JC病毒T抗原诱发晶状体肿瘤的分子病理学特点及发癌机理解析

John Cunningham virus (JCV) constitutes a family of polyoma viruses. Human and animal experiments indicated its close association with cacinogenesis. In our previous study, there appears lens tumor in transgenic (TG) mice induced by JCV T antigen using αA-crystallin promoter and lung carcinoma using cytokeratin 19 promoter. The alternative splicing of T antigen is of no cell specificity. Therefore, it was hypothesized that the cell specificity of JCV T antigen in the carcinogenic induction might be linked to the existence of T antigen protein and its corresponding biological functions. Here, we aim to observe the pathomolecular features of the lens tumorigenesis and subsequent progression in TG mice. The changes in cytobiological phenotypes of primarily-cultured lens epithelial and tumor cells are being measured and the related molecular mechanisms analyzed after T antigen overexpression and knockdown respectively. To clarify the cellular specificity of T antigen-induced tumorgenesis,the modulating effects of T antigen complex with other binding protein on target genes of T antigen will be explored in various cells. Additionally, the existing fragements of JCV T antigen and their biological functions will be explored in all-mentioned cells. The study will enrich the molecular mechanisms of T antigen- induced oncogenesis by insertion into genome and correct expression. The clarification of target proteins, genes and related pathways will be helpful to screen the anti-tumor agents and monitor the gene target therapy using the TG spotaneous tumor model of T antigen.

JC病毒(JCV)是多瘤病毒家族成员，人体和动物实验证明其与肿瘤发生关系密切。我们发现JCV T抗原在αA晶体蛋白或细胞角蛋白19启动子引导下分别诱发出自发晶状体肿瘤和肺肿瘤，T抗原选择性剪接没有细胞特异性，推测JCV T抗原嵌入基因组诱发肿瘤细胞特异性与其蛋白存在状态和功能有关。本项目拟揭示JCV T抗原诱发晶状体肿瘤发生、发展的分子病理学特点，观察JCV T抗原表达改变对晶状体上皮和肿瘤细胞生物学表型的影响及分子机制，探讨不同类型细胞中JCV T抗原与靶蛋白结合以及复合物对靶基因表达的调控作用，再分析不同类型细胞中JCV T抗原蛋白存在状态及生物学功能，进而阐明JCV T抗原诱发肿瘤细胞特异性的分子机理。本项目将深化JCV T抗原基因组嵌入诱发肿瘤发生的分子机制，T抗原作用靶蛋白、调控基因及相关信号传导途径的阐明，将有助于本转基因自发肿瘤模型在抗癌药物筛选和肿瘤靶向基因治疗监中的应用。

JC 病毒(JCV)是多瘤病毒家族成员，人体和动物实验证明其与肿瘤发生关系密切。本项目从 JCV T 抗原诱发晶状体自发肿瘤转基因动物模型入手，研究其发生和演进的分子病理学特点，阐明 JCV T抗原致癌分子机理，揭示 JCV T 抗原与大分子相互作用以及蛋白存在的细胞特异性。 为研究 JCV相关肿瘤的分子病理学特点及T抗原致癌分子机理提供了一个转基因动物操作技术平台。本转基因动物模型中T抗原作用靶蛋白和调控靶基因的阐明，将有助于本自发肿瘤转基因动物模型用于抗肿瘤药物筛选和基因治疗监控，可避免环境致癌物所造模型对抗肿瘤药物筛查的影响，具有操作简单、方便和快捷的特点。