Integrative Analysis Reveals the Prognostic Value and Functions of Splicing Factors Implicated in Hepatocellular Carcinoma

Abstract

Splicing factors (SFs) play critical roles in the pathogenesis of various cancers through regulating tumor-associated alternative splicing (AS) events. However, the clinical value and biological functions of SFs in hepatocellular carcinoma (HCC) remain obscure. In this study, we identified 40 dysregulated SFs in HCC and established a prognostic model composed of four SFs (DNAJC6, ZC3H13, IGF2BP3, DDX19B). The predictive efficiency and independence of the prognostic model were confirmed to be satisfactory. Gene Set Enrichment Analysis (GSEA) illustrated the risk score calculated by our prognostic model was significantly associated with multiple cancer-related pathways and metabolic processes. Furthermore, we constructed the SFs-AS events regulatory network and extracted 108 protein-coding genes from the network for following functional explorations. Protein-protein interaction (PPI) network delineated the potential interactions among these 108 protein-coding genes. GO and KEGG pathway analyses investigated ontology gene sets and canonical pathways enriched by these 108 protein-coding genes. Overlapping the results of GSEA and KEGG, seven pathways were identified to be potential pathways regulated by our prognostic model through triggering aberrant AS events in HCC. In conclusion, the present study established an effective prognostic model based on SFs for HCC patients. Functional explorations of SFs and SFs-associated AS events provided directions to explore biological functions and mechanisms of SFs in HCC tumorigenesis.

Spliceosomal profiling identifies EIF4A3 as a novel oncogene in hepatocellular carcinoma acting through the modulation of FGFR4 splicing

“…In HCC, certain spliceosomal components are dysregulated and associated with liver oncogenesis, such as SF3B1, SRSF3, ESRP2 or MBNL3 18 ; however, the expression profile of key spliceosome components and splicing factors has been only superficially explored in HCC. [19][20][21] Therefore, this study aimed to comprehensively describe the pattern of dysregulation in the expression levels of a representative set of relevant spliceosome components and splicing factors and their relationship with clinical and molecular features, as well as their putative pathological role in HCC to further characterize the molecular basis underlying hepatic carcinogenesis.…”

“…Dysregulations in the spliceosomal landscape (spliceosome components and splicing factors) induce altered and/or aberrant splicing processes, which may be associated with the development and progression of different pathologies, including diabetes, 13 fatty liver disease 8 and tumour pathologies (pituitary and pancreatic tumours and prostate or brain cancers 14–17 ). In HCC, certain spliceosomal components are dysregulated and associated with liver oncogenesis, such as SF3B1, SRSF3, ESRP2 or MBNL3 18 ; however, the expression profile of key spliceosome components and splicing factors has been only superficially explored in HCC 19–21 . Therefore, this study aimed to comprehensively describe the pattern of dysregulation in the expression levels of a representative set of relevant spliceosome components and splicing factors and their relationship with clinical and molecular features, as well as their putative pathological role in HCC to further characterize the molecular basis underlying hepatic carcinogenesis.…”

Integrated analysis using ToppMiR uncovers altered miRNA– mRNA regulatory networks in pediatric hepatocellular carcinoma—A pilot study

“…Analysis was performed using downregulated target mRNAs of upregulated miRNAs (left) and upregulated target mRNAs of downregulated miRNAs (right) liver cancer, and dysregulation of miRNAs is often associated with disturbance of the splicing process in many diseases. [59][60][61][62][63] Our results suggest that several miRNAs are deregulated in pediatric HCC as compared to no disease controls and these miRNAs are upstream of biological processes involved in tumor development and progression.…”