Related Experiment Video

Updated: Oct 13, 2025

An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis

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RABL2A-CCDC34 Axis Promotes Sorafenib Resistance in Hepatocellular Carcinoma

Mingxiu Zhou1,2, Xue Chen1,2, Hansong Bai1,2

  • 1Cancer Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China.

DNA and Cell Biology
|November 12, 2021
PubMed

Insights

CCDC34 and RABL2A form an axis that promotes sorafenib resistance in hepatocellular carcinoma (HCC) by activating MAPK signaling pathways. Targeting this axis could restore sensitivity to sorafenib treatment in HCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Hepatocellular carcinoma (HCC) is a major global health concern.
  • Sorafenib is a standard treatment for advanced HCC, but acquired resistance is a significant clinical challenge.
  • Understanding the molecular mechanisms underlying sorafenib resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the role of CCDC34 in sorafenib sensitivity in HCC.
  • To identify functional partners of CCDC34 involved in sorafenib resistance.
  • To elucidate the signaling pathways mediated by CCDC34 and its partners in HCC.

Main Methods:

  • Utilized *in vitro* cell models of sorafenib-resistant HCC (Huh7/SR, Hep3B/SR).
  • Employed immunofluorescence staining and co-immunoprecipitation to assess protein interactions.
  • Assessed cell response to sorafenib using CCK-8, TUNEL, PI/Annexin V staining, and western blot analysis.

Main Results:

  • *CCDC34* expression was upregulated in resistant HCC cells and associated with poor survival.
  • RABL2A, interacting with CCDC34 in its GTP-bound state, was upregulated in resistant cells.
  • RABL2A depletion sensitized cells to sorafenib, while RABL2A Q80L mutant overexpression increased resistance.
  • CCDC34 depletion abrogated RABL2A-mediated resistance and attenuated p38/MAPK and JNK/MAPK activation.

Conclusions:

  • The RABL2A-CCDC34 axis plays a critical role in mediating acquired sorafenib resistance in HCC.
  • This axis contributes to resistance by activating p38/MAPK and JNK/MAPK signaling pathways.
  • Targeting the RABL2A-CCDC34 interaction may represent a novel therapeutic strategy to overcome sorafenib resistance in HCC.
Keywords:
CCDC34MAPKRABL2Ahepatocellular carcinomasorafenib

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