Abstract: This study aimed to compare, analyze, and verify the differentially expressed genes（DEGs） obtain from primary gastric cancer cells infected with East Asian and Western strains of Helicobacter pylori to understand the difference in pathogenic mechanisms between East Asian and Western strains of H.pylori. The primary gastric cancer cells were infected with the East Asian strain GZ7 and the Western strain 26695 of H. pylori for 6 h at multiplicity of infection（MOI） 50∶1 and were collected for transcriptome sequencing. DEGs were screened with |log₂FC|＞1 and FDR≤0.05. Bioinformatics analysis of the DEGs was performed using the online OmicsBean-Cancer tool. 4 important genes of the DEGs were selected for further analysis by the TCGA database and validated by Western blot. There were 31 DEGs between the GZ7-infected and uninfected gastric cancer cells and 109 DEGs between the 26695-infected and uninfected gastric cancer cells groups, 22 DEGs were shared between GZ7-and 26695-infected groups, 9 DEGs were present only in GZ7 infected groups, and 87 DEGs present only in 26695-infected groups. These DEGs were involved in inflammation（TNF and NF-κB signaling pathway）, cell surface receptors（Toll-like and NOD-like receptor signaling pathway） and so on. Analysis of the TCGA database revealed that IL6 and DKK1 in gastric cancer tissue were significantly higher than that in normal tissue（P＜0.001）, higher expression of IL6 and DKK1 was negatively associated with a 10-year survival rate of gastric cancer patients（P＜0.01）. Western blot result confirmed that H. pylori infection up-regulated the expression of protein JUN and FOSL1（two transcription factors）, IL6 and DKK1（DEGs unique to East Asian strain） proteins in gastric cancer cells, and downregulation of JUN gene in cells suppressed the expression of IL6 and DKK1. When GZ7 was used to reinfect JUN-downregulated and control cells, protein expression of JUN, IL6 and DKK1 was restored. In conclusion, there is a clear difference in the DEGs generated by gastric cancer cells infected with the East Asian and Western strains of H. pylori which may be one of the reasons for the difference in the incidence of gastric cancer between East Asian and Western countries.