Functional characterization of long non-coding RNAs (lncRNAs) and their pathological relevance is still a challenging task. Abnormal expression of a few long non-coding RNAs have been found associated with hepatocellular carcinoma, with potential implications to both improve our understanding of molecular mechanism of liver carcinogenesis and to discover biomarkers for early diagnosis or therapy. However, the understanding of the global role of lncRNAs during HCC development is still in its infancy.
In this study, researchers from the International Agency for Research on Cancer, France produced RNA-Seq data from 23 liver tissues (controls, cirrhotic and HCCs) and applied statistical and gene network analysis approaches to identify and characterize expressed lncRNAs. They detected 5,525 lncRNAs across different tissue types and identified 57 differentially expressed lncRNAs in HCC compared with adjacent non-tumour tissues using stringent criteria (FDR<0.05, Fold Change>2). Using weighted gene co-expression network analysis (WGCNA), the researchers found that differentially expressed lncRNAs are co-expressed with genes involved in cell cycle regulation, TGF-β signalling and liver metabolism. Furthermore, they found that more than 20% of differentially expressed lncRNAs are associated to actively transcribed enhancers and that the co-expression patterns with their closest genes change dramatically during HCC development.
Gene co-expression network analysis of differentially expressed genes.
A. Gene clustering and module identification. Each co-expression cluster has a different colour. B. LncRNAs distribution in the different modules. C. Co-expression matrix showing relations across the different modules. D. Eigengene heatmap showing correlation among the different eigengene vectors of each module.
This study provides the most comprehensive compendium of lncRNAs expressed in HCC, as well as in control or cirrhotic livers. These results identified both known oncogenic lncRNAs (such as H19 and CRNDE) and novel lncRNAs involved in cell cycle deregulation and liver metabolism deficits occurring during HCC development.