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HAND2-AS1 Promotes Ferroptosis to Reverse Lenvatinib Resistance in Hepatocellular Carcinoma by TLR4/NOX2/DUOX2 Axis

Zheng Song1,2, Yu Zhang1,2, Wei Luo2

  • 1Peking University 302 Clinical Medical School, Beijing, China.

Current Cancer Drug Targets
|March 11, 2024
PubMed
Abstract

Insights

HAND2-AS1 overexpression reverses lenvatinib resistance in hepatocellular carcinoma (HCC) by promoting ferroptosis. This suggests HAND2-AS1 as a potential therapeutic target and early recurrence indicator for HCC patients.

Area of Science:

  • Hepatobiliary Medicine
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • Lenvatinib resistance limits treatment efficacy in hepatocellular carcinoma (HCC), with objective response rates below 40%.
  • Identifying novel therapeutic targets is crucial to overcome lenvatinib resistance in HCC.
  • HAND2-AS1 is recognized as a significant tumor suppressor gene across various cancer types.

Purpose of the Study:

  • To investigate the role of HAND2-AS1 in the molecular mechanisms underlying lenvatinib resistance in HCC.
  • To explore HAND2-AS1 as a potential therapeutic strategy to reverse lenvatinib resistance.

Main Methods:

  • Assessed HAND2-AS1 expression in lenvatinib-resistant HCC cells (HepG2-LR) and HCC tissues, correlating with progression-free intervals using TCGA data.
  • Overexpressed HAND2-AS1 (OE-HAND2-AS1) in HepG2-LR cells to evaluate its impact on lenvatinib sensitivity (IC50).
  • Measured intracellular malondialdehyde (MDA), lipid reactive oxygen species (ROS), and the glutathione to glutathione disulfide ratio (GSH/GSSG) to assess ferroptosis induction.

Main Results:

  • HAND2-AS1 expression was found to be low in HepG2-LR cells and HCC tissues, correlating with shorter progression-free intervals.
  • Overexpression of HAND2-AS1 significantly decreased the IC50 of lenvatinib in HepG2-LR cells, thereby reversing lenvatinib resistance.
  • OE-HAND2-AS1 promoted ferroptosis by increasing MDA and lipid ROS levels and decreasing the GSH/GSSG ratio.
  • In vivo xenograft models demonstrated that OE-HAND2-AS1 reversed lenvatinib resistance and reduced tumor formation.
  • HAND2-AS1 was shown to promote ferroptosis and reverse lenvatinib resistance by upregulating the expression of ferroptosis-related genes (TLR4, NOX2, DUOX2) via competition with miR-219a-1-3p.

Conclusions:

  • HAND2-AS1 promotes ferroptosis in HCC cells and effectively reverses lenvatinib resistance through the regulation of the TLR4/NOX2/DUOX2 axis.
  • HAND2-AS1 presents potential as a therapeutic target for overcoming lenvatinib resistance in HCC.
  • Low HAND2-AS1 levels may serve as an indicator of early recurrence in HCC patients post-resection.
Keywords:
Hepatocellular carcinomacancercellsdeathslenvatinib.reactive oxygen species

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