Comprehensive network analysis reveals alternative splicing-related lncRNAs in hepatocellular carcinoma

Abstract: Emerging evidence suggests that long non-coding RNAs (lncRNAs) play a crucial role in regulating alternative splicing (AS) and may contribute to the aggressiveness of hepatocellular carcinoma (HCC). However, the genome-wide extent and mechanisms by which lncRNAs influence AS remain largely unclear. In this study, we analyzed RNA-seq data from 369 HCC samples and 160 normal liver tissues, quantifying over 198,000 isoform transcripts and identifying 1,375 significant AS events. To uncover novel AS-associated lncRNAs, we constructed an integrative multi-layered network that incorporates co-expression profiles, protein-protein interactions, and epigenetic regulation, linking lncRNAs, splicing factors, transcription factors, and miRNAs to their AS target genes. We developed a random walk-based multi-graphic (RWMG) algorithm to prioritize functionally relevant lncRNAs within this heterogeneous network. The RWMG model demonstrated strong performance based on cross-validation and bootstrapping analysis. Our approach identified 31 AS-related lncRNAs, including well-known cancer-associated lncRNAs such as MALAT1 and HOXA11-AS, as well as novel candidates like DNM1P35 and DLX6-AS1 with potential regulatory roles. Survival analysis further supports the clinical relevance of these findings, providing new insights into the molecular mechanisms and potential biomarkers of AS regulation in liver cancer.

Wang J, Wang X, Bhat A, Chen Y, Xu K, Mo Y, Yi SS and Zhou Y (2020) Comprehensive Network Analysis Reveals Alternative Splicing-Related lncRNAs in Hepatocellular Carcinoma. Front. Genet. 11:659.