MECHANISMS OF XMRV ONCOGENESIS IN PROSTATE CELLS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 1.假设 已知逆转录病毒科的γ逆转录病毒属感染多种哺乳动物物种，并且这些感染可导致白血病发生和其他疾病，但通常仅影响动物。最近，当在晚期前列腺癌患者组织中检测到γ逆转录病毒异嗜性小鼠白血病病毒（MLV）相关病毒（XMRV）时，提出了γ逆转录病毒真实感染人类的罕见证据。在两份独立的报告中提供的数据表明，XMRV可以感染人前列腺细胞，并强烈暗示XMRV在前列腺肿瘤发生中，尽管关于XMRV是否直接参与前列腺癌的发病机制仍存在一些差距。 因此，确定XMRV是否参与前列腺肿瘤发生，以及XMRV是否利用直接机制（感染上皮细胞）来实现其对前列腺上皮的作用至关重要。解决这些问题可能会产生前所未有的机会，开发XRMV作为前列腺癌的新诊断标志物和/或新方法，以预防和消除XMRV感染的细胞与特异性免疫增强XMRV DNA疫苗，帮助降低死亡率由于前列腺癌的发展或进展。我们的具体假设是：（1）XMRV感染非致瘤性Bph 1前列腺上皮细胞可以启动或促进肿瘤发生，（2）XMRV感染通过3' LTR反式激活机制诱导参与细胞增殖的基因表达。 2.具体目标。在这些修订后的目标，我们将研究是否XMRV感染可以启动或促进肿瘤的BPH 1，一个非致瘤性的人前列腺细胞系，并评估潜在的贡献的反式激活细胞增殖基因的致癌过程。因此，这一目标可能导致发现新的，直接的XMRV介导的肿瘤发生机制，可用于特异性靶向治疗感染的细胞。修订后的具体目标1.确定XMRV感染非致瘤性Bph 1前列腺上皮细胞是否可以启动或促进肿瘤发生。修订后的具体目标2。确定XMRV感染是否通过3' LTR反式激活机制诱导参与细胞增殖的基因表达。 3.理由和意义 动物癌症病毒为我们提供了对肿瘤发生机制方面的深刻见解，例如细胞原癌基因和肿瘤抑制蛋白的发现（2）。最近，病毒参与人类癌症的研究已经确立（3）。据估计，全球20-25%的人类癌症有病毒病因，实例包括来自几个家族的病毒（乳多空病毒、疱疹病毒、逆转录病毒、嗜肝DNA病毒、黄病毒），这些病毒是与宫颈癌、肛门生殖器癌、淋巴瘤、卡波西肉瘤、成人T细胞白血病、肝细胞癌、乳腺癌、睾丸癌和其他癌症相关的病原体（4）。在某些情况下，病毒通过表达改变细胞生长特性的病毒蛋白直接促进肿瘤发生。在其他情况下，病毒可能间接导致癌症。Urisman等人推导出了一种可能参与前列腺肿瘤发生的新型药物的序列，即异嗜性小鼠白血病病毒（MLV）相关病毒或XMRV（5）。该序列表明，全长，潜在的复制能力的逆转录病毒密切相关的嗜异性MLV。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 1. Hypothesis The gammaretrovirus genus of Retroviridae are known to infect a diverse range of mammalian species, and these infections can result in leukemogenesis and other diseases, but typically only affecting animals. Recently, a rare evidence of authentic infection of humans by gammaretroviruses was presented when the gammaretrovirus xenotropic murine leukemia virus (MLV)-related virus (XMRV) was detected in late-stage prostate cancer patient tissues. The data, presented in two independent reports, suggested that XMRV could infect human prostate cells, and strongly implicated XMRV in prostate tumorigenesis, although several gaps remained regarding whether or not XMRV was directly implicated in the pathogenesis of prostate cancer. Therefore, it is critical to determine if XMRV is involved in prostate tumorigenesis, and whether XMRV utilizes direct mechanisms (infection of epithelial cells) to achieve its effect on prostate epithelia. Answering these questions could yield unprecedented opportunities to develop XRMV as a new diagnostic marker for prostate cancer and/or new methods to prevent and eliminate XMRV infected cells with specific immunity-boosting XMRV DNA vaccines, helping reduce mortality due to prostate cancer development or progression. Our specific hypotheses are that (1) XMRV infection of nontumorigenic Bph1 prostate epithelial cells can initiate or promote tumorigenesis, and (2) XMRV infection induces expression of genes involved in cellular proliferation through a 3' LTR transactivation mechanism. 2. Specific Aims. In these revised aims we will examine whether XMRV infection can initiate or promote tumorigenesis of BPH1, a nontumorigenic human prostate cell line, and to assess the potential contribution of transactivation of cell proliferation genes to the oncogenesis process. As a result, this aim could lead to the discovery of novel, direct mechanisms of XMRV-mediated tumorigenesis, which could be utilized for targeting therapy specifically to infected cells. Revised Specific Aim 1. To determine whether XMRV infection of non-tumorigenic Bph1 prostate epithelial cells can initiate or promote tumorigenesis. Revised Specific Aim 2. To determine whether XMRV infection induces expression of genes involved in cellular proliferation through a 3' LTR transactivation mechanism. 3. Rationale and Significance Animal cancer viruses have provided us with great insight into the mechanistic aspects of tumorigenesis, such as the discovery of cellular protooncogenes and tumor suppressor proteins (2). More recently, the involvement of viruses in human cancer has been established (3). It is now estimated that 20-25% of human cancers worldwide have a contributing viral etiology, and examples include viruses from several families (papovavirus, herpesvirus, retrovirus, hepadnavirus, flaviviruses) that are etiological agents linked to cervix, anogenital, lymphoma, Kaposi's sarcoma, adult T cell leukemias, hepatocellular carcinomas, breast, testicular, and other cancers (4). In some cases, virusesdirectly promote tumorigenesis through expression of viral proteins that alter the growth properties of the cell. In other cases, the viruses may indirectly cause cancer. Urisman et al. deduced the sequence of a novel agent that may be involved in prostate tumorigenesis, the Xenotropic Murine Leukemia Virus (MLV)-related Virus, or XMRV (5). This sequence indicated a full-length, potentially replication competent retrovirus closely related to xenotropic MLVs.