Identification of prognostic alternative splicing signatures in hepatitis B or/and C viruses related hepatocellular carcinoma

BackgroundAlternative splicing (AS) takes a crucial part in tumor process. We aim to analyze AS in Hepatitis B virus (HBV) or/and hepatitis C virus (HCV) related hepatocellular carcinoma (HCC).MethodsCox regression analysis was conducted to screen survival-associated AS events. The receiver operating characteristic curve used to evaluate the predictive accuracy. Splicing network was built to investigate the relationship between splicing factors and AS events.ResultsNinety-six survival-associated AS events were obtained by univariate Cox regression. Final prognostic model could significantly distinguish the prognosis. We identified RBFOX2 as the hub gene in splicing network based on differentially expressed splicing factors, and obtained MAP3K13_AT as the key AS event in survival-related splicing network.ConclusionOur results highlight the AS signatures in HCC patients with HBV or/and HCV infection. Meanwhile, AS events and splicing factors in different virus-infected HCC subgroups can provide novel perspectives as biomarkers and individualized therapeutic targets.     

Prevalent intron retention fine‐tunes gene expression and contributes to cellular senescence

Intron retention (IR) is the least well‐understood alternative splicing type in animals, and its prevalence and function in physiological and pathological processes have long been underestimated. Cellular senescence contributes to individual aging and age‐related diseases and can also serve as an important cancer prevention mechanism. Dynamic IR events have been observed in senescence models and aged tissues; however, whether and how IR impacts senescence remain unclear. Through analyzing polyA⁺ RNA‐seq data from human replicative senescence models, we found IR was prevalent and dynamically regulated during senescence and IR changes negatively correlated with expression alteration of corresponding genes. We discovered that knocking down (KD) splicing factor U2AF1, which showed higher binding density to retained introns and decreased expression during senescence, led to senescence‐associated phenotypes and global IR changes. Intriguingly, U2AF1‐KD‐induced IR changes also negatively correlated with gene expression. Furthermore, we demonstrated that U2AF1‐mediated IR of specific gene (CPNE1 as an example) contributed to cellular senescence. Decreased expression of U2AF1, higher IR of CPNE1, and reduced expression of CPNE1 were also discovered in dermal fibroblasts with age. We discovered prevalent IR could fine‐tune gene expression and contribute to senescence‐associated phenotypes, largely extending the biological significance of IR.