circSPIDR通过miR-431-5p海绵和A1CF互作调控子宫颈HPV相关腺癌进展的分子机制研究

子宫颈腺癌发生率不断上升，预后差，严重影响妇女健康，故加强对子宫颈腺癌的基础研究，寻找潜在治疗靶点，是降低子宫颈腺癌死亡率的关键。本项目通过测序和验证发现新的环状RNA circSPIDR在子宫颈HPV相关腺癌组织中特异性表达下降，结合前期扎实研究基础，拟通过多种细胞功能检测明确circSPIDR对肿瘤细胞生长和侵袭的影响；利用多种细胞模型阐释HPV18 E7对circSPIDR的调控；利用FISH、RIP、荧光素酶报告基因检测、RNA-pulldown、蛋白质谱分析、CLIP-seq等多种检测手段解析circSPIDIR分别作为miR-431-5p海绵和与A1CF互作影响下游靶分子从而调控子宫颈HPV相关腺癌进展过程的分子机制；最后通过大样本组织验证和动物实验，证实circSPIDR的潜在临床应用价值和治疗价值。本项目为探索子宫颈HPV相关腺癌具有潜在临床应用价值的治疗靶点提供新的思路。

In China, the incidence of cervical adenocarcinoma is still increasing, threatening the health of women. However, our knowledge on cervical adenocarcinoma is limited. Strengthening the basic research on cervical adenocarcinoma and elucidating its molecular mechanism to identify therapeutic targets are the key steps to reducing the incidence of cervical adenocarcinoma. HPV-associated cervical adenocarcinoma is the main subtype of cervical adenocarcinoma. Our preliminary studies have identified a novel circular RNA named circSPIDR by circRNA sequencing, which was significantly downregulated in HPV-associated cervical adenocarcinoma tissues. On the basis of our preliminary reliable studies, we will explore the functional roles of circSPIDR in HPV-associated cervical adenocarcinoma cells. Combining with CRISPR targeted knockout and knock-in cell models, the HPV18 E7 regulatory mechanisom on circSPIDR will be explored to explain why circSPIDR was downregulated in HPV-associated cervical adenocarcinoma. Combining with FISH, RIP, Luciferase reporter assay, RNA-pulldown, Protein profiling, CLIP-seq and other detection methods, the regulatory molecular mechanisms of circSPIDIR acting as a miR-431-5p sponge and interact with A1CF to affect downstream moleculars will be investigated to improve the theory of circSPIDR function. Finally, large clinical tissue sample validation and animal models will be conducted to confirm the potential clinical application value and therapeutic value of the circSPIDR regulatory pathway. This project provides theoretical basis for elucidating the molecular mechanism of HPV-associated cervical adenocarcinoma, and also provides new ideas for exploring therapeutic targets with potential clinical value during the progression of HPV-associated cervical adenocarcinoma.