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BACKGROUND Protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1) contributes to the proliferative, migratory, invasive and colony forming capabilities of oncocytes. Dysregulated expression of PKMYT1 is associated with numerous malignancies. However, at present, the functional role of PKMYT1 in osteosarcoma is still not clarified. OBJECTIVE The present study, therefore, aimed to investigate the prognostic value of PKMYT1 in osteosarcoma, and to explore the underlying molecular mechanism(s). METHODS To meet this end, the expression level of PKMYT1 in osteosarcoma was measured by immunohistochemical analysis. The prognostic value of PKMYT1 in osteosarcoma was analyzed on the basis of R2: Genomics Analysis and Visualization Platform. The functional role of PKMYT1 was subsequently investigated in MG63 cells by knocking down PKMYT1 expression via lentivirus encoding shRNA. MTT assay, scratch wound and Transwell assays were then used to determine whether PKMYT1 fulfills a role in the proliferative and invasive capabilities of the MG63 cells. Subsequently, the role of PKMYT1 in the apoptosis of the cells was assessed using western blot and immunofluorescence analyses. Finally, to determine whether PKMYT1 exerts its role through the NF κB pathway, fibroblast stimulating lipopeptide 1 (FSL 1) was used as an NF κB activator. RESULTS Compared with normal tissues, osteosarcoma tissues showed a significantly increased level of PKMYT1 expression. The clinical survival analysis indicated that patients with high PKMYT1 expression were associated with lower probabilities of overall survival and metastasis free survival compared with those with low PKMYT1 expression levels. Knockdown of PKMYT1 inhibited the migratory and invasive capabilities of the MG63 cells, and also facilitated their apoptosis. Moreover, the knockdown of PKMYT1 restrained the NF κB pathway in MG63 cells, whereas activating the NF κB pathway ameliorated the effects of silencing PKMYT1 on MG63 cells, suggesting that PKMYT1 functions via the NF κB pathway in MG63 cells. CONCLUSION Taken together, the results of the present study have shown that a high expression level of PKMYT1 is associated with poor prognosis of osteosarcoma, and that PKMYT1 is able to aggravate the malignant progression of MG63 cells via negatively regulating the NF κB pathway, suggesting that PKMYT1 may be a potential molecular therapeutic target for the treatment of osteosarcoma.