Role of Dystroglycan in Prostate Cancer Progression

目前，我们对前列腺癌如何从局部的、可治疗的 一种传播性的不治之症。我们的长期目标是了解 潜在的前列腺癌进展和转移，以改善这种疾病的诊断和治疗 疾病前列腺癌进展中涉及的一种机制是细胞凋亡的改变。 与细胞外基质（ECM）的相互作用。我们一直关注肌营养不良蛋白聚糖（DG）a ECM蛋白的细胞受体。DG已被证明参与了开发， 正常上皮细胞的功能，并且其表达在晚期癌中减少或消除，包括 前列腺癌还已知DG的细胞外部分的适当碳水化合物修饰， 部分由LARGE蛋白介导，是其结合ECM配体的能力所必需的，我们 在这里显示，这在人类前列腺癌细胞系和临床标本中被破坏。但 这对疾病进展的影响以及这是否可以区分侵袭性病例和惰性病例 目前还不清楚。基于我们的初步数据，我们假设DG的不适当糖基化导致 ECM的结构和功能扰动导致前列腺癌进展。这里我们 已经将基于细胞的测定、前列腺癌的动物模型和前列腺癌的评估结合在一起， 临床标本，以解决这一假设与以下具体目标：1）评价原因的DG 低糖基化及其对前列腺癌进展的影响; 2）确定DG丢失的影响 在前列腺癌的小鼠模型中测定对肿瘤进展和转移的作用; 3）测定在前列腺癌的小鼠模型中对肿瘤进展和转移的作用。 人前列腺癌中<$DG糖基化状态和LARGE表达的预后意义。的 这些研究的成功完成将确定一种新的致病机制和疾病生物标志物 潜在的前列腺癌进展。了解驱动前列腺癌进展的生物学机制对于开发新的 治疗和诊断这种疾病的方法。在这项提案中，我们关注的是肌营养不良蛋白聚糖，一种 细胞外基质蛋白参与了这一过程。

We currently have a limited understanding of how prostate cancer progresses from a localized, treatable disease to a disseminated incurable one. Our long term goal is to understand the biological mechanisms underlying prostate cancer progression and metastasis in order to improve diagnosis and treatment of this disease. One mechanism that has been implicated in prostate cancer progression is alteration of cellular interactions with the extracellular matrix (ECM). We have been focusing on the role of dystroglycan (DG) a cellular receptor for ECM proteins in this process. DG has been shown to be involved in the development and function of normal epithelia and its expression is reduced or eliminated in advanced carcinomas, including prostate cancer. It is also known that appropriate carbohydrate modification of the extracellular portion of DG, which is in part mediated by the LARGE protein, is necessary for its ability to bind its ECM ligands, and we show here that this is disrupted in human prostate cancer cell lines and clinical specimens. However, the consequences of this for disease progression and whether this can distinguish aggressive from indolent cases is not yet known. Based on our preliminary data, we hypothesize that inappropriate glycosylation of DG results in structural and functional perturbations of the ECM that contribute to prostate cancer progression. Here we have brought together a combination of cell-based assays, animal models of prostate cancer, and evaluation of clinical specimens to address this hypothesis with the following specific aims: 1) Evaluate cause of ¿DG hypoglycosylation and its effects on prostate cancer progression; 2) Determine the effects of loss of DG function on tumor progression and metastasis in a mouse model of prostate cancer; 3) Determine the prognostic significance of ¿DG glycosylation status and LARGE expression in human prostate cancer. The successful completion of these studies will define a novel pathogenic mechanism and disease biomarker underlying prostate cancer progression. Understanding the biological mechanisms driving prostate cancer progression is essential for developing new ways to treat and diagnose this disease. In this proposal, we are focusing on how dystroglycan, a receptor for extracellular matrix proteins, is involved in this process.