Construction of a Combined Hypoxia-related Genes Model for Hepatocellular Carcinoma Prognosis

Background Hepatocellular carcinoma (HCC) is the most common liver malignancy where tumorigenesis and metastasis are believed to be tied to the hallmarks of hypoxia and tumor microenvironment (TME). Methods In this study, to investigate the relationships among hypoxia, TME, and HCC prognosis, we collected two independent datasets from a public database (TCGA-LIHC for identification, GSE14520 for validation) and identified the hypoxia-related differentially expressed genes (DEGs) from the TCGA data, and the univariable Cox regression and lasso regression analyses were performed to construct the prognosis model. An HCC prognosis model with 4 hypoxia-related DEGs (NDRG1, ENO1, SERPINE1, ANXA2) was constructed, and high- and low-risk groups of HCC were established by the median of the model risk score. Results The survival analysis revealed significant differences between the two groups in both datasets, with the results of the AUC of the ROC curve of 1, 3, and 5 years in two datasets indicating the robustness of the prognosis model. Meanwhile, for the TCGA-LIHC data, the immune characteristics between the two groups revealed that the low-risk group presented higher levels of activated NK cells, monocytes, and M2 macrophages, and 7 immune checkpoint genes were found upregulated in the high-risk group. Additionally, the two groups have no difference in molecular characteristics (tumor mutational burden, TMB). The proportion of recurrence was higher in the high-risk group, and the correlation between the recurrence month and risk score was negative, indicating high-risk correlates with a short recurrence month. Conclusion In summary, this study shows the association among hypoxic signals, TME, and HCC prognosis and may help reveal potential regulatory mechanisms between hypoxia, tumorigenesis, and metastasis in HCC. The hypoxia-related model demonstrated the potential to be a predictor and drug target of prognosis.

Automated summary

In this study, a liver cancer prognosis model was constructed using four hypoxia-related genes (NDRG1, ENO1, SERPINE1, ANXA2) identified from two independent datasets. The model showed significant differences in survival and immune characteristics between high- and low-risk groups, indicating its potential as a predictor and drug target for liver cancer prognosis. This study provides insights into the association between hypoxia, tumor microenvironment, and liver cancer prognosis.