基于NGS的大规模挖掘早期卵巢癌预后的环状RNA分子标志物

Ovarian cancer is the leading cause of death from gynecological malignancy. Most deaths (~70%) are of patients presenting with advanced-stage, high-grade serous ovarian cancer. No reliable molecular predictors are currently available for identifying those at high risk for developing ovarian cancer.Except PARP inhibitors targeting BRCA1/2 mutations, targeted therapies are very limited in patients with ovarian cancer. .Circular RNA (or circRNA) is a type of noncoding RNA which, unlike the better known linear RNA, forms a covalently closed continuous loop, i.e., in circular RNA the 3' and 5' ends normally present in an RNA molecule have been joined together. Because circular RNAs do not have 5' or 3' ends, they are resistant to exonuclease-mediated degradation and are presumably more stable than most linear RNAs in cells. These circRNAs are enriched in different cell types and involved in gene regulation during development. Some circular RNAs have recently shown potential as prognostic markers and novel targets for cancer therapies. CircRNAs are widely involved in physiological and pathological processes, and studies have found that circRNAs can be involved in biological activities by acting as a miRNA sponge, binding RBPs, and translating peptides. So far, few studies have been performed in ovarian cancer..Our hypothesis is that CircRNAs play an important role in gene regulation during ovarian cancer progression and metastasis. To test this hypothesis, three specific aims will be implemented: 1) Large-scale discovery of circRNAs differentially expressed between ovarian tumor and normal tissues using circle-Seq; 2) Identifying a signature of circRNAs highly predictive of survival and recurrence of patients with ovarian cancer; 3) Demonstrating molecular mechanisms of circRNAs involved in ovarian cancer metastasis by functional assays of several key circRNAs. .At the completion of this project, we will identify a powerful circRNA-based expression signature that can accurately predict overall survival and recurrence of patients with ovarian cancer. Such results are highly significant and timely as the identified genomic signature will not only help clinicians in selecting the most effective treatment options for ovarian cancer, but also provide new targets for anti-cancer therapy in addition to fundamentally advancing the knowledge of circRNA in ovarian cancer progression and recurrence.

环状RNA是具有闭环结构的一类非编码RNA，表达稳定，具有组织特异性及发育阶段特异性，使它可能成为肿瘤治疗靶点和预后标志物，其独具的竞争性内源RNA特征可为药物开发提供新思路。卵巢癌是死亡率最高的妇科肿瘤，但还没有可靠的分子预测方法来鉴定病人临床结果，目前除BRCA1/2外也无特效的抗癌药物靶点。近年研究发现环状RNA参与多种生理和病理过程尤其是肿瘤的发生，但在卵巢癌发生复发的作用机制尚不清楚。基于我们的前期研究，本项目假设环状RNA参与了卵巢癌转移复发的基因调控，将通过大规模circle-Seq分析系统鉴定卵巢癌特异表达的环状RNA，获得能有效预测早期癌症病人生存期和复发的环状RNA表达谱,功能分析若干环状RNA，揭示其在癌症转移复发中的分子机制。本项目完成后，预期发展的分子预测方法能为卵巢癌病人治疗方案提供重要参考，延长病人生存期和提高生活质量，有望筛选出抗肿瘤转移复发的药物新靶点。

环状RNA是具有闭环结构的一类非编码RNA，表达稳定，具有组织特异性及发育阶段特异性，使它可能成为肿瘤治疗靶点和预后标志物，其独具的竞争性内源RNA特征可为药物开发提供新思路。卵巢癌是死亡率最高的妇科肿瘤，但还没有可靠的分子预测方法来鉴定病人临床结果，目前除BRCA1/2外也无特效的抗癌药物靶点。近年研究发现环状RNA参与多种生理和病理过程尤其是肿瘤的发生，但在卵巢癌发生复发的作用机制尚不清楚。本项目构建了一个与疾病相关的circRNA数据库（Circ2Disease），为同行进行环状RNA功能研究提供重要的生物信息资源。此外本项目通过大规模circle-Seq分析系统鉴定了卵巢癌特异表达的环状RNA，获得能有效预测早期癌症病人生存期和复发的环状RNA表达谱, 针对其中的3个环状RNA进行了深入的功能分析，揭示其在癌症发生发展及转移复发中的分子机制。其中circPLEKHM3在卵巢癌中是一个抑癌因子，通过吸附miR-9促进BRCA1、KLF4、DNAJB6的表达、同时抑制AKT1的表达，并且circPLEKHM3-miR-9-BRCA1/KLF4/ DNAJB6-AKT1轴在卵巢癌耐药中也发挥重要作用。circFBXO7也是一个抑癌分子，与miR-96-5p直接结合并抑制miR-96-5p的活性，通过miR-96-5p/MTSS1/Wnt/β-catenin信号通路调控卵巢癌的发展。另一个在卵巢癌中起抑癌作用的环状RNA分子circMETTL6与RNA Binding 蛋白NONO存在物理结合，通过RNA聚合酶II调节GDF15的转录水平，从而影响卵巢癌细胞的增殖、迁移和侵袭。本项目鉴定的这些circRNAs有望作为卵巢癌治疗和抗卵巢癌转移复发的药物新靶点和临床诊断标志物，为卵巢癌病人治疗方案提供重要参考，延长病人生存期和提高生活质量，为将来卵巢癌病人的个性化治疗打下基础。