JPH3基因在胃肠肿瘤发生发展中的作用及其表达调控和分子机制研究

Our preliminary study found that JPH3, a member of the family of key junctional membrane complex protein Junctophilin (JPH), is significantly down-regulated or silenced in gastrointestinal cancer and its protein expression level is closely related to the prognosis of the patients. Restoring JPH3 expression in gastrointestinal cancer cells can dramatically increase calcium ion concentration in cytoplasm and significantly enhance the tumor cell apoptosis under the endoplasmic reticulum stress (ER stress). Junctophilin's main function is to form the coupling membrane complex, make the plasma membrane and endoplasmic reticulum membrane keep very close and provide structure foundation for the signal transduction between the two membranes. Previous studies have found that the main signal transmission medium of Junctophilin is calcium ions (Ca2+). So far, there is no report about the relationship between JPH family genes and tumor. This project will study the expression and the expression control mechanisms of JPH3 gene, analyze the correlation of these with the clinicpathological features and explore by in vitro and in vivo experiments that whether JPH3 gene plays an important biological role in carcinogenesis and progression of gastrointestinal cancer and the molecular mechanisms especially the control of calcium ion signal pathway and ER　stresss reaction. This study will provide scientific basis for gastrointestinal cancer diagnosis and theatment based on JPH3.

我们前期研究发现Junctophilin家族成员JPH3基因在原发胃肠肿瘤组织中的表达显著下降或沉默，并与患者的预后密切相关。JPH3转染后能够明显增加胃肠肿瘤细胞中的胞浆钙离子浓度并显著促进肿瘤细胞在内质网应激状态下的凋亡。Junctophilin的主要功能是参与形成耦联膜复合体，使细胞膜和内质网保持一个非常近的距离，为细胞膜与内质网之间的信号转导提供结构基础。已有研究发现Junctophilin提供信号传导的主要介质是钙离子（Ca2+）。迄今为止，JPH家族基因与肿瘤的关系尚未见任何报道。本项目将检测JPH3在胃肠肿瘤组织中的表达及其调控机制，分析其与临床病理特征之间的关系，通过体内外实验研究JPH3在胃肠肿瘤发生发展中所起的生物学作用及其分子机制，尤其是JPH3是否主要通过调控钙离子信号通路和内质网应激反应发挥作用，为基于JPH3的胃肠肿瘤诊断和治疗提供科学依据。

胃肠肿瘤发病率高，预后差，疗效不佳，原因在于病因和发病机理还不清楚。我们发现Junctophilin家族成员JPH3在胃癌和结直肠癌组织中的表达显著下降或沉默，并与胃癌和结直肠癌患者的预后密切相关。JPH3基因转染后能够明显增加胃癌细胞MKN-28和肠癌细胞HCT116中的胞浆钙离子浓度并显著促进肿瘤细胞在内质网应激状态下calpain蛋白的活化，引起线粒体膜电位通透性的增加最终诱导线粒体凋亡，体内外实验证明其为一个新的胃肠肿瘤抑制基因。本项目在国际上首次报道了JPH家族基因与肿瘤的关系，JPH3可能是胃肠肿瘤治疗的新靶点，而JPH3甲基化状态可为肿瘤早期诊断和预后的表观遗传标志物，为基于JPH3的胃肠肿瘤诊断和治疗提供了科学依据。