Regulation of tumor-supporting monocyte infiltration and macrophage polarization by tumor cell HuR

肿瘤细胞 HuR 对肿瘤支持单核细胞浸润和巨噬细胞极化的调节

• 批准号: 254118769
• 负责人: Professor Dr. Bernhard Brüne
• 金额: --
• 依托单位: Institut für Biochemie I: Pathobiochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/254118769?language=en
• 关键词: Regulation; tumor; supporting; monocyte; infiltration

Posttranscriptional events regulated by the mRNA binding protein HuR (human antigen R) often promote tumor malignancy. Yet, the impact of tumor HuR on the tumor microenvironment, specifically on monocytes and macrophages, remains elusive. Monocytes and macrophages represent an essential part of the tumor stroma. Upon infiltration of tumors, monocytes differentiate into macrophages and are educated to a tumor-associated macrophages (TAM) phenotype, which contributes to tumor growth. We hypothesize that the expression of HuR in tumor cells contributes to the chemoattractance of monocytes and their polarization towards TAM, thus, affecting tumor progression. To study the communication between tumor cells and monocytes/macrophages with regard to the HuR status in tumor cells we use hepatocellular carcinoma cells (HepG2) with a stable knockdown of HuR vs. cells overexpressing HuR. Culturing these cells as 3D tumor spheroids we follow infiltration of human monocytes and assess their polarization towards TAM. We aim at identifying the HuR-dependent factors that cause monocyte infiltration/polarization. To prove a cause-effect relation we attenuate the production of these factors in HepG2 cells. In addition, we characterize the molecular mechanisms of the HuR-dependent regulation of promising candidates. After verifying our results in a mouse hepatoma cell line (Hepa 1-6), we will use a syngraft model with tumor cells showing a genetically modified HuR status to test our in vitro findings in vivo. Our work increases the understanding how HuR in tumor cells contributes in shaping the tumor microenvironment, i.e. macrophage responses.

由mRNA结合蛋白HuR（人抗原R）调节的转录后事件常常促进肿瘤恶性。然而，肿瘤HuR对肿瘤微环境的影响，特别是对单核细胞和巨噬细胞的影响，仍然难以捉摸。单核细胞和巨噬细胞是肿瘤间质的重要组成部分。在肿瘤浸润后，单核细胞分化成巨噬细胞，并被训练成肿瘤相关巨噬细胞（TAM）表型，这有助于肿瘤生长。我们假设肿瘤细胞中HuR的表达有助于单核细胞的趋化性及其对TAM的极化，从而影响肿瘤的进展。为了研究肿瘤细胞和单核细胞/巨噬细胞之间关于肿瘤细胞中HuR状态的通讯，我们使用具有稳定敲低HuR的肝细胞癌细胞（HepG 2）与过表达HuR的细胞。将这些细胞培养为3D肿瘤球状体，我们跟踪人单核细胞的浸润并评估其向TAM的极化。我们的目的是确定HuR依赖的因素，导致单核细胞浸润/极化。为了证明因果关系，我们减弱了HepG 2细胞中这些因子的产生。此外，我们表征的分子机制的HuR依赖的调节有前途的候选人。在小鼠肝癌细胞系（Hepa 1-6）中验证我们的结果后，我们将使用具有显示遗传修饰HuR状态的肿瘤细胞的同系移植模型来测试我们在体内的体外发现。我们的工作增加了对肿瘤细胞中HuR如何影响肿瘤微环境（即巨噬细胞反应）的理解。