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RPL28 mediates sorafenib resistance in hepatocellular carcinoma by downregulating CDC6 expression

Yi Shi1, Fangfang Chen1, Yuanyuan Weng1

  • 1Department of Molecular Pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China.

Frontiers in Oncology
|March 4, 2026
PubMed
Abstract

Insights

Ribosomal protein L28 (RPL28) drives sorafenib resistance in hepatocellular carcinoma (HCC) by upregulating CDC6. Targeting the RPL28-CDC6 pathway may overcome drug resistance in advanced HCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Resistance Mechanisms

Background:

  • Sorafenib is a key targeted therapy for advanced hepatocellular carcinoma (HCC).
  • Resistance to sorafenib significantly limits its clinical effectiveness in HCC patients.
  • The precise molecular mechanisms of sorafenib resistance in HCC are not fully understood, with the role of ribosomal proteins (RPs) being an area of ongoing investigation.

Purpose of the Study:

  • To investigate the functional role of ribosomal protein L28 (RPL28) in sorafenib resistance in HCC.
  • To elucidate the molecular mechanisms by which RPL28 influences sorafenib sensitivity and resistance in HCC.
  • To identify potential therapeutic targets for overcoming sorafenib resistance in HCC.

Main Methods:

  • Utilized HepG2 and HCCLM3 cell models of sorafenib-resistant HCC.
  • Performed RPL28 knockdown using siRNA to assess effects on cell proliferation, migration, and sorafenib sensitivity (IC50).
  • Conducted integrated transcriptomic and proteomic analyses to identify downstream targets and pathways, with validation by Western blotting.

Main Results:

  • RPL28 expression was significantly reduced in sorafenib-resistant HCC cells following knockdown.
  • RPL28 knockdown inhibited proliferation and migration in resistant HCC cells.
  • CDC6 was identified as a key downstream target of RPL28, with its expression decreasing upon RPL28 knockdown; immune markers MHC-I and PD-L1 remained unchanged.

Conclusions:

  • RPL28 promotes sorafenib resistance in HCC by upregulating CDC6, thereby contributing to tumor proliferation and drug resistance.
  • The novel RPL28-CDC6 axis represents a significant mechanism underlying sorafenib resistance in HCC.
  • Targeting the RPL28-CDC6 pathway offers a potential therapeutic strategy to overcome sorafenib resistance in advanced HCC.
Keywords:
CDC6hepatocellular carcinomaproteomeribosomal proteins L28 (RPL28)sorafenib resistancetranscriptome

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