2. Academic Validation
  3. Overexpression of ELF3 in the PTEN-deficient lung epithelium promotes lung cancer development by inhibiting ferroptosis

Overexpression of ELF3 in the PTEN-deficient lung epithelium promotes lung cancer development by inhibiting ferroptosis

  • Cell Death Dis. 2024 Dec 18;15(12):897. doi: 10.1038/s41419-024-07274-5.
Zengzhuang Yuan # 1,  Xinyan Han # 1,  Manyu Xiao # 1,  Taoyu Zhu 1 2,  Yaping Xu 1 2,  Qian Tang 1 2,  Chen Lian 1,  Zijin Wang 1 2,  Junming Li 1 2,  Boyu Wang 1,  Changhui Li 1 2,  Xiaochen Xiang 1 2,  Ruobai Jin 1 2,  Yufei Liu 1 2,  Xinyu Yu 1 2,  Kehang Zhang 1 2,  Songsong Li 1,  Madhumita Ray 3,  Rong Li 4,  Artiom Gruzdev 5,  Shiqun Shao 6,  Fangwei Shao 7 8 9,  Hua Wang 10,  Wang Lian 11,  Yong Tang 12,  Di Chen 13,  Ying Lei 14,  Xuru Jin 14 15,  Qinglin Li 16,  Weiwen Long 17,  Huaqiong Huang 18,  Francesco J DeMayo 3,  Jian Liu 19 20 21 22 23
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK.
  • 3 Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, USA.
  • 4 Department of Obstetrics, Gynecology and Women' Health, University of Missouri, Columbia, MO, USA.
  • 5 Gene Editing and Mouse Model Core, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, USA.
  • 6 Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
  • 7 Zhejiang University-University of Illinois Urbana-Champaign Institute, Zhejiang University, Haining, China.
  • 8 Biomedical and Heath Translational Research Center of Zhejiang Province, Haining, Zhejiang, China.
  • 9 National Key Laboratory of Biobased Transportation Fuel Technology, ZJU-UIUC Institute, Zhejiang University, Hangzhou, China.
  • 10 Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 11 Department of Thoracic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
  • 12 Department of Thoracic Surgery, Shenzhen Nanshan People's Hospital, Shenzhen, China.
  • 13 Center for Regeneration and Cell Therapy of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 14 Department of Respiratory and Critical Care Medicine, The Quzhou Affiliated Hospital of Wenzhou Medical Hospital, Quzhou People's Hospital, Wenzhou, China.
  • 15 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 16 Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
  • 17 Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA.
  • 18 Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 19 Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Centre for Infection Immunity and Cancer (IIC) of Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China. JianL@intl.zju.edu.cn.
  • 20 Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK. JianL@intl.zju.edu.cn.
  • 21 Biomedical and Heath Translational Research Center of Zhejiang Province, Haining, Zhejiang, China. JianL@intl.zju.edu.cn.
  • 22 Zhejiang Key Laboratory of Medical Imaging Artificial Intelligence, Haining, Zhejiang, China. JianL@intl.zju.edu.cn.
  • 23 Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, China. JianL@intl.zju.edu.cn.
  • # Contributed equally.
PMID: 39695109 DOI: 10.1038/s41419-024-07274-5
Abstract

Ferroptosis has been shown to play a crucial role in preventing Cancer development, but the underlying mechanisms of dysregulated genes and genetic alternations driving Cancer development by regulating Ferroptosis remain unclear. Here, we showed that the synergistic role of ELF3 overexpression and PTEN deficiency in driving lung Cancer development was highly dependent on the regulation of Ferroptosis. Human ELF3 (hELF3) overexpression in murine lung epithelial cells only caused hyperplasia with increased proliferation and Ferroptosis. hELF3 overexpression and PTEN genetic disruption significantly induced lung tumor development with increased proliferation and inhibited Ferroptosis. Mechanistically, we found it was due to the induction of SCL7A11, a typical Ferroptosis inhibitor, and ELF3 directly and positively regulated SCL7A11 in the PTEN-deficient background. Erastin-mediated inhibition of SCL7A11 induced Ferroptosis in cells with ELF3 overexpression and PTEN deficiency and thus inhibited cell colony formation and tumor development. Clinically, human lung tumors showed a negative correlation between ELF3 and PTEN expression and a positive correlation between ELF3 and SCL7A11 in a subset of human lung tumors with PTEN-low expression. ELF3 and SCL7A11 expression levels were negatively associated with lung Cancer patients' survival rates. In summary, Ferroptosis induction can effectively attenuate lung tumor development induced by ELF3 overexpression and PTEN downregulation or loss-of-function mutations.

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