MECHANISMS OF XMRV ONCOGENESIS IN PROSTATE CELLS

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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.