权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Nuclear Neuropilin2: a novel molecular mediator for aggressive Prostate Cancer

Nuclear Neuropilin2：一种治疗侵袭性前列腺癌的新型分子介质

基本信息

批准号：
10607992
负责人：
Kaustubh Datta
金额：
$ 34.08万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607992
关键词：
Active Biological Transport Androgen Receptor Androgens Binding Biological Assay Cancer Patient Castration Categories Cell Nucleus Cell physiology Cell surface Cells Classification Clinical Complex Detection Development Diffusion Disease Disease Progression Disease Resistance Disseminated Malignant Neoplasm Event Gene Expression Genes Genetic Transcription Goals Golgi Apparatus Growth Human Impairment Indolent Knowledge Ligands Malignant Neoplasms Malignant neoplasm of prostate Mediating Mediator Medical center Membrane Modality Modeling Molecular Mutation Nebraska Neuropilin-2 Neuropilins Newly Diagnosed Nuclear Nuclear Envelope Nuclear Inner Membrane Nuclear Pore Nuclear Pore Complex Proteins Oncogenes Operative Surgical Procedures Pathologic Patients Pattern Pore Proteins Process Prognosis Prognostic Factor Prognostic Marker Promoter Regions Prostatic Neoplasms Protein Kinase Radiation Receptor Signaling Recurrence Reproducibility Retrospective Studies Role Route Signal Transduction Stains Sumoylation Pathway System Techniques Testing Therapeutic Intervention Tissues Universities advanced prostate cancer androgen deprivation therapy cancer biomarkers castration resistant prostate cancer cohort curative treatments deprivation effective therapy high risk migration molecular marker novel novel therapeutic intervention nucleocytoplasmic transport overexpression overtreatment prostate cancer cell prostate cancer progression protein complex receptor receptor function recruit retrograde transport risk prediction superresolution microscopy therapeutically effective transcription factor treatment strategy tumor tumor growth

项目摘要

Abstract Localized prostate cancer is often categorized as either indolent or aggressive based largely on clinical and pathological features. Despite our understanding of genetic alterations that are associated with different stages of prostate cancer (PCa), there is no clear molecular classification system, which can predict the risk for developing aggressive PCa. As a result, it is currently difficult to discriminate the aggressive and indolent PCa in their early stages, and develop appropriate therapy for the patients with aggressive cancer. Surgery, radiation and less often androgen deprivation therapies are the available treatment options for localized tumor, although cancers of 30-35% of patients recur and some of them evolve into metastatic disease. There are very limited treatment options for advanced stage PCa. It is therefore important to identify the molecular mediators that promote the advancement of PCa. A comprehensive knowledge on the function of these mediators will not only help us to determine the molecular factors that can distinguish the aggressive and indolent PCa but also to establish effective treatment modalities for those patients who are at high risk to develop metastatic cancer. Our preliminary results indicated that Neuropilin-2 (NRP2) could be a mediator of aggressive PCa by regulating the global transcription of genes required for cancer promotion. Mechanistically, NRP2 can translocate from ER to nuclear membrane through retrograde transport and stabilize the transcription machineries necessary for the expression of cancer promoting genes. Based on these novel observations, we hypothesized that nuclear NRP2 is critical for the transcription of genes required for the advancement of PCa. Hence, NRP2 is not only a predictor for aggressive PCa but also a target for effective treatment strategy. Two specific aims have been proposed. In aim 1, we will study the underlying mechanisms of how nuclear membrane-bound NRP2 interacts with the transcription factors in PCa cells and facilitates their activity. We will also determine using a cohort of human PCa tissues whether nuclear NRP2 can be a prognostic factor, which can discriminate between indolent and aggressive PCa. Aim 2 will focus on the molecular mechanism of how NRP2 migrates to nuclear membrane and determine whether inhibition of this translocation can block the prostate tumor growth. Altogether, our proposal will determine how nuclear NRP2 promotes PCa and thus can be an effective predictor for aggressive PCa. Moreover, it will identify whether targeting NRP2 axis such as blocking its nuclear transport is an effective therapeutic approach to treat aggressive PCa.

摘要局限性前列腺癌通常被分类为惰性或侵袭性，主要基于临床和病理特征。尽管我们了解基因改变，与前列腺癌（PCa）的不同阶段相关，目前还没有明确的分子分类该系统可以预测发展侵袭性PCa的风险。因此，目前在早期阶段难以区分侵袭性和惰性PCa，为侵袭性癌症患者提供适当的治疗。手术，放疗，雄激素剥夺疗法是局部肿瘤的可用治疗选择，尽管 30-35%的患者的癌症复发，并且其中一些发展成转移性疾病。有晚期PCa的治疗选择非常有限。因此，必须确定促进前列腺癌进展的分子介质。全面了解这些介体的功能不仅有助于我们确定能够区分侵袭性和惰性PCa，同时建立有效的治疗方式对于那些有高风险发展为转移性癌症的患者。我们的初步结果表明Neuropilin-2（NRP 2）可能通过调节全身神经元的表达而成为侵袭性PCa的介导因子促进癌症所需的基因转录。从机制上讲，NRP 2可以从 ER通过逆行转运到达核膜，稳定转录机制这是癌症促进基因表达所必需的。根据这些新的观察，我们假设核NRP 2对于转录所需基因至关重要 PCa的进展因此，NRP 2不仅是侵袭性PCa的预测因子，而且也是侵袭性PCa的靶点。有效的治疗策略。提出了两个具体目标。在目标1中，我们将研究核膜结合的NRP 2如何与细胞核相互作用的潜在机制 PCa细胞中的转录因子，并促进其活性。我们还将确定使用队列核NRP 2是否可以作为一个预后因子，这可以区分惰性前列腺癌和侵袭性前列腺癌的区别目标2将集中在分子机制如何 NRP 2迁移到核膜并确定抑制这种移位是否可以阻止前列腺肿瘤生长。总之，我们的建议将决定核NRP 2 促进PCa，因此可以是侵袭性PCa的有效预测因子。此外，它将识别靶向NRP 2轴如阻断其核转运是否是有效的治疗方法治疗侵袭性前列腺癌的方法。