RAD21介导的DNA损伤修复在肝细胞癌中的作用和机制

Hepatitis B virus (HBV) and alfatoxin (AF) are two major risk factors of hepatocellular carcinoma (HCC) since they induce genomic instability and promote DNA mutations. Cohesin complex mediates the segregation of replicated sister chromatids, and plays critical roles in cell proliferation, DNA damage repairing and gene transcriptional regulation. In AF-induced HCC, we have previously identified high frequency of C>A mutation in DNA binding sites of cohesin. Moreover, amplification of RAD21, a core subunit of cohesin complex, has been found in 18% HCC samples from TCGA database. Increased RAD21 levels associate with poor prognosis of HCC patients. However, the roles of RAD21 in initiation and progression of HCC remain largely unknown.In this study, we set out to analyze the association between RAD21 and multiple histopathologic properties of HCC patients, and to delineate the functions and the underlying mechanisms of RAD21 in HBV synergizes with aflatoxin induced HCC, which can deepen our understanding into HCC etiology and provide solid evidence to transform RAD21 into future clinical practice.

HBV感染和黄曲霉素暴露可通过破坏基因组稳态维持系统，提高DNA突变率来诱发肝细胞癌（HCC）。Cohesin负责姐妹染色单体连接，在细胞分裂、DNA损伤修复和基因转录中起重要作用。Cohesin核心亚基RAD21在18%的HCC样本中存在DNA扩增，且高表达量预示不良预后。在黄曲霉素诱发的HCC中，我们发现cohesin的DNA结合位点存在高频的C>A突变，但具体的功能和机制尚不明确。据此假设：RAD21扩增引起的cohesin功能异常与黄曲霉素诱导的DNA损伤协同作用，导致cohesin在基因组中结合位点发生突变，促进了HCC发生。本研究拟从RAD21突变、表达与临床病理特征相关性出发，利用肝癌细胞系和HBV/黄曲霉素诱发的小鼠肝癌模型，深入探讨RAD21在HCC发生、发展过程中的功能及机制，为阐明HBV/黄曲霉素协同致癌机理及评估RAD21在HCC诊疗中的应用价值提供实验依据。

Cohesin负责姐妹染色单体连接，在细胞分裂、DNA损伤修复和基因转录中起重要作用。我们前期研究发现Cohesin核心亚基RAD21在多种肿瘤组织中存在DNA扩增，且高表达量预示不良预后。本研究在前期工作的基础上进一步探讨了RAD21在肿瘤发生和进展中的作用和相关的分子机制。我们的研究发现DNA损伤能促使RAD21表达增高，RAD21通过介导同源重组修复调控了肿瘤细胞对DNA损伤药物的敏感性，敲降RAD21可诱导放疗抵抗的食管癌细胞恢复对放射处理的敏感性。上述研究结果将有望为RAD21高表达的肿瘤患者的精准治疗提供新靶点。此外我们还对课题实施过程中筛查发现的LHX2在食管癌中的功能及分子机制进行了深入研究，发现LHX2可通过转录调控下游靶基因，介导食管癌的恶性表型，可作为食管癌的预后评估和靶向治疗新的分子标志物。