CAV2介导的COL6A1在高尔基体上的正确加工转运在去势抵抗性前列腺癌中的作用

Treating Castration resistance prostate cancer (CRPC) is a tough work for both physicians and researchers. Previous studies demonstrated that tumor microenvironment (TME) has an important role in CRPC formation and progression. Our previous work reported that an extracellular matrix (ECM) component COL6A1 modulated by DNA methylation was upregulated in CRPC. Further study found another DNA methylation regulated gen CAV2 was also higher in CRPC. CAV2 isoform b localizes in Golgi body and take part in protein assemble and transportation. CAV2 isoform a most existed in lipid droplets and play an important role in vesicular trafficking. Thus, we hypothesis that CAV2 act like a regulator in the ECM remodeling of CRPC. Detail studies on CAV2 regulate COL6A1 assembling and vesicular trafficking could reveal the mechanisms of CRPC development and progression via ECM remodeling. Simultaneously study on exosomes, an vesicular trafficking products associated with CAV2 and find new biomarkers. This project may shed light on new methods and targets of CRPC management as well as new biomarkers which is valuable in both academic and practical interest.

去势抵抗性前列腺癌（CRPC）是前列腺癌治疗的难点和研究的热点。有证据表明CRPC的形成和肿瘤与肿瘤微环境间的相互作用密切相关。本课题组前期工作首次报道细胞外基质的胶原蛋白COL6A1在CRPC中表达上调，且其表达受DNA甲基化调控。进一步研究中发现与之共同受甲基化调控的CAV2基因在CRPC中同样高表达。CAV2的异构体a在高尔基体中参与细胞外分泌蛋白的加工和转运。CAV2异构体b参与细胞的内吞和包膜转运。据此我们提出假设，CAV2蛋白在CRPC中参与细胞外基质的重塑。本课题拟通过研究CAV2对COL6A1在细胞内的加工和转运，揭示CAV2对CRPC肿瘤微环境的作用机制及调控。同时研究CAV2参与的膜泡运输产物外泌体，筛选CRPC肿瘤标记物。本课题的实施有望揭示CRPC肿瘤微环境调控机理，为治疗CRPC提供新思路和靶点，以及预测疗效的肿瘤标记物，具有重要的科学意义和临床应用价值。

去势抵抗性前列腺癌（CRPC）是前列腺癌治疗的难点和研究的热点。有证据表明CRPC的形成和肿瘤与肿瘤微环境间的相互作用密切相关。本课题组前期工作首次报道细胞外基质的胶原蛋白COL6A1在CRPC中表达上调，且其表达受DNA甲基化调控。进一步研究中发现与之共同受甲基化调控的CAV2基因在CRPC中同样高表达。CAV2的异构体a在高尔基体中参与细胞外分泌蛋白的加工和转运。CAV2异构体b参与细胞的内吞和包膜转运。据此我们提出假设，CAV2蛋白在CRPC中参与细胞外基质的重塑。本项目主要由体外试验来研究 CAV2在 CRPC 中的作用。通过动物实验发现COL6A1对前列腺癌的增殖和转移具有一定促进作用。通过对 TCGA数据库分析发现，CAV2 和 COL6A1 的表达具有正相关的关系。通过免疫荧光的方法证实了CAV2与COL6A1在胞浆高尔基体中共定位，并且通过免疫共沉淀的方法也验证了他们在体内的相互作用。通过敲低CAV2-A和CAV2-C基因发现 CAV2 对 CRPC 的增殖及迁移起到促进作用。