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Updated: Aug 20, 2025

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells
Published on: May 1, 2020
Spliceosomal profiling identifies EIF4A3 as a novel oncogene in hepatocellular carcinoma acting through the
Juan L López-Cánovas1,2,3,4, Natalia Hermán-Sánchez1,2,3,4, Maria Trinidad Moreno-Montilla1,2,3,4
1Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Cordoba, Spain.
Introduction:
Altered splicing landscape is an emerging cancer hallmark; however, the dysregulation and implication of the cellular machinery controlling this process (spliceosome components and splicing factors) in hepatocellular carcinoma (HCC) is poorly known. This study aimed to comprehensively characterize the spliceosomal profile and explore its role in HCC.
Methods:
Expression levels of 70 selected spliceosome components and splicing factors and clinical implications were evaluated in two retrospective and six in silico HCC cohorts. Functional, molecular and mechanistic studies were implemented in three cell lines (HepG2, Hep3B and SNU-387) and preclinical Hep3B-induced xenograft tumours.
Results:
Spliceosomal dysregulations were consistently found in retrospective and in silico cohorts. EIF4A3, RBM3, ESRP2 and SRPK1 were the most dysregulated spliceosome elements in HCC. EIF4A3 expression was associated with decreased survival and greater recurrence. Plasma EIF4A3 levels were significantly elevated in HCC patients. In vitro EIF4A3-silencing (or pharmacological inhibition) resulted in reduced aggressiveness, and hindered xenograft-tumours growth in vivo, whereas EIF4A3 overexpression increased tumour aggressiveness. EIF4A3-silencing altered the expression and splicing of key HCC-related genes, specially FGFR4. EIF4A3-silencing blocked the cellular response to the natural ligand of FGFR4, FGF19. Functional consequences of EIF4A3-silencing were mediated by FGFR4 splicing as the restoration of non-spliced FGFR4 full-length version blunted these effects, and FGFR4 inhibition did not exert further effects in EIF4A3-silenced cells.
Conclusions:
Splicing machinery is strongly dysregulated in HCC, providing a source of new diagnostic, prognostic and therapeutic options in HCC. EIF4A3 is consistently elevated in HCC patients and associated with tumour aggressiveness and mortality, through the modulation of FGFR4 splicing.
Insights
Altered splicing is key in liver cancer (HCC). This study found splicing factor EIF4A3 is elevated in HCC, driving tumor growth and poor survival by affecting FGFR4 splicing, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Altered splicing is an emerging hallmark of cancer.
- The role of spliceosome components and splicing factors in hepatocellular carcinoma (HCC) is not well understood.
Purpose of the Study:
- To comprehensively characterize the spliceosomal profile in HCC.
- To investigate the functional role of spliceosome elements in HCC progression.
Main Methods:
- Analysis of 70 spliceosome components in HCC cohorts (retrospective and in silico).
- In vitro and in vivo functional studies using HCC cell lines and xenografts.
- Evaluation of EIF4A3 expression, splicing alterations, and downstream effects.
Main Results:
- Consistent spliceosomal dysregulation observed in HCC cohorts.
- EIF4A3, RBM3, ESRP2, and SRPK1 were significantly dysregulated.
- Elevated EIF4A3 correlated with decreased survival, increased recurrence, and higher plasma levels.
- EIF4A3 silencing reduced HCC aggressiveness and tumor growth by modulating FGFR4 splicing.
Conclusions:
- Spliceosome machinery is significantly dysregulated in HCC, offering diagnostic and therapeutic potential.
- Elevated EIF4A3 is a marker of HCC aggressiveness and mortality, acting via FGFR4 splicing modulation.
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