BK Virus as a Co-Factor in Prostate Cancer

描述（由申请人提供）：BK病毒（BKV）是多瘤病毒家族的一员，是一种普遍存在的人类病原体，在儿童早期感染几乎100%的大多数人群。在健康个体中，该病毒建立了终生的尿路亚临床感染。该病毒可在免疫功能低下的人，特别是接受肾脏和骨髓移植的人体内重新激活，导致肾脏或膀胱出现严重疾病。多年来，人们已经知道灵长类多瘤病毒BKV、JCV和SV40可以通过直接感染或转基因动物在实验动物中诱导肿瘤。灵长类病毒编码两种癌蛋白，大T抗原和小T抗原，它们会解除对细胞生长的控制。最近，一些报告将BKV与各种人类癌症联系起来，包括泌尿道癌症。该项目的长期目标是确定BKV是否在前列腺癌的病因学中起作用。在前列腺癌进展过程中，视网膜母细胞瘤易感性（RB1）和p53基因的突变分别很少或较晚发生，这表明一种干扰这些关键肿瘤抑制途径的病毒可能在癌变的早期阶段发挥作用。BKV在正常和异常前列腺上皮中均检测到，异常细胞中表达大T抗原。这些细胞中的大T抗原位于细胞质中，而不是其正常位置，即细胞核中，这表明病毒没有进行裂解复制。此外，p53与大T抗原共定位，表明它不作为肿瘤抑制因子。大T抗原在正常前列腺中的检出率明显低于癌性前列腺。本提案的目的是继续对正常和癌前列腺的病毒和关键宿主蛋白进行分子分析，分析从肿瘤样本中克隆的病毒株的生物学特性，并了解大T抗原如何在前列腺上皮细胞的细胞质中被隔离以及细胞质大T抗原对细胞的影响。总之，这些研究将有助于更好地确定BKV是否在前列腺癌中起作用，并将促进我们对BKV生物学的理解。如果BKV在前列腺癌中的作用存在，就有可能开发出针对该病毒的治疗方法或疫苗，从而降低这种癌症的发病率、死亡率，甚至发病率。

DESCRIPTION (provided by applicant): BK Virus (BKV), a member of the polyomavirus family, is a ubiquitous pathogen of humans, infecting virtually 100% of most populations during early childhood. In healthy individuals, the virus establishes a lifelong, subclinical infection of the urinary tract. The virus can reactivate in immunocompromised persons, particularly recipients of renal and bone marrow transplants, leading to severe disease in the kidney or urinary bladder. It has been known for many years that the primate polyomaviruses, BKV, JCV, and SV40, can induce tumors in experimental animals, either by direct infection or in the context of transgenic animals. The primate viruses encode two oncoproteins, large T antigen and small t antigen, that deregulate cell growth control. Recently, a number of reports have associated BKV with various human cancers, including those of the urinary tract. The long term goal of this project is to determine whether BKV plays a role in the etiology of prostate cancer. Mutations in the retinoblastoma susceptibility (RB1) and p53 genes occur rarely or late, respectively, during prostate cancer progression, indicating that a virus which interferes with these critical tumor suppressor pathways may play a role during the early stages of carcinogenesis. BKV has been detected in normal and abnormal prostate epithelium, and large T antigen is expressed in the abnormal cells. The large T antigen in these cells is found in the cytoplasm rather than its normal location, the nucleus, indicating that the virus is not undergoing lytic replication. Moreover, p53 co-localizes with large T antigen, indicating that it is not functioning as a tumor suppressor. The frequency of detection of large T antigen in normal prostates is significantly lower than that in cancerous prostates. The aims of this proposal are to continue a molecular analysis of both normal and cancerous prostates with respect to the virus and key host proteins, to analyze the biology of virus strains cloned from tumor samples, and to understand how large T antigen is sequestered in the cytoplasm of prostate epithelial cells and the effects of cytoplasmic large T antigen on the cell. Together these studies will allow a better determination of whether BKV plays a role in prostate cancer and will advance our understanding of the biology of BKV. If a role for BKV in prostate cancer exists, there is the possibility of developing therapeutics or vaccines that are specific for the virus, thereby reducing the morbidity, mortality, and even the incidence of this cancer.