• 作者： Chia-Hung Chien, Jian-Ying Chuang, Shun-Tai Yang, Wen-Bin Yang, Pin-Yuan Chen, Tsung-I Hsu, Chih-Yuan Huang, Wei-Lun Lo, Ka-Yen Yang, Ming-Sheng Liu, Jui-Mei Chu, Pei-Hsuan Chung, Jr-Jiun Liu, Shao-Wen Chou, Shang-Hung Chen and Kwang-Yu Chang
• 作者服務機構： 1. National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan 2. Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan 3. The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, Taiwan 4. Division of Neurosurgery, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan 5. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan 6. Department of Neurosurgery, Chang Gung Memorial Hospital at Keelung, Keelung City, Taiwan 7. School of Medicine, Chang Gung University, Taoyuan, Taiwan 8. Division of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan 9. Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 10. Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
• 中文摘要：
• 英文摘要：
  Background
  Intratumor subsets with tumor-initiating features in glioblastoma are likely to survive treatment. Our goal is to identify the key factor in the process by which cells develop temozolomide (TMZ) resistance.
  
  Methods
  Resistant cell lines derived from U87MG and A172 were established through long-term co-incubation of TMZ. Primary tumors obtained from patients were maintained as patient-derived xenograft for studies of tumor-initating cell (TIC) features. The cell manifestations were assessed in the gene modulated cells for relevance to drug resistance.
  
  Results
  Among the mitochondria-related genes in the gene expression databases, superoxide dismutase 2 (SOD2) was a significant factor in resistance and patient survival. SOD2 in the resistant cells functionally determined the cell fate by limiting TMZ-stimulated superoxide reaction and cleavage of caspase-3. Genetic inhibition of the protein led to retrieval of drug effect in mouse study. SOD2 was also associated with the TIC features, which enriched in the resistant cells. The CD133+ specific subsets in the resistant cells exhibited superior superoxide regulation and the SOD2-related caspase-3 reaction. Experiments applying SOD2 modulation showed a positive correlation between the TIC features and the protein expression. Finally, co-treatment with TMZ and the SOD inhibitor sodium diethyldithiocarbamate trihydrate in xenograft mouse models with the TMZ-resistant primary tumor resulted in lower tumor proliferation, longer survival, and less CD133, Bmi-1, and SOD2 expression.
  
  Conclusion
  SOD2 plays crucial roles in the tumor-initiating features that are related to TMZ resistance. Inhibition of the protein is a potential therapeutic strategy that can be used to enhance the effects of chemotherapy.
• 中文關鍵字：
• 英文關鍵字： SOD2, ROS, Glioblastoma, Tumor-initiating cells, Temozolomide