Comprehensive Characterization of the Interplay between Alternative Splicing and RNA Binding Proteins in Hepatocellular Carcinoma

Abstract

Background: Pervasive perturbation of alternative splicing (AS) has been observed in cancer. RNA-binding proteins (RBPs) are master regulators of post-transcriptional processing, including AS. Thus, it is important to identify the associations between AS and RBPs. Results: Here, we comprehensively profiled aberrant splicing in hepatocellular carcinoma (HCC) and identified cancer phenotypes contributed by different mRNA isoforms. Additionally, we found that aberrant splicing impacted gene expression minimally, and was mostly regulated by the expression of RBPs. Remarkably, our analyses revealed that splicing-related pathways were perturbed by the altered AS events of RBPs. Further analyses indicated that 67 RBPs had double defects, both in AS and in gene expression, and had higher levels of mRNA expression in HCC. Therefore, we propose a model where the perturbation of AS might be triggered by autoregulatory and cross-regulatory networks among RBPs, such as ILF3 and UPF1. We demonstrate that RBPs can exacerbate HCC malignancy through AS and expression changes. To reveal associations between those two aspects, we performed stratification analyses of all patients based on the hub AS events of RBPs, and identified cancer subtypes with distinct clinical outcomes and RBP expressions. Additionally, we detected 60 RBPs with the highest expression levels in the subtype with the poorest survival rate. Conclusions: Our work details the interplay between the splicing and expression of RBPs, and highlights a key contributory role for RBPs in oncogenesis through widespread perturbations of AS. Funding: This work was supported by the following: the Natural Science Foundation of Zhejiang Province (No. LY15H160046), Ningbo Science and Technology Innovation Team Project (No. 2011B82016) and Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province (No. 2019E10020). Declaration of Interest: The authors declare no competing financial interests. Ethical Approval: MIssing