Journal
STEM CELL RESEARCH & THERAPY
Volume 12, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13287-021-02394-7
Keywords
MiR-375; SLC7A11; Ferroptosis; Stemness; Gastric cancer
Funding
- National Natural Science Foundation of China [81971562]
- Basic Scientific Research Business Expense Project of China Pharmaceutical University [2632020ZD10]
- Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions
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The study revealed that miR-375 can reduce the stemness of gastric cancer cells by targeting SLC7A11 and triggering ferroptosis. The miR-375/SLC7A11 regulatory axis may serve as a potential therapeutic target to attenuate the stemness of gastric cancer cells.
BackgroundGastric cancer stem cells (CSCs) are the main causes of metastasis and drug resistance. We previously indicated that miR-375 can inhibit Helicobacter pylori-induced gastric carcinogenesis; here, we aim to explore the effects and mechanisms of miR-375 on gastric cancer (GC) cell stemness.MethodsLentivirus infection was used to construct GC cells with ectopic expression of miR-375. In vitro and in vivo experiments, including analysis of tumor spheroid formation, CD44+ sub-population with stemness, stemness marker expression, and tumor-initiating ability, were performed to evaluate the effects of miR-375 on the stemness of GC cells. Furthermore, microarray and bioinformatics analysis were performed to search the potential targets of miR-375 in GC cells. Luciferase reporter, RNA immunoprecipitation, and RNA-FISH assays were carried out to verify the targeting of miR-375. Subsequently, combined with tissue microarray analysis, erastin-resistant GC cells, transmission electron microscopy, a series of agonists and oxidative stress markers, the underlying mechanisms contributing to miR-375-mediated effects were explored.ResultsMiR-375 reduced the stemness of GC cells in vitro and in vivo. Mechanistically, SLC7A11 was identified as a direct target of miR-375 and miR-375 attenuated the stemness of GC cells mainly through triggering SLC7A11-dependent ferroptosis.ConclusionMiR-375 can trigger the ferroptosis through targeting SLC7A11, which is essential for miR-375-mediated inhibition on GC cell stemness. These results suggest that the miR-375/SLC7A11 regulatory axis could serve as a potential target to provoke the ferroptosis and thus attenuate the stemness of GC cells.
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