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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在58%的前列腺癌标本中，白细胞介素17(IL-17)细胞因子升高。IL-17A和IL-17F与IL-17RA和IL-17RC两种受体结合。IL-17RA在前列腺间质和上皮细胞中均有表达，而IL-17RC主要在上皮细胞中表达。IL-17RC有13种不同的剪接异构体。我们的一般假设是，在慢性炎症状态下，前列腺上皮中全长非糖基化IL-17RC的上调增强了细胞对IL-17A和IL-17F细胞因子的反应，导致核因子-βB、Akt和ERK通路的激活，促进了细胞的增殖和存活。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参与前列腺癌的发病机制，并开发抗炎干预措施来预防和治疗前列腺癌。提出了三个具体目标。目的1确定正常、前列腺上皮内瘤变(PIN)和癌细胞中IL-17RC亚型平衡的变化。我们的假设是，全长未糖基化的IL-17RC在PIN和癌细胞中上调。将研究人类前列腺细胞系和代表正常、PIN和癌症的组织的IL-17RC mRNA异构体、蛋白质水平和蛋白质糖基化。目的2是确定不同IL-17RC亚型功能的潜在机制。我们的假设是，全长未糖化的IL-17RC蛋白与IL-17A和IL-17F细胞因子结合，而外显子缺失和/或糖基化的IL-17RC蛋白不与配体结合。配体-受体相互作用激活了下游的核因子-B、Akt和ERK信号通路，促进了细胞的增殖和存活。目的3是利用具有IL-17RC基因敲除和前列腺癌特异性条件性Pten基因敲除背景的小鼠模型，在体内测试IL-17RC在前列腺癌发生中的作用。我们的假设是，当IL-17RC表达缺失时，条件性Pten基因敲除小鼠的自发前列腺癌形成将被预防或推迟。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.