In conclusion, we identified 11 key genes (RRM2, NDC80, ECT2, CCNB1, ASPM, CDK1, PRC1, KIF20A, DTL, TOP2A, and PBK) that may play a vital role in the pathogenesis of HCC and drive the communication between tumor cells and the TME and act as a promising diagnostic, therapeutic, and prognostic biomarker in HCC patients. This evidence concerns the gene TOP2A and hepatocellular carcinoma.