Function of non-coding RNAs in liver cancer

• Applicant: Professor Dr. Sven Diederichs
• Subject Area: General Genetics and Functional Genome Biology ; Pathology ; Cell Biology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260051043

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.

• DFG Programme: Research Grants