Integrated multi-omics analysis of the clinical relevance and potential regulatory mechanisms of splicing factors in hepatocellular carcinoma

Abstract

Splicing factors (SFs) have been increasingly documented to perturb the genome of cancers. However, little is known about the alterations of SFs in hepatocellular carcinoma (HCC). This study comprehensively delineated the genomic and epigenomic characteristics of 404 SFs in HCC based on the multi-omics data from the Cancer Genome Atlas database. The analysis revealed several clinically relevant SFs that could be effective biomarkers for monitoring the onset and prognosis of HCC (such as, HSPB1, DDX39A, and NELFE, which were the three most significant clinically relevant SFs). Functional enrichment analysis of these indicators showed the enrichment of pathways related to splicing and mRNA processes. Furthermore, the study found that SF copy number variation is common in HCC and could be a typical characteristic of hepatocarcinogenesis; the complex expression regulation of SFs was significantly affected by copy number variant and methylation. Several SFs with significant mutation patterns were identified (such as, RNF213, SF3B1, SPEN, NOVA1, and EEF1A1), and the potential regulatory network of SFs was constructed to identify their potential mechanisms for regulating clinically relevant alternative splicing events. Therefore, this study established a foundation to uncover the broad molecular spectrum of SFs for future functional and therapeutic studies of HCC.

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

“…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.…”

“…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.…”

Mutant SF3B1 promotes malignancy in PDAC

“…The splicing factor subunit 3b 1 (SF3B1) is amongst the most commonly mutated components of the splicing machinery, with high incidence in myelodysplastic syndromes (MDS; Je et al, 2013 ) and chronic lymphocytic leukemia (CLL; Miao et al, 2019 ). However, also in various solid tumors, SF3B1 is recurrently mutated, including uveal melanoma (UVM; Furney et al, 2013 ), breast cancer (BRCA; Fu et al, 2017 ; Maguire et al, 2015 ; Sun et al, 2020 ), prolactinomas ( Li et al, 2020 ), hepatocellular carcinoma (HCC; Zhao et al, 2021 ), and pancreatic adenocarcinoma (PDAC; Bailey et al, 2016 ; Yang et al, 2021 ). As part of the U2 small nuclear ribonucleoprotein (U2 snRNP) SF3B1 exerts an essential function in RNA splicing by recognizing the branchpoint sequence (BPS) of nascent RNA transcripts ( Wahl et al, 2009 ; Zhang et al, 2020 ).…”

Immune-Related lncRNA Pairs Clinical Prognosis Model Construction for Hepatocellular Carcinoma

“…Therefore, finding effective biomarkers for the prognosis of HCC is still a major challenge in the diagnosis and treatment of HCC. 2 As an inflammation-related tumor, HCC has an immunosuppressive tumor microenvironment (TME), 3,4 which can promote immune tolerance through various mechanisms. 5 A series of progress has been made in immunotherapy.…”