miRNA-223-3p regulates ECT2 to promote proliferation, invasion, and metastasis of gastric cancer through the Wnt/β-catenin signaling pathway.

PURPOSE

Expression of the guanine nucleotide exchange factor epithelial cell transforming 2 (ECT2) is elevated in gastric cancer (GC) but its biological function in GC is poorly understood. MicroRNAs (miRNAs) have great potential as therapeutic targets for GC through their ability to modulate gene expression. In the present study, we sought to identify potential miRNA-mRNA-protein regulatory pathways that might control ECT2 expression and function in GC.

METHODS

ECT2 expression was examined in clinical GC specimens by immunohistochemical staining, and protein levels were correlated with clinicopathological features and prognosis. TargetScan was used to identify potential ECT2 mRNA-complementary miRNAs, and the roles of ECT2 and miRNA-223-3p (miR-223-3p) in GC cell biology and signaling pathway activation were examined by targeted knockdown (KD) or overexpression (OE) of ECT2 and miR-223-3p in GC cell lines. A murine GC xenograft model was developed to explore the impact of ECT2 OE on tumor growth in vivo.

RESULTS

ECT2 expression was significantly elevated in GC specimens compared with normal gastric tissues and the level correlated positively with depth of invasion, ulceration, vascular tumor thrombus, neural invasion, and lymph node metastasis (p < 0.05). ECT2 was an independent prognostic factor for overall survival of GC patients (high ECT2 expression v.s. low ECT2 expression: χ = 29.831, p < 0.001). ECT2 KD or miR-223-3p OE markedly suppressed the proliferation, migration, and invasion of GC cells in vitro, whereas ECT2 OE had the opposite effects. ECT2 OE also promoted the growth of GC tumors in vivo. Tumor expression of Wnt2, β-catenin, and several downstream target proteins in GC cells were decreased by ECT2 KD or miR-223-3p OE but increased by ECT2 OE.

CONCLUSIONS

miR-223-3p regulates ECT2 expression to promote tumorigenic behavior of GC via activation of the Wnt/β-catenin signaling pathway, suggesting that ECT2 and miR-223-3p as potential therapeutic targets for GC.