BK Virus as a Co-Factor in Prostate Cancer

BK 病毒是前列腺癌的辅助因素

• 批准号: 7472467
• 负责人: MICHAEL J. IMPERIALE
• 金额: $ 28.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472467
• 关键词: Abnormal Cell; Animal Model; Animals; Antigens; Apoptosis; Apoptotic; Atrophic; BK Virus; Biological Assay; Biology; Bladder; Bone Marrow; Bone Marrow Transplantation; Cancerous; Cell Cycle; Cell Cycle Arrest; Cell Line; Cell Nucleus; Cells; Cloning; Cytoplasm; DNA Methyltransferase; DNA Modification Methylases; DNA replication origin; Data; Detection; Disease; Duct (organ) structure; Early Promoters; Environment; Epithelial Cells; Epithelium; Etiology; Family; Frequencies; Genes; Goals; Growth; Human; Immunocompromised Host; Incidence; Individual; Infection; Interphase Cell; Investigation; Kidney; Kidney Transplantation; Large T Antigen; Localized; Location; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular Analysis; Morbidity - disease rate; Mutation; Nucleic Acid Regulatory Sequences; Numbers; Oncogene Proteins; Oncogenic; Pathway interactions; Patients; Persons; Play; Polyomavirus; Population; Predisposition; Primates; Property; Prostate; Protein p53; Proteins; RB1 gene; Radical Prostatectomy; Reporting; Research Personnel; Retinoblastoma; Role; Sampling; Sequence Analysis; Signal Pathway; Simian virus 40; Somatomedins; Specimen; Staging; T Virus; TP53 gene; Testing; Therapeutic; Tissues; Transcription Coactivator; Transgenic Animals; Transplant Recipients; Tumor Suppressor Proteins; Urinary tract; Urinary tract infection; Vaccines; Viral; Viral Genome; Viral Physiology; Viral Tumor Antigens; Virus; Virus Replication; base; carcinogenesis; cell growth; cell transformation; early childhood; lytic replication; member; mortality; pathogen; physical state; programs; response; sialosyl-T antigen; tumor; tumor progression; viral DNA

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.

描述(申请人提供)：BK病毒(BKV)是多瘤病毒家族的成员，是人类普遍存在的病原体，几乎100%的人在儿童早期感染。在健康的个体中，该病毒建立了终生的、亚临床的尿路感染。这种病毒可以在免疫受损的人身上重新激活，特别是肾脏和骨髓移植的接受者，导致肾脏或膀胱的严重疾病。多年来已经知道，灵长类多瘤病毒BKV、JCV和SV40可以通过直接感染或在转基因动物的环境中诱发实验动物的肿瘤。灵长类病毒编码两种癌蛋白，大T抗原和小T抗原，它们破坏了细胞生长控制。最近，一些报告将BKV与各种人类癌症联系在一起，包括尿路癌症。该项目的长期目标是确定BKV是否在前列腺癌的病因中发挥作用。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，这表明干扰这些关键抑癌途径的病毒可能在前列腺癌发生的早期阶段发挥作用。BKV在正常和异常的前列腺上皮细胞中均可检测到，异常细胞中表达大T抗原。这些细胞中的大T抗原是在细胞质中发现的，而不是它的正常位置，即细胞核，这表明病毒没有进行裂解复制。此外，P53与大T抗原共定位，表明它不是肿瘤抑制因子。正常前列腺组织中大T抗原阳性率明显低于前列腺癌组织。这项建议的目的是继续对正常和癌前列腺进行病毒和关键宿主蛋白的分子分析，分析从肿瘤样本克隆的病毒株的生物学，并了解大T抗原是如何滞留在前列腺上皮细胞胞浆中的，以及细胞质大T抗原对细胞的影响。总之，这些研究将使我们能够更好地确定BKV是否在前列腺癌中发挥作用，并将促进我们对BKV生物学的理解。如果BKV在前列腺癌中发挥作用，就有可能开发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。