Rad50通过激活NF-κB信号通路促进卵巢癌恶性行为的分子机制研究

高级别浆液性卵巢癌（High-grade serous ovarian carcinoma，HGSOC）是预后较差的最常见卵巢恶性肿瘤。癌症基因组图谱计划（TCGA）分析发现50%以上HGSOC样本中存在DNA同源重组修复通路异常，但其异常表达的机制及生物学意义尚未阐明。课题组前期实验研究发现Rad50在HGSOC中普遍高表达，并与患者的不良预后及转移密切相关，初步功能实验结果发现Rad50促进卵巢癌细胞的增殖、侵袭，并激活NF-κB信号通路。本课题拟通过干预表达，利用体外和体内实验明确其在HGSOC中的生物学功能；利用免疫沉淀、质谱分析、GST pull-down等方法分析与其相互作用的蛋白，阐明Rad50激活NF-κB信号通路的具体分子机制；利用组织芯片，通过免疫组化分析Rad50及其相关DNA修复网络的表达情况。本研究将有助于揭示Rad50在HGSOC分子分型和靶向治疗中的应用价值。

High-grade serous ovarian carcinoma (HGSOC) is the most common with poor prognosis subtype of ovarian cancer. Abnormal DNA homologous recombinational repair (HRR) pathway was found in above 50% of HGSOC cases according to the analysis of the Cancer Genome Atlas (TCGA) and the regulatory mechanism and biological significances remain obscure. Rad50 was found to be overexpressed and associated with poor clinical prognosis and metastasis of HGSOC in our preliminary study. Rad50 could promote the proliferation and invasion of ovarian cancer cells and it was also found to activate NF-κB signaling pathway in our previous work. This study was aimed to determine the biological functions by in vitro and in vivo assays through interfering with its expression. We will analyze the proteins that could interact with Rad50 to clarify the concrete mechanism that Rad50 activates NF-κB pathway by immunoprecipitation, mass spectrometric analysis and GST pull-down assay. We will characterize the expression of Rad50 and related DNA damage and repair network of HGSOC through our tissue microarrays based immunohistochemistry staining analysis. This study is beneficial to nominate the application value of Rad50 for molecular classification and targeted treatment of HGSOC.