ONECUT2 which is targeted by hsa-miR-15a-5p enhances stemness maintenance of gastric cancer stem cells

Gastric cancer is the third dominating cause of cancer-associated death. MiroRNAs are potential clinical tools for cancer diagnosis and therapy. In this project, we demonstrated significant overexpression of ONECUT2 and down-regulation of hsa-miR-15a-5p in gastric cancer via bioinformatics analysis and in vitro assays. Meanwhile, ONECUT2 expression is related to clinical prognosis in gastric cancer and inversely proportional to the differentiation degree of gastric adenocarcinoma according to immunohistochemistry results. Then, we separated CD133+/CD44+ MKN45 by flow cytometry and found that, compared with parental MKN45, CD133+/CD44+ MKN45 gastric cancer stem cells (GCSCs) had higher levels of ONECUT2 and lower levels of hsa-miR-15a-5p. In addition, we applied both in vivo and ex vivo assays to demonstrate hsa-miR-15a-5p regulates the stemness maintenance, epithelial-mesenchymal transition, and chemosensitivity of GCSCs through targeting ONECUT2. Also, hsa-miR-15a-5p inhibits G0 phase block of GCSCs by regulating ONECUT2/β-catenin signaling pathway. However, this study has provided novel perspective into the dynamic control of cancer stem cells for advanced gastric cancer treatment.