MicroRNAs are single-stranded RNA of 18-24 nt expressed endogenously that play important roles in cancer development. Here, we show that expression of miR-378 enhances cell survival, reduces caspase-3 activity, and promotes tumor growth and angiogenesis. Proteomic analysis indicates reduced expression of suppressor of fused (Sufu), a potential target of miR-378, which was confirmed in vitro and in vivo. Expression of a luciferase construct containing the target site in Sufu was repressed when cotransfected with miR-378. Transfection of a Sufu construct reversed the effect of miR-378, suggesting an important role for miR-378 in tumor cell survival. We also discovered that miR-378 targets Fus-1. Expression of luciferase constructs harboring the target sites in Fus-1 was repressed by miR-378. Fus-1 constructs with or without its 3' UTR were also generated. Cotransfection experiments showed that the presence of miR-378 repressed Fus-1 expression. Suppression of Fus-1 expression by siRNA against Fus-1 enhanced cell survival. Transfection of the Fus-1 construct reversed the function of miR-378 in cell survival. Our results suggest that miR-378 transfection enhanced cell survival, tumor growth, and angiogenesis through repression of the expression of two tumor suppressors, Sufu and Fus-1.