Mechanisms of Viral Resistance Mediated by MAP3K7 and CHD1 in Prostate Cancer

MAP 3 K7和CHD 1介导的前列腺癌病毒耐药机制 病毒必须逃避或抑制宿主细胞部署的防御才能进行复制。这场斗争， 是病毒组织嗜性和致病性决定因素。水泡性口炎病毒（VSV）， 原型弹状病毒是一种病毒，其组织嗜性由宿主的抗病毒反应决定，而VSV的 成功或失败抑制反应。例如，VSV选择性地感染免疫受损的人， 癌组织的细胞。这为VSV等病毒作为潜在溶瘤病毒的应用奠定了基础 治疗VSV能够感染大多数癌症，然而，一些癌症通过以下方式保持对VSV感染的抗性： 组成型表达抗病毒基因。 前列腺癌（PCa）对病毒感染表现出不同程度的抵抗力。我们的实验室已经证明 PC-3细胞组成型表达抗病毒基因产物。我们的数据表明，这是一种新的结果， MAP 3 K7和CHD 1基因产物介导的抗病毒信号传导机制。当这些 基因沉默，PC-3细胞变得更容易受到病毒感染。RNA-Seq分析显示， 沉默CHD 1或MAP 3 K7和CHD 1两者降低抗病毒基因mRNA表达，但沉默 沉默MAP 3 K7可降低STAT 1的磷酸化水平。这表明 MAP 3 K7以转录后方式调节抗病毒基因表达。病毒易感性和抗病毒 将在PC-3细胞中测量基因表达，其中MAP 3 K7和/或CHD 1已被用 CRISPR/Cas9系统MAP 3 K7对抗病毒基因转录后调控机制的研究将有助于进一步阐明MAP 3 K7的抗病毒基因转录后调控机制。 通过Polysome-Seq和蛋白酶体抑制来确定。抗病毒作用的下游介质 将用ChIP-Seq鉴定MAP 3 K7和CHD 1的表达。最后，用MAP 3 K7， 将在小鼠中建立CHD 1或两者敲除。小鼠将用静脉内VSV治疗，并且任何VSV治疗都将在小鼠体内进行。 将确定MAP 3 K7或CHD 1对肿瘤应答的影响。

Mechanisms of Viral Resistance Mediated by MAP3K7 and CHD1 in Prostate Cancer A virus must evade or inhibit the defenses deployed by the host cell in order to replicate. This struggle between host and pathogen is a determinant of viral tissue tropism and pathogenicity. Vesicular stomatitis virus (VSV), the prototype rhabdovirus, is a virus whose tissue tropism is dictated by the host anti-viral response, and VSV's success or failure in suppressing that response. For example, VSV selectively infects the immune-impaired cells of cancer tissue. This is the basis for the use of VSV and other viruses as potential oncolytic virus therapies. VSV is able to infect most cancers, however some cancers maintain resistance to VSV infection by constitutively expressing anti-viral genes. Prostate cancers (PCa) display variable levels of resistance to viral infection. Our laboratory has shown that PC-3 cells constitutively express anti-viral gene products. Our data indicate that this is the result of a novel anti-viral signaling mechanism that is mediated by the gene products of MAP3K7 and CHD1. When these genes are silenced, PC-3 cells become more susceptible to viral infection. RNA-Seq analysis shows that silencing CHD1 or both MAP3K7 and CHD1 decreases anti-viral gene mRNA expression, but silencing MAP3K7 alone increases it. Silencing MAP3K7 decreases phosphorylation of STAT1. This suggests that MAP3K7 regulates anti-viral gene expression in a post-transcriptional manner. Viral susceptibility and anti-viral gene expression will be measured in PC-3 cells in which MAP3K7 and/or CHD1 have been knocked out with the CRISPR/Cas9 system. The mechanism of post-transcriptional regulation of anti-viral genes by MAP3K7 will be determined through Polysome-Seq and proteasome inhibition. Downstream mediators of the anti-viral effect of MAP3K7 and CHD1 will be identified with ChIP-Seq. Finally, xenografts of PC-3 tumors with MAP3K7, CHD1, or both knocked out will be established in mice. The mice will be treated with intravenous VSV, and any effect of MAP3K7 or CHD1 on the tumors' response will be determined.