MiR-508-3p由p53介导表达的可能机制及其靶向CCNA2及下游信号调控卵巢癌增殖、周期及凋亡

The high rate of lethality from ovarian cancer is mainly due to the advanced stage (stage III and stage IV) of disease at the time of diagnosis. Studies revealed that miR-508-3p was down-modulated in patients of ovarian cancer with early relapse and poor prognosis. We have found that miR-508-3p can suppress the proliferation and cell cycle and promotes apoptosis of ovarian cancer cells, and the expression of miR-508-3p is associated with the genotype of TP53, but the mechanisms of these effects are not clear. Signal pathway analysis and luciferase reporter assay confirmed that miR-508-3p can directly target CCNA2. This study will focus on “MiR-508-3p is induced by p53 and regulates proliferation, cell cycle and apoptosis by targeting CCNA2 and downstream signals in ovarian cancer”. In this study, we plan to further analyze the possible mechanism that miR-508-3p is induced by p53 and the effect of miR-508-3p on ovarian cancer proliferation, cell cycle, and apoptosis, which may include targeting CCNA2 and downstream signals Rb/p27/CDKs and E2F1/caspase-3/Bcl-2 through in vitro, in vivo and retrospective clinical experiments. We will evaluate the effects of miR-508-3p on tumor growth in ovarian cancer xenografts mouse model. The results of this study will provide new mechanism of miR-508-3p on regulating tumor proliferation, cell cycle and apoptosis in ovarian cancer, and will also provide theory evidence for new indicators predicting prognosis and new therapeutic targets for ovarian cancer.

卵巢癌致死率高主要由于多数患者就诊时已属晚期。研究发现miR-508-3p表达低的患者复发时间短，预后差。课题组前期研究发现miR-508-3p可抑制卵巢癌增殖、周期，促进凋亡，且在卵巢癌细胞中的表达与TP53的基因型有关，但具体机制尚不清楚。信号通路及荧光素酶报告基因分析证实miR-508-3p可直接调控CCNA2。本课题集中在“MiR-508-3p由p53介导表达的可能机制及其靶向CCNA2及下游信号调控卵巢癌增殖、周期及凋亡”，拟通过体外实验、体内实验和临床病例资料，深入研究miR-508-3p由p53介导表达的可能机制及其通过靶向抑制CCNA2，进而调控下游Rb/p27/CDKs、E2F1/caspase-3/Bcl-2等途径，形成多重功能网络影响卵巢癌增殖、周期及凋亡，并评估miR-508-3p在体内对卵巢癌生长的影响，为筛选反映卵巢癌预后指标及小分子靶向治疗卵巢癌提供理论依据。

卵巢癌致死率高主要由于多数患者就诊时已属晚期。研究发现miR-508-3p表达低的患者复发时间短，预后差。体外实验发现在卵巢癌细胞中过表达的p53，能通过结合Drosha复合物上调miR-508-3p的表达；miR-508-3p能导致细胞周期阻滞、抑制其生长，这一过程是通过miR-508-3p直接结合CCNA2实现的。利用卵巢癌裸鼠移植瘤模型分析发现miR-508-3p能抑制裸鼠移植瘤的生长，且移植瘤组织中miR-508-3p与CCNA2的表达呈负相关。在卵巢癌患者组织中检测miR-508-3p的表达，发现miR-508-3p表达低的患者组织中CCNA2表达水平高。miR-508-3p表达低的患者，生存预后更差；CCNA2表达高的患者，生存预后更差。在此基础上课题组还发现miR-508-3p能直接结合另一分子MMP7，从而抑制MMP7的表达，抑制卵巢癌细胞迁移及侵袭。对卵巢癌患者组织标本的检测发现，miR-508-3p表达低的患者组织中MMP7表达水平高，从而验证了二者的负相关关系。本研究为揭示miR-508-3p通过多重信号通路对卵巢癌增殖、凋亡的影响及筛选反映预后的指标、开辟新的小分子治疗靶点提供理论基础。