2. Academic Validation
  3. GPX4 transcriptionally promotes liver cancer metastasis via GRHL3/PTEN/PI3K/AKT axis

GPX4 transcriptionally promotes liver cancer metastasis via GRHL3/PTEN/PI3K/AKT axis

  • Transl Res. 2024 May 24:271:79-92. doi: 10.1016/j.trsl.2024.05.007.
Ruogu Pan 1,  Zhenjun Zhao 2,  Dongwei Xu 1,  Chunlai Li 3,  Qiang Xia 4
Affiliations

Affiliations

  • 1 Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200217, China.
  • 2 Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200217, China; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden.
  • 3 Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200217, China; Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. Electronic address: chunlai.lee@gmail.com.
  • 4 Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200217, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200217, China; Shanghai Institute of Transplantation, Shanghai 200217, China. Electronic address: xiaqiang@medmail.com.cn.
PMID: 38797432 DOI: 10.1016/j.trsl.2024.05.007
Abstract

Hepatocellular carcinoma (HCC) is among the most fatal types of malignancy, with a high prevalence of relapse and limited treatment options. As a critical regulator of Ferroptosis and redox homeostasis, Glutathione Peroxidase 4 (GPX4) is commonly upregulated in HCC and is hypothesized to facilitate Cancer metastasis, but this has not been fully explored in HCC. Here, we report that up-regulated GPX4 expression in HCC is strongly associated with tumor metastasis. FACS-based in vivo and in vitro analysis revealed that a cell subpopulation featuring lower cellular Reactive Oxygen Species levels and Ferroptosis resistance were involved in GPX4-mediated HCC metastasis. Mechanistically, GPX4 overexpressed in HCC tumor cells was enriched in the nucleus and transcriptionally silenced GRHL3 expression, thereby activating PTEN/PI3K/Akt signaling and promoting HCC metastasis. Functional studies demonstrated that GPX4 Amino acids 110-145 are a binding site that interacts with the GRHL3 promoter. As Akt is a downstream target of GPX4, we combined the Akt Inhibitor, AKT-IN3, with lenvatinib to effectively inhibit HCC tumor cell metastasis. Overall, these results indicate that the GPX4/GRHL3/PTEN/PI3K/Akt axis controls HCC cell metastasis and lenvatinib combined with AKT-IN3 represents a potential therapeutic strategy for patients with metastatic HCC.

Keywords

GPX4; Lenvatinib; Liver Cancer; Metastasis; Transcriptional Regulate.

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