2. Academic Validation
  3. Oxidative stress and Kras mutation in Mist1+ cells act in a double-hit manner to drive gastric tumorigenesis

Oxidative stress and Kras mutation in Mist1+ cells act in a double-hit manner to drive gastric tumorigenesis

  • Cell Rep. 2025 Jul 22;44(7):116014. doi: 10.1016/j.celrep.2025.116014.
Fan Chen 1,  Yi Han 2,  Jingwu Yue 3,  Hui Zhang 3,  Luyang Tian 3,  Zhifa Cao 2,  Mengwen Zhu 3,  Wenjia Wang 3,  Yan Meng 2,  Liwei An 2,  Feng Li 4,  Huanhu Zhang 4,  Wenqi Bai 4,  Yanfeng Xi 5,  Zaisheng Ye 6,  Shi Jiao 7,  Zhaocai Zhou 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China; CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 2 Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China.
  • 3 State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China.
  • 4 Department of Digestive Sciences, Shanxi Cancer Hospital, Taiyuan 030001, China.
  • 5 Department of Pathology, Shanxi Cancer Hospital, Taiyuan 030013, China. Electronic address: xiyanfeng1998@163.com.
  • 6 Department of Gastric Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, China. Electronic address: flyingengel@sina.com.
  • 7 State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China. Electronic address: jiaoshi@fudan.edu.cn.
  • 8 State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China; Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: zhouzhaocai@fudan.edu.cn.
PMID: 40652510 DOI: 10.1016/j.celrep.2025.116014
Abstract

Oxidative stress is a "double-edged sword" in mediating cellular activities. Here, we report that Mist1+ cells are resistant to oxidative-stress-induced cell death and that persistent oxidative stress and Kras mutation act in Knudson's "two-hit" paradigm to promote gastric Cancer initiation. Reactive Oxygen Species (ROS) accumulation causes metaplastic lineage expansion of Mist1+ cells, licensing them as a cellular origin of gastric Cancer. Mechanistically, the transcription factor Mist1 upregulates its downstream target genes Bnip3 and Tmed6, enhancing ROS resistance. Persistent ROS induce R-loop accumulation and activate YAP signaling in Mist1+ cells for proliferation and tumorigenesis. Importantly, ROS and Kras mutation synergistically drive the malignant transformation of Mist1+ cells, while ROS or Kras mutation alone could not do so. Collectively, our study offers insights into the two-hit theory by demonstrating that oxidative stress and oncogenic mutation cooperatively drive Mist1+ cell expansion and transcriptional reprogramming-critical events during early tumor initiation.

Keywords

CP: Cancer; Mist1(+) cells; gastric tumorigenesis; oxidative stress; “two hit” hypothesis.

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