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患者高发病率和致死率相关的骨骼。为了确定预防或治疗转移性 PCa 的新治疗靶点，人们正在努力更好地了解 PCa 细胞骨转移转变的分子机制。除了众所周知的癌基因和抑癌基因的遗传改变外，基因转录调控元件、翻译后修饰和蛋白质降解的异常活性也主要导致PCa细胞的转移潜力。其中，含有三联基序的蛋白质 (TRIM) 家族已被确定为驱动转移的细胞过程的关键调节因子，并且在多种癌症类型中具有改变的活性。在我们的前期工作中，我们发现 TRIM24 在 PCa 骨转移中高度过表达并可预测结果。此外，TRIM8、TRIM11、TRIM47 和 TRIM68 已被描述在 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 TRIM 蛋白在 PCa 的侵袭性和转移性微环境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 PCa 组织（包括原发肿瘤和转移瘤）中 TRIM 的表达和遗传状态。利用大型且临床特征良好的队列，我们​​将把我们的分子数据与不同的临床病理参数和患者的生存率联系起来。其次，将使用骨转移 PCa 细胞进行体外实验，以研究 TRIM 的功能作用。我们将探讨转移过程中关键步骤所需的细胞特征是否受到特定 TRIM 的影响。对参与这些过程的信号分子的详细分析将得出有关 TRIM 介导的 PCa 转移潜力的潜在分子机制的结论。第三，将应用共培养实验来研究TRIM是否影响骨转移PCa细胞和形成骨微环境的细胞之间的通讯。该项目的结果将有助于更好地了解促进 PCa 骨转移的分子过程。由于迄今为止转移性 PCa 无法治愈，针对特定分子（如特定 TRIM 蛋白）可能是转移性 PCa 患者的一种治疗选择。