Background and purpose: Destroying the balance of copper ions in the body may promote the occurrence and development of cancer. This study aimed to investigate the effects of copper ion on cell proliferation and elucidate the clinical significance of copper chaperone genes in lung cancer. Methods: The effects of copper ion on cell proliferation were determined by trypan blue exclusion experiment. Western blot assays were performed to test the effects of copper on the expressions of extracellular regulated protein kinase (ERK) and phosphorylated ERK (p-ERK). Tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) was used to induce lung cancer in mice

and the copper content in lung cancer tissues and normal lung tissues was detected by inductively coupled plasma mass spectrometry (ICP-MS). Databases including The Cancer Genome Atlas (TCGA)

Oncomine and the Kaplan-Meier Plotter website containing the microarray data of patients with non-small cell lung cancer (NSCLC) were used to analyze the correlation between the mRNA expression levels of copper chaperone for superoxide dismutase (CCS)

cytochrome C oxidase copper chaperone (COX17) and antioxidant 1 copper chaperone (ATOX1) and the prognosis of lung cancer patients. Results: In vitro experimental results showed that copper ions at a concentration of 5 μmol/L was able to significantly promote the proliferation of lung cancer cells and normal lung epithelia cells

and induced the activation of intracellular ERK signaling pathways. In the NNK-induced lung cancer mouse model

the concentration of copper ion was significantly higher in cancer tissues than in normal lung tissues. In TCGA and Oncomine databases

the expression levels of CCS

COX17 and ATOX1 were significantly higher in cancer tissues than in counterpart normal controls. The expression levels were inversely associated with prognosis of the patients. Conclusion: Under specific concentration range

copper ions can promote cell proliferation. The copper chaperone genes could potentially be used as biomarkers to predict the prognosis of lung cancer patients.