2. Academic Validation
  3. Loss of GABARAPL1 confers ferroptosis resistance to cancer stem-like cells in hepatocellular carcinoma

Loss of GABARAPL1 confers ferroptosis resistance to cancer stem-like cells in hepatocellular carcinoma

  • Mol Oncol. 2022 Oct;16(20):3703-3719. doi: 10.1002/1878-0261.13305.
Xiaojing Du 1 2,  Zhuoran Qi 3,  Jinzhi Xu 3,  Mengzhou Guo 3,  Xingxing Zhang 2 4,  Zhijie Yu 2 5,  Xin Cao 6,  Jinglin Xia 1 2 3
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai, China.
  • 2 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, China.
  • 3 Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 4 Department of Gastroenterology, Anhui University of Science and Technology Affiliated Fengxian Hospital, Shanghai Fengxian District Central Hospital, China.
  • 5 Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, China.
  • 6 Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China.
PMID: 36062307 DOI: 10.1002/1878-0261.13305
Abstract

Cancer stem-like cells (CSLC) are considered a major contributor to the development and progression of hepatocellular carcinoma (HCC). Previous studies indicated that CSLC are characterized by resistance to Ferroptosis, a type of lipid peroxidation-dependent cell death. Here, we identified a set of ferroptosis-related stemness genes (FRSG) and found that these genes may be involved in immune infiltration in HCC. A four-FRSG (CDKN2A, GABARAPL1, HRAS, RPL8) risk model with prognostic prediction was constructed by a COX analysis in HCC. Among these four genes, GABARAPL1 was downregulated in HCC tumor-repopulating cells (TRC; a type of CSLC). Its downregulation decreased the sensitivity of HCC TRC to erastin- or sorafenib-triggered Ferroptosis. Together, we uncovered a molecular mechanism via which CSLC could achieve tolerance to Ferroptosis. Further studies may provide potential therapeutic strategies targeting CSLC in HCC.

Keywords

GABARAPL1; cancer stem-like cell; ferroptosis; hepatocellular carcinoma; sorafenib.

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