miR-345 inhibits migration and stem-like cell phenotype in gastric cancer via inactivation of Rac1 by targeting EPS8

• Published in: Acta biochimica et biophysica Sinica 2020-03, Vol.52 (3), p.259-267
• Main Authors: Zhang, Jieyun, Wang, Chenchen, Yan, Shican, Yang, Yanan, Zhang, Xiaowei, Guo, Weijian
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adult; Aged; Aged, 80 and over; Cell Line, Tumor; Cell Movement - physiology; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Humans; Male; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Neoplasm Metastasis; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Prognosis; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; RNA Interference; Signal Transduction; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology
• ISSN: 1672-9145; 1745-7270
• DOI: 10.1093/abbs/gmz166

Tumor metastasis is the main cause of treatment failure and death in patients with late stage of gastric cancer (GC). Studies showed that microRNAs (miRNAs) are important regulators in the process of tumor metastasis. In this study, we used miRNA array analysis to search for metastasis-associated miRNAs in primary and matched metastasis tissues of patients with GC and found that miR-345-5p (miR-345) was significantly higher in primary sites. Decreased expression of miR-345 was observed in GC tissues and cell lines, which was correlated with aggressive stage and grade. Patients with a higher level of miR-345 had a better prognosis. miR-345 could inhibit the migration and spheroid formation abilities in GC cell lines in transwell assay and spheroid formation assay. RNA sequencing and bioinformatics analysis revealed that miR-345 downregulated the epidermal growth factor receptor pathway substrate 8 (EPS8) and its downstream Rac1 signaling. Mechanistically, we confirmed that miR-345 could target EPS8 by directly binding to its 3' untranslated region by luciferase reporter assay. Further rescue assay showed that the ability of miR-345 in inhibiting the migration, stem-like cell phenotype, and epithelial-mesenchymal transition (EMT) in GC was partly dependent on targeting EPS8. In conclusion, miR-345 plays an inhibitory role in GC metastasis through inhibiting cell migration, EMT, and cancer stem cell phenotype via inactivation of Rac1 signaling by targeting EPS8, which provides the potential therapeutic and predictive value of miR-345 in GC.