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Aim: Recent studies have suggested that the paired box 5 (PAX5) gene is connected with tumorigenesis of a wide variety of tumors.However,the link between PAX5 and non-small cell lung cancer (NSCLC) remains unclear.The aim of this study was to examine the expression of PAX5,its epigenetic inactivation,biological functions and molecular mechanism in NSCLC.Methods: The expression of PAX5 was examined by RT-PCR,immunohistochemical staining and western blotting.Promoter methylation of PAX5 was evaluated by methylation-specific polymerase chain reaction (MSP) and bisulfite genomic sequencing (BGS).The actions of ectopic PAX5 expression were detected by viability assay,colony formation,flow cytometry cell cycle and apoptosis analyses,transwell migration and invasion assays,along with in vivo tumorigenicity assay.The PAX5 target signal pathway was identified by western blotting.Results: PAX5 was silenced or down-regulated in seven of eight NSCLC cell lines tested.PAX5 was down-regulated significantly in NSCLC compared with adjacent non-cancerous tissues.The down-regulation of PAX5 was closely linked to the hypermethylation stims of the promoter and could be restored by demethylation.Ectopic expression of PAX5 in silenced NSCLC cell lines (A549 and H1975) inhibited colony formation and cell viability,arrested cell cycle,induced apoptosis,suppressed cell migration and invasion and repressed tumorigenicity in nude mice.We further found that PAX5 up-regulated p53 accumulation and reduced p-AKT protein leve.Conclusion: PAX5 appears to be a functional tumor suppressor which is inactivated by promoter methylation involved in NSCLC development and progression.PAX5 inhibits cell proliferation and induces,cell apoptosis through up-regulating p53 and down-regulating the p-AKT pathway.