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- Title
A SOX2 Reporter System Identifies Gastric Cancer Stem-Like Cells Sensitive to Monensin.
- Authors
Pádua, Diana; Barros, Rita; Luísa Amaral, Ana; Mesquita, Patrícia; Filipa Freire, Ana; Sousa, Mafalda; Filipe Maia, André; Caiado, Inês; Fernandes, Hugo; Pombinho, António; Filipe Pereira, Carlos; Almeida, Raquel
- Abstract
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.
- Subjects
CELL proliferation; CELL physiology; DRUG resistance; FLUOROURACIL; GENE expression; HETEROCYCLIC compounds; IMMUNOHISTOCHEMISTRY; MICE; POLYMERASE chain reaction; STEM cells; STOMACH tumors; TRANSCRIPTION factors; XENOGRAFTS; HIGH throughput screening (Drug development); DESCRIPTIVE statistics; IN vivo studies
- Publication
Cancers, 2020, Vol 12, Issue 2, p495
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers12020495