact molecular mechanisms that TRIP13 induce radioresistance in TNBC are still unclear. Therefore, this project aims to further investigate the mechanisms by which TRIP13 induce radioresistance in TNBC, using modern experimental technology, such as cell biology, orthotopic animal model, et al. We will also explore the correlation between TRIP13 and clinical characteristics of TNBC patients prospectively and retrospectively. Our study may help identify novel markers and therapeutic targets for radioresistance of TNBC, and have a potential to improve the clinical outcome of TNBC.

三阴型乳腺癌（TNBC）预后差，放疗相对抵抗是其局部区域复发率高的主要原因，如何预测其放疗敏感性并进行靶向放疗增敏是亟待解决的问题。甲状腺激素受体交互子13（TRIP13）已被证实在头颈部恶性肿瘤中可能通过参与NHEJ、促进DNA损伤修复而诱导放化疗抵抗。我们的前期研究结果显示：TRIP13在TNBC中异常高表达，高表达者对放疗相对抵抗；并且TRIP13可能通过以下机制诱导TNBC的放疗抵抗：①激活NHEJ而促进DNA损伤修复；②与TNFR1结合而激活NF-κB信号通路、进而增强肿瘤干细胞特性并抑制肿瘤细胞凋亡。然而TRIP13诱导TNBC放疗抵抗的具体分子机制尚不清楚。本研究将采用细胞生物学、原位接种动物模型等现代实验技术，更深层次解析TRIP13诱导TNBC放疗抵抗的分子机制，并结合临床，验证TRIP13可否作为TNBC放疗抵抗的新指标及放疗增敏的新靶点，从而提高TNBC的放疗疗效。

三阴型乳腺癌（TNBC）预后差，放疗相对抵抗是其局部区域复发率高的主要原因。甲状腺激素受体交互子13（TRIP13）已被证实在多种恶性肿瘤中调控放化疗抵抗。然而其在乳腺癌中调控放疗耐受的机制尚不明确。. 在临床上，我们在探究TRIP13表达水平对乳腺癌的预后及放疗敏感性时发现乳腺癌的临床病理分期可作为独立危险因素，通过数据库分析发现第8版AJCC病理预后分期能够提供更准确的分期分层并指导治疗决策。在探索TRIP13与乳腺癌21基因评分的关系时我们发现21基因复发评分可能对于不同患者的放疗决策具有一定程度的指导作用。并且乳腺癌的不同病理亚型和术前全身炎症反应等作为独立危险因素也对放疗敏感性产生一定的影响。. 本课题研究发现TRIP13在TNBC中异常高表达，并且在乳腺癌中高表达者对放疗抵抗。在项目执行期间，我们发现TRIP13除了基因座扩增，还受到转录和转录后水平的调控，并且糖基化酶α-1，3-甘露糖基转移酶（ALG3）参与到了TRIP13的糖基化过程，进而影响肿瘤坏死因子受体（TNFR1）在细胞膜上的定位。说明ALG通过调控TRIP13的糖基化程度调节TNFR1。分析乳腺癌的mRNA谱时发现ALG3与TNFR1呈正相关，说明ALG3可以作为潜在的放射敏感标志物。并在研究中发现ALG3调节TGF-β受体II的糖基化影响放疗抵抗。