microRNA-1228⁎ impairs the pro-angiogenic activity of gastric cancer cells by targeting macrophage migration inhibitory factor

Our previous study has shown that microRNA-1228⁎ (miR-1228⁎) is downregulated in gastric cancer tissues and restoration of its expression retards tumor growth in a gastric cancer xenograft model. In this work, we aimed to explore the role of miR-1228⁎ in gastric cancer cell cycle progression and angiogenesis and to identify its functional target gene(s). It was found that miR-1228⁎ overexpression significantly inhibited the proliferation and colony formation of gastric cancer cells, compared to vector-transfected cells. As determined by propidium iodide staining, overexpression of miR-1228⁎ resulted in an enrichment of G0/G1 phase cells in gastric cancer cells. miR-1228⁎-overexpressing cells showed a significant reduction of vascular endothelial growth factor expression and secretion. Conditioned media from miR-1228⁎-overexpressing cells showed a reduced capacity to promote endothelial cell migration and tube formation. Mechanistically, macrophage migration inhibitory factor (MIF) was identified as a direct target gene of miR-1228⁎. Enforced expression of MIF rescued gastric cancer cells from miR-1228⁎-mediated suppression of proliferation and angiogenesis. In vivo xenograft mouse studies further demonstrated that co-expression of MIF with miR-1228⁎ in gastric cancer cells significantly restored tumor growth and increased microvascular density. Taken together, miR-1228⁎ acts as a negative regulator of gastric cancer growth and angiogenesis through downregulation of MIF. This work suggests miR-1228⁎ as a potential target for anti-angiogenic therapy against gastric cancer.