A novel five-gene hypoxia-related gene signature predicts prognosis in patients with hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) has posed a serious threat to public health worldwide over the past decades. Despite advances in surgery, targeted therapy, and immunotherapy, the prognosis of patients with HCC remains poor. Therefore, more accurate prognostic models are urgently needed. Objective: To explore the relationship between hypoxia and HCC and construct a hypoxia-related gene prognostic model. To predict the overall survival of HCC patients by our model. Methods: Gene set variation analysis (GSVA) was performed using the GSE14520 dataset to identify the Hallmark gene set most strongly associated with the prognosis of HCC patients. A hypoxia-related gene (HRG) signature was then established and validated through multiple bioinformatics approaches. Gene set enrichment analysis was conducted to explore the potential signaling pathways associated with this novel five-gene HRG signature. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess the expression of the five HRGs in HCC patients. Results: GSVA identified the hypoxia Hallmark gene set as the factor most significantly correlated with HCC prognosis. A novel five-gene HRG signature was developed and validated across datasets. The area under the curve values for predicting 1–5-year survival were consistently >0.7. Both the five-gene HRG signature and tumor–node–metastasis (TNM) stage were independent prognostic factors in The Cancer Genome Atlas and GSE14520 cohorts. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enrichment in cell cycle, fatty acid metabolism, and peroxisome proliferator-activated receptor signaling pathways. qRT-PCR results indicated that most HRGs (except Lactate Dehydrogenase A (LDHA)) were differentially expressed between HCC and adjacent normal tissues. Conclusion: We constructed and validated a novel five-gene HRG signature and a prognostic nomogram. Combining this HRG signature with TNM stage improved the accuracy of prognostic prediction for HCC patients.