胃癌中SHCBP1通过中间体残余体调控初级纤毛发生异常的机制研究

细胞器异常是胃癌等肿瘤发生的重要原因之一。研究表明，细胞表面的初级纤毛在肿瘤发生过程中出现异常丢失，是抑制肿瘤生长的细胞器。然而，初级纤毛丢失及其调控胃癌发生的机制仍不清楚。在正常细胞中，初级纤毛的发生依赖一种特殊细胞器——中间体残余体。中间体残余体通过与中心体的结合启动初级纤毛的发生，随后引起中间体残余体的降解。申请人前期研究发现，癌基因SHCBP1可定位于胃癌细胞初级纤毛及中间体残余体，敲除SHCBP1可恢复初级纤毛的发生、促进中间体残余体的降解。基于此推测：SHCBP1可通过影响中间体残余体与中心体的结合，进而抑制初级纤毛的生长并促进胃癌的发生。本项目拟以胃癌细胞和肿瘤类器官为模型，采用荧光融合蛋白示踪、高内涵活细胞成像和透射电子显微镜等技术，探究SHCBP1通过中间体残余体调控初级纤毛发生的机制，以阐明初级纤毛丢失与胃癌发生的关系，为胃癌发生机制研究提供新的理论依据。

Organelle abnormality is one of the important causes of gastric cancer and other tumors. It has been found that primary cilium, a tumor suppressor organelle, is degenerated in cancer tissues. However, the precise mechanisms of primary cilia in gastric tumorigenesis have not been fully elucidated. In non-cancer cells, the ciliogenesis is always dependent on another special organelle, midbody remnant, which contributes to cilia formation by interacting with centrosome, and then the midbody remnant is degraded. We have previously found that oncogenic SHCBP1 is localized in the primary cilium and midbody remnant, and knockout SHCBP1 restores the primary cilium and promotes the degradation of the midbody remnant in gastric cancer cells. Therefore, we hypothesize that SHCBP1 regulates abnormal interactions of midbody remnant and centrosome is responsible for primary cilia degeneration in gastric tumorigenesis. Using fluorescent fusion protein tracing, living cell imaging and transmission electron microscopy, we intend to investigate how SHCBP1 regulates ciliogenesis through midbody remnant and the precise role of primary cilium degeneration in gastric carcinogenesis, which will provide a new theoretical explanation for gastric tumorigenesis.