circNOLC1内源性竞争miR-9/129/194-5p调控其靶基因RhoA/CDK1促进卵巢癌增殖、侵袭转移的分子机制解析

Ovarian cancer is one of the most common gynecologic cancer and the leading course of women death. Studies have shown that circRNAs could participate in the tumorigenesis and progression of cancer as a competing endogenous RNA against miRNAs and relieve their inhibition to the downstream proteins. Our previous studies showed that circNOLC1 was overexpressed in ovarian cancer tissues, circNOLC1 overexpression could induce ovarian cancer cell proliferation, migration, invasion, and reduce cell apoptosis. Bioinformatics analysis demonstrated that there were binding sites for miR-9-5p, miR-129-5p, miR-194-5p near the splice sites of circNOLC1, and miR-9-5p, miR-129-5p, miR-194-5p also inhibit RhoA/CDK1 expression through binding with the 3'UTR region of RhoA or CDK1. Therefore, we suggest that circNOLC1 may promote ovarian cancer tumorigenesis and progression through function as a competing endogenous RNA against miR-9/129/194-5p and relieve their inhibition on the target gene RhoA/CDK1. This study intends to use a variety of biological techniques and methods to comprehensive verificat this hypothesis from the histology, cytology, and animal model, and study the molecular mechanism of tumorigenesis and progression of ovarian cancer in-depth.

卵巢癌是女性生殖系统常见恶性肿瘤之一，死亡率居妇科肿瘤首位。研究表明环状RNA可作为“miRNA海绵”，竞争性抑制miRNA，解除其对下游靶蛋白的抑制，参与癌症发生和发展。我们发现circNOLC1在卵巢癌组织中高表达，卵巢癌细胞上调circNOLC1后促进细胞增殖及侵袭，抑制凋亡。生物信息学预测表明，circNOLC1剪切位点附近存在miR-9-5p、miR-129-5p、miR-194-5p结合位点，且上述三种miRNA分别结合RhoA或CDK1的3’UTR区，抑制RhoA及CDK1表达。本课题拟在前期工作基础上验证假说：circNOLC1内源性竞争结合miR-9/129/194-5p，解除其对靶基因RhoA/CDK1的抑制，进而促进卵巢癌的发生和发展。本研究拟运用多种生物学技术和方法，从组织学，细胞学，动物模型进行多角度多层次全面验证此假说，深入探讨卵巢癌发生发展的分子机制。

卵巢癌是女性生殖系统常见恶性肿瘤之一，死亡率居妇科肿瘤首位。研究表明环状RNA可作为“miRNA海绵”，竞争性抑制miRNA，解除其对下游靶蛋白的抑制，亦可与蛋白质相结合，从而参与基因表达调控并影响蛋白质的功能进而参与癌症发生和发展。因此，环状RNA (circRNA) 在肿瘤形成中的调控作用也越来越受到重视。本团队研究发现，circNOLC1在卵巢癌组织中高表达，其表达水平与卵巢癌FIGO分期、分化程度以及血清肿瘤学标记物CA125表达水平相关；卵巢癌细胞上调circNOLC1后促进细胞增殖及侵袭，抑制凋亡；沉默circNOLC1可以抑制卵巢癌细胞增殖、侵袭及迁徙，促进细胞凋亡，抑制裸鼠皮下成瘤。我们通过生物信息学预测发现circNOLC1可能通过结合ESRP1蛋白从而参与卵巢癌发生发展。进一步通过多种生物学技术和方法，从组织学，细胞学，动物模型进行多角度多层次全面验证，证实circNOLC1通过结合ESRP1并调节CDK1和RhoA表达来促进卵巢癌的发生和发展。除此之外，我们还发现了多条参与卵巢癌发生发展的非编码RNA，例如：SNORA70E、circWHSC1、circCRIM1、circCSPP1、circRhoC、circPUM1等，通过不同的作用机制参与卵巢肿瘤生长和进展。本研究的顺利实施，将丰富卵巢恶性肿瘤发生发展的理论研究，并可能为其阻断治疗提供新的靶点。