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Targeting THOC2-Mediated mRNA Export Induces PARP Inhibitor Vulnerability in DNA Repair-Competent Hepatocellular

Xinli Li1, Songpeng Yang1, Mengxin Zhang1

  • 1State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing 102206, China.

International Journal of Biological Sciences
|June 22, 2026
PubMed

Insights

THOC2 regulates DNA damage response (DDR) by controlling mRNA export. Targeting THOC2 with Poly (ADP-ribose) polymerase inhibitors (PARPi) shows promise for treating hepatocellular carcinoma (HCC) by inducing synthetic lethality.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Hepatocellular carcinoma (HCC) presents limited therapeutic options due to low mutation rates in DNA repair genes.
  • Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective in tumors with DNA repair defects, but their utility in HCC is restricted.
  • Enhanced DNA repair capacity in HCC limits the efficacy of conventional treatments.

Purpose of the Study:

  • To identify novel regulators of DNA damage response (DDR) in hepatocellular carcinoma (HCC).
  • To investigate the role of THO complex component 2 (THOC2) in DDR and its potential as a therapeutic target.
  • To explore strategies for overcoming PARPi resistance in HCC.

Main Methods:

  • Proteomic analysis of two independent HCC cohorts (n=260).
  • Investigated THOC2's role in mRNA nuclear export of DDR and proliferation-related genes.
  • Assessed the synergistic effect of THOC2 knockdown and PARPi (Olaparib) on HCC cell lines and tumor growth.

Main Results:

  • THOC2 was identified as a master regulator of DDR through mRNA nuclear export control.
  • THOC2 overexpression correlated with poor HCC patient survival and increased DDR gene expression.
  • THOC2 knockdown induced synthetic lethality with PARPi, significantly reducing Olaparib efficacy and suppressing tumor growth.

Conclusions:

  • THOC2 is a prognostic biomarker and therapeutic target for hepatocellular carcinoma (HCC).
  • Targeting mRNA transport offers a novel strategy to modulate DDR and overcome PARPi resistance.
  • This study expands the concept of synthetic lethality beyond genetic defects to include post-transcriptional regulation in cancer therapy.
Keywords:
DNA repairHCCPARPiTHO complexcombination therapymRNA export

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