RAB2A调控MAPK/ERK信号通路参与宫颈癌恶性进展的机制研究

宫颈癌是目前发病率最高的妇科恶性肿瘤，高危型HPV是宫颈癌的主要危险因素。然而，HPV介导的宫颈癌变过程中涉及的关键分子变化和机制仍未完全阐明。申请人在前期研究中，采用同一随访患者在不同时间点、不同恶性程度的宫颈病变配对标本，在多个组学层面探索宫颈癌恶性进展的动态规律，发现RAB2A是影响宫颈癌恶性进展的关键作用分子。基于前期测序和预实验结果，进一步提出科学假说：RAB2A通过与ERK1/2直接作用调控MAPK/ERK信号通路，参与宫颈癌恶性进展。本项目拟通过GST pulldown，Co-IP，免疫荧光等实验探索RAB2A调控MAPK/ERK信号通路参与宫颈癌恶性进展的相关机制，并利用自发成瘤的K14-HPV16转基因小鼠模型，探索ERK抑制剂在体内逆转宫颈癌恶性进展过程及其潜在机制，进而在临床标本中进行进一步验证，为宫颈癌的诊治提供新的靶点和实验室证据。

Cervical cancer is the most common gynecological tumor, and high-risk HPV is the main risk factor for cervical cancer. However, the key molecular changes and mechanisms involved in HPV-mediated cervical carcinogenesis have not been fully elucidated. In the preliminary study, the applicant used cervical cancer specimens of the same follow-up patient at different time points and different stages to explore the dynamic changes of the cervical cancer process at multiple omics levels and found that RAB2A is a key role in affecting the malignant progression of cervical cancer molecular. Based on the results of bioinformatics and preliminary experiments, a scientific hypothesis is put forward: RAB2A directly regulates the MAPK/ERK signaling pathway by interacting with ERK1/2 and participates in the development of cervical cancer. This project intends to explore the mechanism of RAB2A regulating the MAPK/ERK signaling pathway and participating in the malignant progression of cervical cancer through GST pulldown, Co-IP, immunofluorescence and other experiments. We also use the K14-HPV16 transgenic mouse model of spontaneous tumor formation to explore whether ERK inhibitors could reverse the malignant progression of cervical cancer and its underlying mechanism in vivo. This project will clarify the role and mechanism of RAB2A in the occurrence and development of cervical cancer from three levels of clinical specimens, cellular molecules and animal experiments, and provide new targets and laboratory evidence for the diagnosis and treatment of cervical cancer.