HPV16整合相关外泌体circMAP3K5诱导periostin+CAF活化促进宫颈上皮内瘤变进展的作用机制

高危HPV整合诱导感染后微环境（PIM）形成是决定CIN转归的关键因素。HPV相关的成纤维细胞活化与PIM重塑明显关联，其调控机制仍不明确。预实验显示HPV16整合的CIN细胞外泌体富含circMAP3K5，可能通过吸附miR-181b-5p/181c-5p，诱导periostin+CAF活化，后者重塑ECM，可干扰CD8+T细胞向CIN募集，促进免疫抑制微环境形成。由此我们提出HPV整合相关外泌体circMAP3K5通过调控periostin+CAFs，诱导PIM免疫抑制状态的新机制。本项目利用KRT-14-HPV16小鼠和模拟HPV相关PIM的类器官模型，采用外泌体示踪、双光子荧光成像等关键技术，从多层面验证PIM中HPV16整合宫颈上皮细胞→periostin+CAF→ECM重塑→免疫抑制状态这一级联链中的信号分子、互动关系及调控机制，为临床早期预测、诊断及阻断CIN进展提供新靶点。

The post-infection microenvironment (PIM) induced by high-risk HPV integration key factor to determine the outcome of cervical intraepithelial neoplasia (CIN). HPV-related fibroblast activation is clearly related to PIM remodeling, and its regulatory mechanism is still unclear. Preliminary experiments show that HPV16 integrated CIN exosomes are rich in circMAP3K5, which can induce periostin+CAF activation by adsorbing miR-181b-5p/-181c-5p. Periostin+CAF interferes with CD8+T cell recruitment to CIN by remodeling ECM and promotes the formation of an immunosuppressive microenvironment. Therefore, we propose a new mechanism by which HPV16 integration-related exosomes circMAP3K5 adsorb miR-181b-5p/-181c-5p through sponges, activate cervical fibroblast into periostin+CAFs, and promote the formation of PIM immunosuppressive status. This study uses the KRT14-HPV16 mouse model and an organoid model that simulates HPV-related PIM, combined with some key technologies (such as SHG, multicolor immunofluorescence, et al.) to identify the signal molecules, interaction and regulatory mechanisms in the cascade chain formed by HPV16 integration→CINExo circMAP3K5→periostin+CAFs→ECM remodeling→Immunosuppressive status in the PIM, which provide scientific evidence for exploring early prediction and diagnostic marker and effective therapeutic targets of inhibiting the progression in CIN.