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

细胞因子受体 IL-17RC 在前列腺癌发生中的作用

• 批准号: 8360724
• 负责人: Zongbing You
• 金额: $ 27.35万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-17 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360724
• 关键词: Alternative Splicing; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Cell Line; Cell Proliferation; Cell Survival; Cells; Chronic; Cytokine Receptors; Epithelial Cells; Epithelium; Equilibrium; Exons; Funding; Genetic Programming; Grant; Human; Inflammation; Inflammatory; Interleukin-17; Interleukins; Intervention; Knock-out; Knockout Mice; Length; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mentors; Messenger RNA; National Center for Research Resources; Pathway interactions; Principal Investigator; Prostate; Prostatic; Prostatic Epithelium; Prostatic Intraepithelial Neoplasias; Protein Binding; Protein Glycosylation; Protein Isoforms; Proteins; Research; Research Infrastructure; Resources; Role; Signal Pathway; Source; Specimen; Stromal Cells; Testing; Tissues; United States National Institutes of Health; Up-Regulation; cancer cell; cancer genetics; cancer initiation; cost; cytokine; in vivo; mouse model; prevent; receptor; response

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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且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。 子项目可能列出的总成本 代表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。 58% 的前列腺癌标本中白细胞介素 17 (IL-17) 细胞因子增加。 IL-17A 和 IL-17F 与两种受体 IL-17RA 和 IL-17RC 结合。 IL-17RA在前列腺基质细胞和上皮细胞中表达，而IL-17RC主要在上皮细胞中表达。 IL-17RC 具有超过 13 种选择性剪接亚型。我们的一般假设是，慢性炎症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 NF-¿B、Akt 和 ERK 通路的激活，从而促进细胞增殖和存活。长期目标是阐明炎症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来预防和治疗前列腺癌。提出了三个具体目标。目标 1 是确定正常细胞、前列腺上皮内瘤变 (PIN) 和癌细胞中 IL-17RC 亚型平衡的变化。我们的假设是全长非糖基化 IL-17RC 在 PIN 和癌细胞中上调。将研究代表正常、PIN 和癌症的人类前列腺细胞系和组织的 IL-17RC mRNA 亚型、蛋白质水平和蛋白质糖基化。目标 2 是确定不同 IL-17RC 同工型功能的潜在机制。我们的假设是，全长未糖基化的 IL-17RC 蛋白与 IL-17A 和 IL-17F 细胞因子结合，而外显子删除和/或糖基化的 IL-17RC 蛋白不与配体结合。配体-受体相互作用激活下游 NF-¿B、Akt 和 ERK 信号通路，促进细胞增殖和存活。目标 3 是使用具有 IL-17RC 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-17RC 在体内前列腺癌引发中的作用。我们的假设是，当 IL-17RC 表达缺失时，条件性 Pten 基因敲除小鼠中自发性前列腺癌的形成将被阻止或延迟。