*These authors contributed equally to this work Background: Signal transducer and activator of transcription (STAT) proteins are wellknown transcription factors that play an important role in the progression of cancer. However, the association between STAT family genes and hepatocellular carcinoma (HCC) remains unclear. This study investigates the expression level, the prognostic value and the potential mechanism of STAT family genes in HCC. Methods: Data from 365 HCC patients in The Cancer Genome Atlas (TCGA) database and 241 HCC patients in the Gene Expression Omnibus (GEO) database were used to investigate the diagnostic and prognostic values of STAT genes by survival analysis and nomogram. Gene set enrichment analysis (GSEA) was used to investigate the potential mechanism of the STAT genes in the development of HCC. Results: Our results showed that STAT4/5B mRNA expression levels in HCC tissues were lower than those in normal tissues. Importantly, our results indicated that high expression of STAT5A, STAT5B and STAT6 was associated with better overall survival in HCC patients. Joint effects analysis of STAT5A, STAT5B and STAT6 suggested that the prognosis difference for any combination of genes was more significant than that for any individual gene. Then, we developed a risk score model could predict HCC prognosis and the nomogram visualized gene expression and clinical factors of probability for HCC prognosis. The ROC and calibration curves showed good performance in survival prediction in both the TCGA and the GEO databases. GSEA suggested that high expression of STAT5A, STAT5B and STAT6 were involved in immune-related biological processes, drug metabolism cytochrome P450, JAK-STAT signalling pathway, and PPAR signalling pathways. Conclusion: Our data suggest that STAT5A, STAT5B and STAT6 expression may be potential prognostic markers of HCC and, in combination, have a better predictive value for HCC prognosis.
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