THE ROLE OF CYTOKINE RECEPTOR INTERLEUKIN-17RC IN INITIATION OF PROSTATE CANCER

该子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心赠款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 为子项目列出的总成本可能 表示子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 白细胞介素-17（IL-17）细胞因子在58%的前列腺癌标本中升高。IL-17 A和IL-17 F结合两种受体IL-17 RA和IL-17 RC。IL-17 RA在前列腺基质细胞和上皮细胞中表达，而IL-17 RC主要在上皮细胞中表达。IL-17 RC具有超过13种选择性剪接同种型。我们的一般假设是，在慢性炎症下，前列腺上皮中全长非糖基化IL-17 RC的上调增强了细胞对IL-17 A和IL-17 F细胞因子的反应，导致NF-B、Akt和ERK途径的激活，从而促进细胞增殖和存活。长期目标是阐明炎性细胞因子如何通过其受体和下游信号通路促进前列腺癌发生的机制，并开发抗炎干预措施以预防和治疗前列腺癌。提出了三个具体目标。目的1是确定IL-17 RC亚型在正常、前列腺上皮内瘤变（PIN）和癌细胞中平衡的偏移。我们的假设是全长非糖基化IL-17 RC在PIN和癌细胞中上调。将研究代表正常、PIN和癌症的人前列腺细胞系和组织的IL-17 RC mRNA亚型、蛋白水平和蛋白糖基化。目的2是确定不同IL-17 RC亚型的功能性的潜在机制。我们的假设是全长未糖基化的IL-17 RC蛋白结合IL-17 A和IL-17 F细胞因子，而外显子缺失和/或糖基化的IL-17 RC蛋白不结合配体。配体-受体相互作用激活下游NF-B、Akt和ERK信号通路，促进细胞增殖和存活。目的3是使用具有IL-17 RC敲除和前列腺特异性条件性Pten敲除背景的小鼠模型来测试IL-17 RC在体内前列腺癌起始中的作用。我们的假设是，当IL-17 RC表达缺失时，条件性Pten敲除小鼠中自发性前列腺癌的形成将被阻止或延迟。

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. Interleukin-17 (IL-17) cytokine is increased in 58% of prostate cancer specimens. IL-17A and IL-17F bind to two receptors IL-17RA and IL-17RC. IL-17RA is expressed in both prostatic stromal and epithelial cells, whereas IL-17RC is mainly expressed in the epithelium. IL-17RC has over 13 alternative splice isoforms. Our general hypothesis is that up-regulation of the full-length unglycosylated IL-17RC in prostatic epithelium under chronic inflammation enhances the response of cells to IL-17A and IL-17F cytokines, leading to activation of NF-¿B, Akt and ERK pathways that promotes cell proliferation and survival. The long-term objectives are to delineate the mechanisms of how inflammatory cytokines contribute to prostate cancer initiation through their receptors and downstream signaling pathways and to develop anti-inflammatory interventions to prevent and treat prostate cancer. Three Specific Aims are proposed. Aim 1 is to identify the shift of balance of IL-17RC isoforms in normal, prostatic intraepithelial neoplasia (PIN) and cancer cells. Our hypothesis is that the full-length unglycosylated IL-17RC is up-regulated in PIN and cancer cells. Human prostate cell lines and tissues representing normal, PIN and cancer will be studied for IL-17RC mRNA isoforms, protein levels and protein glycosylation. Aim 2 is to identify the mechanisms underlying the functionality of different IL-17RC isoforms. Our hypothesis is that the full-length unglycosylated IL-17RC protein binds to IL-17A and IL-17F cytokines, whereas the exon-deleted and/or glycosylated IL-17RC proteins do not bind to ligands. The ligand-receptor interaction activates downstream NF-¿B, Akt and ERK signaling pathways that promote cell proliferation and survival. Aim 3 is to test the role of IL-17RC in initiation of prostate cancer in vivo using a mouse model with IL-17RC knockout and prostate-specific conditional Pten knockout background. Our hypothesis is that the spontaneous prostate cancer formation in the conditional Pten knockout mice will be prevented or delayed when IL-17RC expression is absent.