Abstract
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, we 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. We 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), we found that differentially expressed lncRNAs are co-expressed with genes involved in cell cycle regulation, TGF-β signalling and liver metabolism. Furthermore, we 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. Our study provides the most comprehensive compendium of lncRNAs expressed in HCC, as well as in control or cirrhotic livers. Our 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.
Highlights
Liver cancer is the second most common cause of cancer-related mortality worldwide, and is estimated to be responsible for nearly 746,000 deaths in 2012 (9.1% of the total)
We analysed the number of expressed genes in each sample for each tissue type, considering separately 3 gene categories, namely protein coding genes, long non-coding genes, and pseudogenes, as they are defined in Gencode annotation
In agreement with previous studies [38, 39], we observed a higher variability in the number of expressed long non-coding RNAs (lncRNAs) than protein coding genes or pseudogenes in each tissue type, including in control livers
Summary
Liver cancer is the second most common cause of cancer-related mortality worldwide, and is estimated to be responsible for nearly 746,000 deaths in 2012 (9.1% of the total). Recent genome-wide sequencing studies have confirmed the occurrence of gene mutations previously identified, affecting the p53, the retinoblastoma (Rb), the TGF-β and the Wnt/βcatenin pathways. These studies found new frequent mutations in various components of chromatin modifying complexes, ARID1A or ARID2 [7,8,9,10]. Genome-wide aberrant DNA methylation patterns in HCC tumours that are predominantly HCV-related were reported [13]. A total of 2,568 significant CpG sites were located within 684 differentially methylated regions which covered 589 genes, with some of them associated with HCV infection and/or cirrhosis, demonstrating the significance of aberrant DNA methylation in HCC tumourigenesis [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
