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DDX42 Enhances Hepatocellular Carcinoma Cell Proliferation, Radiation and Sorafenib Resistance via Regulating GRB2

Zijian Liu1,2,3, Jingsheng Yuan4,5, Fei Liu6

  • 1Laboratory of Liquid Biopsy and Single Cell Research, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Journal of Cellular and Molecular Medicine
|August 20, 2025
PubMed

Insights

DEAD-box RNA helicase 42 (DDX42) promotes hepatocellular carcinoma (HCC) growth and resistance to radiotherapy and sorafenib by activating the PI3K/AKT pathway and enhancing GRB2 mRNA maturation. Targeting DDX42 and GRB2 may improve HCC treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The DEAD-box RNA helicase (DDX) family regulates RNA metabolism and spliceosome formation.
  • Systematic analysis of DDX family members in hepatocellular carcinoma (HCC) and their roles in treatment resistance is lacking.

Purpose of the Study:

  • To investigate the role of DDX family members in HCC.
  • To identify a specific DDX gene associated with radiosensitivity and sorafenib efficacy.
  • To elucidate the underlying mechanisms of DDX42 in HCC progression and treatment resistance.

Main Methods:

  • Bioinformatic analysis including enrichment analysis, radiosensitivity index (RSI), and IC50 prediction.
  • In vitro studies involving gene overexpression and knockdown in HCC cell lines.
  • Western blotting to assess protein expression and pathway activation (PI3K/AKT).
  • In vivo studies using a subcutaneous xenograft nude mouse model.

Main Results:

  • DDX42 was identified as a highly expressed gene in HCC tissues and a prognostic factor.
  • DDX42 overexpression promoted HCC cell proliferation, radio-resistance, and sorafenib resistance, activating the PI3K/AKT pathway.
  • DDX42 knockdown inhibited cell growth, increased radiosensitivity, enhanced sorafenib efficacy, and inactivated the PI3K/AKT pathway.
  • DDX42 was found to promote GRB2 mRNA maturation, contributing to HCC cell proliferation and treatment resistance.
  • In vivo, DDX42 overexpression significantly promoted tumor growth and increased expression of GRB2, KI-67, and PCNA.

Conclusions:

  • DDX42 plays a crucial role in HCC initiation and the development of resistance to radiotherapy and sorafenib.
  • The DDX42-GRB2 axis is a potential therapeutic target for overcoming treatment resistance in HCC.
  • Targeting DDX42 and GRB2 may offer promising strategies for synergistic treatment with radiotherapy or sorafenib in HCC patients.
Keywords:
RNA maturationcell proliferationhepatocellular carcinomaradio‐resistancesorafenib resistance

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