MECHANISMS OF XMRV ONCOGENESIS IN PROSTATE CELLS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 1.假设 已知逆转录病毒科的伽玛逆转录病毒属可感染多种哺乳动物，这些感染可导致白血病和其他疾病，但通常只影响动物。最近，在晚期前列腺癌患者组织中检测到伽马逆转录病毒异嗜性小鼠白血病病毒(MLV)相关病毒(XMRV)，这是一种罕见的真正感染人类的证据。在两份独立的报告中公布的数据表明，XMRV可以感染人类前列腺细胞，并强烈暗示XMRV与前列腺癌的发生有关，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空白。因此，确定XMRV是否参与了前列腺肿瘤的发生，以及XMRV是否通过直接机制(感染上皮细胞)来实现其对前列腺上皮细胞的作用是至关重要的。回答这些问题可能带来前所未有的机会，将XRMV开发为前列腺癌的新诊断标记物，和/或通过特异性免疫增强XMRV DNA疫苗预防和消除XMRV感染细胞的新方法，有助于降低前列腺癌发生或进展造成的死亡率。我们的具体假设是：(1)XMRV感染非致瘤的Bph1前列腺上皮细胞可以启动或促进肿瘤的发生；(2)XMRV感染通过3‘LTR反式激活机制诱导细胞增殖相关基因的表达。 2.具体目标。在这些修订的目标中，我们将检查XMRV感染是否可以启动或促进非致瘤性人类前列腺细胞系BPH1的肿瘤形成，并评估细胞增殖基因反式激活对肿瘤形成过程的潜在贡献。因此，这一目标可能导致发现XMRV介导的肿瘤发生的新的、直接的机制，该机制可用于针对受感染细胞的靶向治疗。修订的特定目标1。确定XMRV感染非致癌的Bph1前列腺上皮细胞是否可以启动或促进肿瘤的发生。修订的特定目的2.确定XMRV感染是否通过3‘LTR反式激活机制诱导细胞增殖相关基因的表达。 3.理论基础和意义 动物癌症病毒为我们提供了对肿瘤发生机制方面的巨大洞察，例如发现了细胞原癌基因和肿瘤抑制蛋白[2]。最近，病毒与人类癌症的关系已得到证实(3)。目前估计，全世界20-25%的人类癌症与病毒有关，例如来自几个家族的病毒(乳头状病毒、疱疹病毒、逆转录病毒、肝炎病毒、黄病毒)，这些病毒与子宫颈、肛门、淋巴瘤、卡波西肉瘤、成人T细胞白血病、肝细胞癌、乳腺癌、睾丸和其他癌症有关(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的发生。在其他情况下，病毒可能间接导致癌症。Urisman等人。推断了一种可能参与前列腺癌发生的新病原体的序列，即异嗜性小鼠白血病病毒(MLV)相关病毒，或XMRV(5)。这一序列表明了一种与异嗜性MLV密切相关的具有潜在复制能力的全长逆转录病毒。

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.