Proteolipid protein (PLP) was found related to several cancers,including breast cancer,hepatocellular carcinoma,osteosarcoma,and melanoma.PLP enhances proliferation,adhesion and invasion by binding specifically to PI3K to activate AKT pathway in melanoma.Therefore,we speculated that PLP has oncogenic potential.However,the regulatory mechanism of PLP in cancer cells is still unclear.Herein,we found that expression of microRNA-664 (miR-664) was significantly downregulated in melanoma cells and tissues compared with benign melanocytic naevi (BMN).The expression level of miR-664 was significantly correlated with patient survival.Ectopic expression of miR-664 reduced the proliferation and anchorage-independent growth of melanoma cells,while inhibiting miR-664 induced this effect.Furthermore,inhibition of miR-664 in melanoma cells resulted in modulation of their entry into the G1/S transitional phase,which was caused by downregulation of cyclin-dependent kinase (CDK) inhibitors P21 and upregulation of the cell-cycle regulator cyclin D1.Moreover,we demonstrated that miR-664 downregulated PLP expression by directly targeting the PLP 3’UTR.Taken together,our results suggest that miR-664 may play an important role in suppressing proliferation of melanoma cells and present a novel mechanism of microRNA-mediated direct suppression of PLP expression in cancer cells.