Heparan Sulfate in Prostate Cancer

项目总结 前列腺癌(PCa)是最常见的恶性肿瘤之一，也是导致前列腺癌的第二大原因。 与癌症相关的男性死亡。发现控制前列腺癌发生的新机制可能会取得进展 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)，一种 多糖是细胞微环境的重要组成部分，在细胞间起着重要的作用。 以及细胞-基质相互作用和信号传递。最近的研究报道，HS合成和表达 在人类前列腺癌标本中，修饰基因是不受调控的。目前尚不清楚是什么原因造成了这种情况。 HS的异常表达，更重要的是，HS的异常功能后果是什么 在前列腺癌发生中的表达。在这个应用程序中，我们建议检验我们的新假设 在前列腺中导致HS的异常表达，创造了一个独特的细胞环境，增强了 通过追求以下三个具体目标：1.确定异常HS是否 Pten基因缺失诱导人前列腺上皮细胞表达及其与前列腺癌恶性程度的关系 空人类Pca；2.确定Pten缺失诱导的HS异常表达是否增强了前列腺 肿瘤的发生；3.确定Pten-Lost诱导的HS异常表达是否增强了PCa相关 发炎。拟议的研究将使用新的和已建立的遗传、细胞、生化和 生物信息学方法与体外细胞功能和体内人类和小鼠PCA模型相结合。 这些系列研究有望描绘出一种驱动HS异常表达的新机制 在PCa中，HS的异常表达可作为一种新的PCa早期诊断和预后的生物标志物 阐明前列腺组织中HS异常表达的关键作用及其分子机制 肿瘤的发生，这可能有助于为前列腺癌治疗开发新的治疗方法。

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.