A SOX2 Reporter System Identifies Gastric Cancer Stem-Like Cells Sensitive to Monensin

Cancers

Carlos Filipe Pereira¹  Hugo Fernandes¹  Inês Caiado¹  Raquel Almeida²  Rita Barros²  António Pombinho²  Diana Pádua²  Ana Luísa Amaral²  Patrícia Mesquita²  Ana Filipa Freire²  Mafalda Sousa²  André Filipe Maia² 

[1] CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal;i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal;

关键词: cancer stem cells;    gastric cancer;    sox2;    monensin;    sore6-gfp reporter system;    drug resistance;    high-throughput screening;   

DOI  :  10.3390/cancers12020495

来源: DOAJ

【 摘 要 】

Gastric cancer remains a serious health burden with few therapeutic options. Therefore, the recognition of cancer stem cells (CSCs) as seeds of the tumorigenic process makes them a prime therapeutic target. Knowing that the transcription factors SOX2 and OCT4 promote stemness, our approach was to isolate stem-like cells in human gastric cancer cell lines using a traceable reporter system based on SOX2/OCT4 activity (SORE6-GFP). Cells transduced with the SORE6-GFP reporter system were sorted into SORE6+ and SORE6− cell populations, and their biological behavior characterized. SORE6+ cells were enriched for SOX2 and exhibited CSC features, including a greater ability to proliferate and form gastrospheres in non-adherent conditions, a larger in vivo tumor initiating capability, and increased resistance to 5-fluorouracil (5-FU) treatment. The overexpression and knockdown of SOX2 revealed a crucial role of SOX2 in cell proliferation and drug resistance. By combining the reporter system with a high-throughput screening of pharmacologically active small molecules we identified monensin, an ionophore antibiotic, displaying selective toxicity to SORE6+ cells. The ability of SORE6-GFP reporter system to recognize cancer stem-like cells facilitates our understanding of gastric CSC biology and serves as a platform for the identification of powerful therapeutics for targeting gastric CSCs.

【 授权许可】

Unknown