染色体拷贝数异常是驱动癌症发生与化疗耐药的主要原因之一。卵巢癌具有低基因突变率而高拷贝数变异的遗传特性，提示拷贝数异常是驱动卵巢癌发生及治疗耐药的主要因素。我们前期研究发现cohesin基因RAD21存在拷贝数扩增并在卵巢癌中异常高表达，且与患者的不良预后相关；此外，RAD21高表达的细胞株对卡铂相对耐受，而敲降RAD21能抑制卵巢癌细胞增殖并使卡铂耐药细胞株恢复敏感性；全转录组测序结果显示RAD21促进MYC靶基因上调并抑制免疫相关基因及抑癌基因表达，以上结果提示RAD21可能通过cohesin复合体结合不同的转录因子促进卵巢癌发生及耐药。本项目拟在此基础上，进一步在体外和体内模型中确定RAD21对卵巢癌发生及化疗耐药的促进作用，并采用多组学手段探究其分子机理及临床相关性。本项目的完成将阐明RAD21驱动卵巢癌发生及化疗耐药的分子机制，为卵巢癌的综合诊治提供新的分子标志物及新的治疗策略。

Copy number alteration is one of the key driver events of cancer initiation and chemo-resistance. Prevalent copy number alteration with low frequent somatic mutations is a prominent feature of ovarian cancer that drives ovarian tumorigenesis. Our pilot studies indicate that highly amplified RAD21, a component of the cohesion complex, is common in ovarian cancer and its overexpression is associated with poor prognosis. Overexpression of RAD21 is positively correlated with carboplatin resistance in ovarian cancer cells. Conversely, depletion of RAD21 inhibits cell proliferation and re-sensitizes carboplatin-resistant cells. Furthermore, our transcriptome profiling data indicated that RAD21 upregulated MYC-target genes and inhibited immunity-associated genes and tumor suppressors, suggesting that RAD21 may coordinate with other co-regulators to modulate downstream genes. Here, we will further investigate the oncogenic role of RAD21 in both tumor initiation and chemo-resistance in vitro and in vivo. We will perform multi-omics profiling to unravel the molecular mechanisms underlying the downstream gene regulation by RAD21. In addition, the deduced mechanism will be correlated to the clinical relevance of RAD21 and its associated cohesion complexes. Taken together, this study would define RAD21 as a potential biomarker to predict chemo-sensitivity and provide novel therapeutic strategies for treating ovarian cancer.