JC Virus and Tumor Formation in the Human Colon

描述（由申请人提供）：本申请的假设是JC病毒（JCV）感染人胃肠道导致结肠慢性潜伏感染。 在以后的生活中，由于病毒的转录控制区（TCR）的重排，导致JCV T抗原在一些结肠上皮细胞中表达，从而发生病毒的再活化。 最初，T抗原稳定核β-连环蛋白，其允许不受调节的增殖，而不损失APC基因。 T抗原具有触发染色体不稳定性（CIN）的其他特性，这是非整倍体肿瘤的标志。 在增殖和CIN的情况下，杂合性丢失（"LOH"）事件发生在关键的肿瘤抑制基因，包括APC和p53。 该应用表明，JCV是基因组不稳定性的初始原因，该基因组不稳定性启动结肠中的多步致癌作用。 我们有数据表明，JCV DNA存在于89%的结肠癌和大多数人的正常结肠组织中。 我们已经发现，来自结肠癌的JCV分离物的TCR中存在重排，而来自正常结肠的TCR中不存在重排。这些TCR在体外更具有转录活性。 我们已经开发了一种新的体外模型，使用胎儿结肠细胞系，其中JCV感染导致CIN的诱导。 我们还通过转染克隆的JCV T抗原在二倍体结肠细胞系中诱导CIN。 在本申请中，我们建议通过研究结直肠肿瘤的切除标本来严格检验JCV T抗原的表达与β-连环蛋白的稳定、APC的后期丧失和CIN的起始相关的假设。 其次，我们建议确定是否整合到人类基因组中的病毒是必要的T-抗原的表达和CIN的诱导，使用手术切除的组织和体外方法。 第三，我们建议使用我们的JCV感染的体外模型来研究永生化和转化的时间过程。 最后，我们建议测试的假设，重排的TCR的JCV提供了一种机制，使潜伏感染转化为一个活跃的，导致病毒基因的表达。 这项工作的意义是，JCV，这是普遍存在于大多数健康人的胃肠道，可能参与了CIN和结肠癌的启动。 如果这种病毒在人类致癌过程中起着机械作用，这可能会导致新的预防和治疗策略。

DESCRIPTION (provided by applicant): The hypothesis of this application is that infection of the human gastrointestinal tract by JC virus (JCV) leads to a chronic, latent infection in the colon. Later in life, reactivation of the virus occurs due to a rearrangement in the transcription control region (TCR) of the virus, which leads to expression of the JCV T-antigen in some colonic epithelial cells. Initially, the T-antigen stabilizes nuclear beta-catenin, which permits unregulated proliferation, without loss of the APC gene. T-antigen has other properties that trigger chromosomal instability (CIN), which is the hallmark of aneuploid tumors. In the setting of proliferation and CIN, loss of heterozygosity ('LOH') events occurs at critical tumor suppressor genes, including APC and p53. This application suggests that JCV is the initial cause of the genomic instability that initiates multi-step carcinogenesis in the colon. We have data that JCV DNA is present in 89% of colon cancers, and in the normal colonic tissues of most people. We have found that there are rearrangements in the TCRs of JCV isolates from colon cancers that are not present in TCRs from the normal colon. These TCRs are more transcriptionally active in vitro. We have developed a novel in vitro model using a fetal colonic cell line in which infection by JCV leads to the induction of CIN. We have also induced CIN in a diploid colonic cell line by transfection of the cloned JCV T-antigen. In this application, we propose to rigorously test the hypothesis that the expression of JCV T-antigen correlates with the stabilization of beta-catenin, the later loss of APC, and the initiation of CIN by studying resected specimens of colorectal neoplasia. Second, we propose to determine whether the integration of the virus into the human genome is necessary for expression of T-antigen and the induction of CIN, using both surgically resected tissues and in vitro approaches. Third, we propose to use our in vitro models of JCV infection to study the time course of immortalization and transformation. Finally, we propose to test the hypothesis that rearrangements in the TCR of JCV provide a mechanism whereby a latent infection is converted into an active one, leading to expression of the viral genes. The implication of this work is that JCV, which is commonly present in the gastrointestinal tract of the majority of healthy humans, may be involved in the initiation of CIN, and colon cancer. If this virus plays a mechanistic role in human carcinogenesis, this could lead to novel preventive and treatment strategies.