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Function of non-coding RNAs in liver cancer

非编码RNA在肝癌中的功能

基本信息

批准号：
260051043
负责人：
Professor Dr. Sven Diederichs
金额：
--
依托单位：
Klinik für Thoraxchirurgie
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 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/260051043?language=en
关键词：
Function non coding RNAs liver

项目摘要

The aim of our project is to elucidate the function of long non-protein-coding RNAs (lncRNA) in the most frequent form of liver cancer, hepatocellular carcinoma (HCC). We want to understand the molecular mechanisms underlying liver carcinogenesis which might be exploitable for future therapeutic approaches.In our previous work, we successfully discovered novel HCC-associated lncRNAs by compiling a broad landscape of their expression and regulation in HCC compared to normal liver tissue. To select HCC-associated lncRNAs based on their functional importance, we generated a library of 3200 siRNAs targeting 638 cancer-associated lncRNAs. This comparably small, but focused library should be a versatile tool to screen for lncRNAs modulating the hallmarks of cancer. The proposed project aims to screen this unique siRNA library for lncRNAs affecting the proliferation or apoptosis of liver cancer cells. These functional data are then combined with the expression and regulation data for this set of cancer-associated lncRNAs to select the most promising hits for an in-depth functional characterization. In addition, we will further pursue our studies of known lncRNAs for which we have already established a role in HCC (e.g. HULC). The analysis of these known and novel hits includes the generation of loss- and gain-of-function models and their characterization at the cellular and molecular level. Innovative genome editing techniques will be used to create quantitative knockouts of lncRNAs in human HCC cells. Based on the hypothesis that most lncRNAs will act as ribonucleoprotein complexes, we will uncover the lncRNA-protein-network using RNA affinity purifications. Hypotheses on the precise mechanisms of these lncRNAs will be formed and tested based on the observed phenotypes, the identified interaction partners and bioinformatical guilt-by-association predictions.In summary, we will unravel the role of HULC and novel lncRNAs functionally important in HCC at the molecular and cellular level to understand fundamental mechanisms of lncRNA-modulated tumorigenesis in HCC and to identify therapeutic target genes as well as regulatory networks.

我们项目的目的是阐明长非蛋白编码 RNA (lncRNA) 在最常见的肝癌——肝细胞癌 (HCC) 中的功能。我们希望了解肝癌发生的分子机制，这可能可用于未来的治疗方法。在我们之前的工作中，我们通过编制与正常肝组织相比的 HCC 中表达和调控的广泛图谱，成功发现了新型 HCC 相关 lncRNA。为了根据功能重要性选择 HCC 相关 lncRNA，我们生成了一个包含 3200 个 siRNA 的文库，该库针对 638 个癌症相关 lncRNA。这个相对较小但重点突出的文库应该是筛选调节癌症特征的 lncRNA 的多功能工具。拟议的项目旨在筛选这个独特的 siRNA 库，以寻找影响肝癌细胞增殖或凋亡的 lncRNA。然后将这些功能数据与这组癌症相关 lncRNA 的表达和调控数据相结合，以选择最有希望的命中进行深入的功能表征。此外，我们将进一步研究已知的 lncRNA，我们已经在 HCC 中发挥了作用（例如 HULC）。对这些已知和新颖的命中的分析包括功能丧失和获得功能模型的生成及其在细胞和分子水平上的表征。创新的基因组编辑技术将用于在人类 HCC 细胞中定量敲除 lncRNA。基于大多数 lncRNA 将充当核糖核蛋白复合物的假设，我们将使用 RNA 亲和纯化揭示 lncRNA-蛋白质网络。关于这些lncRNA精确机制的假设将根据观察到的表型、确定的相互作用伙伴和生物信息学关联预测来形成和测试。总之，我们将在分子和细胞水平上揭示HULC和新型lncRNA在HCC中的重要功能，以了解lncRNA调节肿瘤发生的基本机制。 HCC 并确定治疗靶基因以及调控网络。