AbstractObjectiveTo screen the gene related to osteosarcoma (OS) metastasis and the molecular mechanism.MethodsGEO database and R2 chip analysis platform were used to screen genes related to OS metastasis. UCSC gene browser was used to find the transcription factor (TF) of CLEC5A. The mRNA level and protein expression of CLEC5A in OS tissues and normal tissues were determined by RT‐PCR and Western blotting, respectively. OS cell lines MG‐63 were transfected with CEBPB recombinant plasmid. After transfection, the expression of CLEC5A in MG‐63 cells was determined and the cell proliferation situation was determined by clone formation assay.ResultsThree genes CLEC5A, ALOX5AP, and RNASE3 were obtained, and CLEC5A has the highest correlation with OS. CLEC5A has screened the gene related to OS metastasis, and CEBPB can be taken as TF regulating downstream gene CLEC5A. CEBPB can regulate the downstream CLEC5A as transcription factor. The relative mRNA level and protein expression of CLEC5A in OS tissues were significantly higher than those in normal tissues. CLEC5A can prevent OS metastasis. Transfection of CEBPB increased the expression of CLEC5A in MG‐63 cells and also inhibited the proliferation of OS.ConclusionCEBPB can inhibit the proliferation of OS cells via regulating the expression of CLEC5A.