The role of TRIM proteins in colonization of the bone and bone microenvironment modulation of metastatic prostate cancer.

TRIM 蛋白在转移性前列腺癌骨定植和骨微环境调节中的作用。

• 批准号: 401179983
• 负责人: Professor Dr. Sven Perner
• 金额: --
• 依托单位: Institut für Pathologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/401179983?language=en
• 关键词: role; TRIM; proteins; colonization; bone

The most common metastatic site of prostate cancer (PCa) is the bone associated with high morbidity and lethality of patients. With the aim to identify novel therapeutic targets which prevent or treat metastasized PCa, major efforts are being made to better understand the molecular mechanisms enabling bone metastatic transition of PCa cells. Besides well-known genetic alterations of oncogenes and tumor suppressor genes, aberrant activity of regulatory elements for gene transcription, post-translational modification and protein degradation mainly contribute to the metastatic potential of PCa cells. Amongst others, the family of tripartite motif containing proteins (TRIMs) have been identified to be crucial regulators of cellular processes driving metastasis, and to possess altered activity in diverse cancer types. In our preliminary work, we found TRIM24 to be highly overexpressed in PCa bone metastases and to predict outcome. In addition, TRIM8, TRIM11, TRIM47 and TRIM68 have been described be overexpressed in PCa or to influence mechanisms driving metastasis. Based on these data, our overall hypothesis is that these specific TRIM proteins have a crucial role in invasiveness and metastatic niche formation of PCa. To test our hypothesis, we will pursue three specific aims. First, we will characterize the expression and genetic status of TRIMs in PCa tissues including primary tumors as well as metastases. Using large and clinically well-characterized cohorts, we will correlate our molecular data with diverse clinic-pathological parameters and patients’ survival. Second, in-vitro experiments using bone metastatic PCa cells will be conducted to investigate the functional role of TRIMs. We will explore whether cellular features which are required for crucial steps during metastasis are influenced by specific TRIMs. Detailed analysis of signaling molecules involved in these processes will allow conclusions about the underlying molecular mechanisms of TRIM mediated metastatic potential of PCa. Third, co-cultivation experiments will be applied to investigate whether TRIMs influence the communication between bone metastatic PCa cells and cells forming the bone microenvironment. Results of this project will contribute to a better understanding of molecular processes promoting PCa metastasis to the bone. Due to the incurable nature of metastatic PCa to date, targeting specific molecules like specific TRIM proteins might be a therapeutic option for patients suffering from metastatic PCa.

前列腺癌（PCA）最常见的转移部位是与高发病率和致死性有关的骨骼。为了鉴定预防或治疗转移PCA的新型治疗靶标，正在做出重大努力，以更好地了解可以使PCA细胞的骨转移过渡的分子机制。除了肿瘤基因和肿瘤抑制基因的遗传改变外，基因转录的调节元素的异常活性，翻译后修饰和蛋白质降解主要有助于PCA细胞的转移潜力。除其他外，含有蛋白质的三方基序（TRIM）家族已被确定为驱动转移的细胞过程的关键调节剂，并可能改变潜水癌症类型的活性。在我们的初步工作中，我们发现TRIM24在PCA骨转移中高表达并预测结果。此外，TRIM8，TRIM11，TRIM47和TRIM68已被描述为PCA中过表达或影响驱动转移的机制。基于这些数据，我们的总体假设是这些特定的修剪蛋白在PCA的侵入性和转移性生态位形成中具有至关重要的作用。为了检验我们的假设，我们将追求三个具体目标。首先，我们将表征在PCA组织中内饰的表达和遗传状态，包括原发性肿瘤和转移酶。使用大型且临床上良好的人群，我们将将分子数据与潜水诊所病理学参数和患者的生存相关联。其次，将进行使用骨转移性PCA细胞的体外实验，以研究TRIM的功能作用。我们将探讨转移过程中至关重要的步骤所需的细胞特征是否受特定的内饰影响。对这些过程涉及的信号分子的详细分析将允许结论PCA的修剪介导的转移潜力的基本分子机制。第三，将使用共培养实验来研究修剪是否影响骨转移性PCA细胞和形成骨微环境的细胞之间的通信。该项目的结果将有助于更好地理解促进PCA转移到骨骼的分子过程。由于迄今为止转移性PCA无法治愈的性质，针对患有转移性PCA的患者，靶向特定的分子（例如特定的装饰蛋白）可能是一种治疗选择。