Heparan Sulfate in Prostate Cancer

项目摘要 前列腺癌（PCa）是恶性肿瘤的最普遍形式之一，也是前列腺癌的第二大常见原因。 与癌症有关的男性死亡揭示控制前列腺肿瘤发生的新机制可能会促进 开发更有效的治疗方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-细胞间相互作用中起着重要作用。 以及细胞-基质相互作用和信号传导。最近的研究报道，HS合成和 修饰基因在人前列腺癌标本中失调。目前，尚不清楚是什么原因导致这一情况 异常HS表达，更重要的是，异常HS的功能后果是什么？ 在前列腺肿瘤发生中的表达。在这个应用中，我们提出测试我们的新假设“Pten损失 导致异常HS表达，从而产生独特的细胞环境， 前列腺肿瘤的发生”通过追求以下三个具体目标：1。确定是否存在异常HS 在人前列腺上皮细胞中的表达由Pten丢失诱导，并与Pten的恶性程度相关。 空人PCa; 2.确定Pten丢失诱导的异常HS表达是否增强前列腺 肿瘤发生; 3.确定Pten丢失诱导的异常HS表达是否增强了PCa相关的 炎症拟议的研究将使用新的和已建立的遗传，细胞，生物化学和 生物信息学方法结合体外细胞功能和体内人和小鼠PCa模型。 这些系列研究有望揭示一种驱动HS异常表达的新机制 在PCa中，HS异常表达可作为PCa早期诊断和预后的新生物标志物， 阐明HS在前列腺组织中异常表达的关键作用及其分子机制， 肿瘤发生，这可能将有助于开发用于PCa治疗的新疗法。

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.