Illustrating the pathogenesis of hepatocellular carcinoma (HCC) pathogenesis as well as identifying specific biomarkers are of great significance. The original CEL files were obtain from Gene Expression Omnibus, then affymetrix package was used to preprocess the CEL files, the function of DEGs were investigated by multiple bioinformatics approach. Finally, typical HCC cell lines and tissue samples were using to validate the role of CDC6 in vitro. Bioinformatics software was used to predict potential microRNA of CDC6. Luciferase assay was used to verify the interactions between CDC6 and microRNA. A total of 445 DEGs were identified in HCC tissues based on two GEO datasets. GSEA results showed that the significant enriched gene sets were only associated with cell cycle signaling pathway. In the co-expression analysis, there were 370 hub genes from the blue modules were screened. We integrated DEGs, hub genes, TCGA cohort and GSEA analyses to further obtain 10 upregulated genes for validation. These genes were overexpressed in HCC tissues and negatively associated with overall and disease-free survival in HCC patients and related to immune cell infiltration in HCC microenvironments. Finally, Cell Division Cycle 6 (CDC6) was highlighted as one of the most probable genes among the 10 candidates participating in cancer process. The expression of CDC6 either in public datasets and HCC tissues sample were commonly high than the non-cancerous counterpart. Furthermore, we recognized that miR-215-5p, could directly bind to the 3'UTR of CDC6. In addition, CDC6 promoted proliferation via regulation of G1 phase checkpoint and was negative regulated by miR-215-5p to involve in the proliferation of HCC. Our study suggested that CDC6 served as a potential therapeutic target for HCC.