BACKGROUND Liver cancer ranks the third cause of cancer-related death worldwide. The most common type of liver cancer is hepatocellular carcinoma(HCC). The survival time for HCC patients is very limited by years due to the lack of efficient treatment, failure of early diagnosis, and poor prognosis. Ubiquitination plays an essential role in the biochemical processes of a variety of cellular functions.AIM To investigate three ubiquitination-associated genes in HCC.METHODS Herein, the expression levels of ubiquitin-conjugating enzymes 2(UBE2) including UBE2 C, UBE2 T, and UBE2 S in tumor samples of HCC patients and nontumor controls at the Cancer Genome Atlas(TCGA) database, was comprehensively analyzed. The relationship of UBE2 gene expression level with cancer stage, prognostic outcome, and TP53 mutant status was studied.RESULTS Our results showed that UBE2 C, UBE2 T, and UBE2 S genes were overexpressed in HCC samples compared to non-tumor tissues. Dependent on the cancer progression stage, three UBE2 genes showed higher expression in tumor tissues at all four stages compared to non-tumor control samples. Furthermore, a significantly higher expression of these genes was found in stage 2 and stage 3 cancers compared to stage 1 cancer. Additionally, overexpression of those genes was negatively associated with prognostic outcome and overall survival time. Patients with TP53 mutation showed a higher expression level of three UBE2 genes, indicating an association between UBE2 expression with p53 function.CONCLUSION In summary, this study shed light on the potential roles of UBE2 C, UBE2 T, UBE2 S on diagnostic and prognostic biomarkers for HCC. Moreover, based on our findings, it is appealing to further explore the correlation of those genes with TP53 mutation in HCC and the related mechanisms.