Existing targeted therapies for hepatocellular carcinoma (HCC) are resistant and have limitations. It is crucial to find new HCC-related target genes. RNA-sequencing data of HCC were gathered from The Cancer Genome Atlas and Gene Expression Omnibus datasets. Initially, differentially expressed genes between normal and tumor tissues were identified from four Gene Expression Omnibus datasets, GSE36376, GSE102079, GSE54236, and GSE45267. GO terms and KEGG pathway enrichment analyses were performed to explore the potential biological functions of differentially expressed genes. A PPI network was constructed by using the STRING database, and up-regulated and down-regulated hub genes were defined through 12 topological approaches. Subsequently, the correlation bounded by up-regulated genes and down-regulated genes in the diagnosis, prognosis, and clinicopathological features of HCC was analyzed. Beyond a shadow of doubt, the key oncogene and tumor suppressor gene were screened out, and the specific mechanism was investigated through GSEA enrichment analysis and immune correlation analysis. The role of in HCC was further verified by western blot, CCK8, transwell, and tube formation experiments. , , , , , and are good indicators of HCC diagnosis and prognosis. The low expressions of , , and indicate malignant progression and poor prognosis of HCC. was found to be closely related to , , and pathways. Experiments showed that promotes HCC cell proliferation, migration, invasion, and tube formation in HUVEC cells. was negatively correlated with the degree of immune infiltration, and low expression of suggested a poor response to immunotherapy. The role of HCC-related oncogenes and tumor-suppressor genes in diagnosis and prognosis was identified. In addition, we have found that may promote tumor proliferation through angiogenesis and may be a predictor of tumor immunotherapy response.