Heparan Sulfate in Prostate Cancer

硫酸乙酰肝素在前列腺癌中的作用

基本信息

批准号：
10246930
负责人：
Houjian Cai
金额：
--
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-13 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246930
关键词：
Ablation Advanced Development Affect Anabolism Biochemical Bioinformatics Biological Assay CXCR4 gene Cancer Cell Growth Cancer Etiology Cancerous Cell physiology Cell surface Cells Cellular Structures Cessation of life Coupled Development Disease EXT1 gene Early Diagnosis Environment Enzymes Epithelial Cells Epitopes Event Extracellular Matrix FGF1 gene FGFR1 gene Gene Expression Genes Genetic Growth Heparitin Sulfate Human IL8RB gene In Vitro Infiltration Inflammation Inflammatory Investigation Knock-out Life Ligands Malignant Neoplasms Malignant neoplasm of prostate Measures Modeling Molecular Mus Mutate Myeloid-derived suppressor cells Play Polymers Polysaccharides Prognosis Prostate Prostate Cancer therapy Prostatic Proteins Public Health Reporting Role Signal Transduction Specificity Specimen Structure System Testing Tumor Suppressor Genes Xenograft procedure autocrine cancer initiation cell motility chemokine in vivo men mouse model neutralizing antibody novel novel marker novel therapeutics overexpression prostate cancer cell prostate cancer cell line prostate cancer model public health relevance recruit therapeutically effective tumor tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Prostate cancer (PCa) is one of the most prevalent forms of malignancy and the second most common cause of cancer-related death in men. Uncovering novel mechanisms that control prostatic tumorigenesis may advance development of more effective therapeutics to treat this life-threatening disease. Heparan sulfate (HS), a type of polysaccharide, is an essential component of the cell microenvironment and plays an important role in cell-cell and cell-matrix interaction and signaling. Recent studies reported that expression of HS-synthesizing and modifying genes are dysregulated in human PCa specimens. Currently, it is not known what causes this aberrant HS expression, and, more importantly, what are the functional consequences of the aberrant HS expression in prostatic tumorigenesis. In this application, we propose to test our novel hypothesis “Pten-loss in prostate leads to aberrant HS expression creating a unique cellular environment that potentiates prostatic tumorigenesis” by pursuing the following three Specific Aims: 1. Determine if aberrant HS expression in human prostate epithelial cells is induced by Pten-loss and correlates with malignancy of Pten- null human PCa; 2. Determine if aberrant HS expression induced by Pten-loss potentiates prostatic tumorigenesis; 3. Determine if aberrant HS expression induced by Pten-loss potentiates PCa-associated inflammation. The proposed studies will use both novel and established genetic, cellular, biochemical and bioinformatics approaches in conjunction with in vitro cell function and in vivo human and mouse PCa models. These serial investigations are anticipated to delineate a novel mechanism that drives aberrant HS expression in PCa, reveal the aberrant HS expression to be a novel biomarker for PCa early diagnosis and prognosis, and elucidate the pivotal roles and their underlying molecular mechanisms of the aberrant HS expression in prostatic tumorigenesis, which likely will contribute to the development of novel therapeutics for PCa treatment.

项目概要前列腺癌 (PCa) 是最常见的恶性肿瘤之一，也是第二大常见原因发现控制前列腺肿瘤发生的新机制可能会促进男性癌症相关死亡。开发更有效的疗法来治疗这种危及生命的疾病（硫酸乙酰肝素（HS））。多糖是细胞微环境的重要组成部分，在细胞间发挥着重要作用最近的研究报道了 HS 合成和信号传导的表达。目前，尚不清楚导致这种情况的原因。异常 HS 表达，更重要的是，异常 HS 的功能后果是什么在本申请中，我们建议测试我们的新假设“Pten 丢失”。前列腺中的 HS 表达异常，创造出独特的细胞环境，增强前列腺肿瘤发生”通过追求以下三个具体目标： 1. 确定 HS 是否异常人前列腺上皮细胞中的表达是由 Pten 缺失诱导的，并且与 Pten 的恶性肿瘤相关无效人 PCa；2. 确定 Pten 缺失诱导的异常 HS 表达是否会增强前列腺功能 3. 确定 Pten 缺失诱导的异常 HS 表达是否会增强 PCa 相关性拟议的研究将使用新颖的和已建立的遗传、细胞、生化和炎症。生物信息学方法与体外细胞功能以及体内人类和小鼠 PCa 模型相结合。这些系列研究预计将描绘出驱动异常 HS 表达的新机制在 PCa 中，揭示异常 HS 表达是 PCa 早期诊断和预后的新型生物标志物，以及阐明前列腺中异常 HS 表达的关键作用及其潜在分子机制肿瘤发生，这可能有助于开发前列腺癌治疗的新疗法。