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.

Abstract

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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