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AIM: To investigate the effect of doublecortin-like kinase 1 (DCLK1) on the biological properties of gastric cancer stem cells, and to explore its possible mechanism. METHODS: Serum-free suspension culture of gastric cancer stem cells and targeted inhibition of DCLK1 activity in gastric cancer stem cells with DCLK1 inhibitor DCLK1-IN-1 were performed. The expression levels of DCLK1, stemness-related proteins (SOX2 and OCT4), proliferation-related proteins (cyclin D1 and c-MYC), drug resistance-related proteins (ABCG2 and TOP2A), epithelial-mesenchymal transition-related proteins (E-cadherin, vimentin and Snail), and PI3K/AKT/mTOR signaling pathway-related proteins in gastric cancer stem cells were examined by Western blot. The effects of DCLK1 on viability and drug resistance of gastric cancer stem cells were determined by CCK-8 assay, and the effects of DCLK1 on self-renewal of gastric cancer stem cells were determined by methylcellulose spheroid-forming assay. Wound-healing and Transwell assays were performed to assess the effect of DCLK1 on the migration and invasion of gastric cancer stem cells. RESULTS: The expression levels of DCLK1 and stemness-related proteins SOX2 and OCT4 in gastric cancer stem cells were significantly higher than those in parental cells (P<0. 01). The proliferation, drug resistance, migration and invasion of gastric cancer stem cells in DCLK1 inhibition group were significantly lower than those in Sphere cell group (P<0. 01). The expression levels of proliferation-related proteins (c-MYC and cyclin D1) and drug resistance-related proteins (TOP2A and ABCG2) were down-regulated, the expression of epithelial marker E-cadherin was up-regulated, the expression of mesenchymal markers vimentin and Snail was down-regulated, and the expression levels of PI3K/AKT/mTOR signaling pathway-related proteins and their phosphorylation levels were reduced in DCLK1 inhibition group (P<0. 05). CONCLUSION: DCLK1 is highly expressed in gastric cancer stem cells, which may be involved in the proliferation, drug resistance and invasion of gastric cancer stem cells by regulating PI3K/AKT/mTOR signaling pathway. It suggests that DCLK1 can be used as a potential target for gastric cancer stem cells. [ABSTRACT FROM AUTHOR]