BACKGROUND This study was carried out to analyze TOP2A expression in lung adenocarcinoma (LUAD) and to assess its value in clinical diagnosis and prognosis. MATERIAL AND METHODS The Cancer Genome Atlas (TCGA) database was used to study the relationship of TOP2A expression with the progression and prognosis of LUAD. For a further elucidation of the value of TOP2A in LUAD, the effect of TOP2A knockout on cell viability and related protein expression of LUAD cell line A549 in vitro was investigated by using RNA interference, MTT, flow cytometry, RT-PCR, and western blot analysis. RESULTS According to the results of database analysis, TOP2A expression in LUAD was higher than that in normal lung tissues. There was a strong correlation of TOP2A expression with clinicopathological and epidemiological parameters of LUAD. The survival rate of LUAD patients with high TOP2A expression was lower than that of patients with low expression (P<0.001). The expression of TOP2A in A549 cells was higher than that in Beas-2B cells. After decreased expression of TOP2A in A549 cells, the proliferation of A549 cells was downregulated and the apoptosis rate was increased. It was further verified that TOP2A low expression exerts a role in LUAD through activation of the ERK/JNK/p-P38/CHOP signaling pathway. CONCLUSIONS The findings from this study showed that TOP2A expression was upregulated in a human lung adenocarcinoma cell line, and this finding was supported by bioinformatics analysis. Further studies are required to determine whether TOP2A expression is a prognostic biomarker and potential therapeutic target in patients with lung adenocarcinoma.