The key signaling networks regulating cancer cell proliferation remain to be defined. The leucine-rich repeat containing G-protein coupled receptor 48 (GPR48) plays an important role in multiple organ development. In the present study, we investigated whether GPR48 functions in cancer cells using MCF-7, HepG2, NCI-N87 and PC-3 cells. We found that GPR48 overexpression promotes while its knockdown using small interfering RNA oligos inhibits cell proliferation. In addition, Wnt/${eta}$-catenin signaling was activated in cells overexpressing GPR48. Therefore, our results indicated that GPR48 activates Wnt/${eta}$-catenin signaling to regulate cancer cell proliferation.