Seven Hypoxia and Immune-Related Features Predict Prognosis in Patients with Hepatocellular Carcinoma

Yun Lu; Xiangyu Li; Kai Zhao; Peng Qiu; Wei Yao

doi:10.1007/s10620-025-09152-2

Seven Hypoxia and Immune-Related Features Predict Prognosis in Patients with Hepatocellular Carcinoma

Dig Dis Sci. 2025 Jun 18. doi: 10.1007/s10620-025-09152-2. Online ahead of print.

Authors

Yun Lu¹, Xiangyu Li², Kai Zhao³, Peng Qiu³, Wei Yao⁴

Affiliations

¹ Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
² Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
³ Department of Biliary and Pancreatic Surgery/Cancer Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
⁴ Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. yw13557@tjh.tjmu.edu.cn.

PMID: 40531258
DOI: 10.1007/s10620-025-09152-2

Abstract

Background: The role of hypoxia and immunity in the progression of hepatocellular carcinoma (HCC) was highly critical. However, there were few application-based studies on hypoxia and immune molecules in HCC prognosis prediction. This study aims to reveal the prognostic significance of hypoxia- and immune-related genes in HCC.

Methods: We identified the hypoxia- and immune-related differentially expressed genes (HIDEGs) from the Cancer Genome Atlas (TCGA). Seven HIDEGs associated with the prognosis of HCC were identified with the Cox regression and LASSO analysis. The prognosis model was validated in both the TCGA (n = 420) and Gene Expression Omnibus (GEO) (GSE14520-GPL3921, n = 222) databases. CIBERSORT was applied to measure the fractions of immune cell types. The drug sensitivity analysis was used to evaluate the applicability of drug treatment to HCC patients. The effect of ADM on the malignant biological behaviors of HCC was measured by plate colony formation assay, Cell Counting Kit-8 (CCK-8) assay, scratch wound assay and Transwell migration and invasion assays.

Results: We identified 78 HIRDEGs associated with survival time in HCC, among them, seven genes were chosen to construct a prognosis model. The prognosis model showed good performance in predicting prognosis in HCC patients in both the TCGA (n = 420) and Gene Expression Omnibus (GEO) (GSE14520-GPL3921, n = 222) databases. Based on the median risk score, HCC patients were classified into high- and low-risk groups. The high-risk group suffered worse survival time and contained higher proportions of M0/M1 macrophages and monocytes, and showed greater expression of classical immune checkpoints, including PD-1, PD-L1, and CTLA4. Furthermore, we presented that ADM was up-regulated by hypoxia, and silencing its expression suppressed HCC cells proliferation, migration, and invasion in vitro.

Conclusion: The hypoxia- and immune-related signatures are promising biomarkers for HCC prognosis. ADM might be a novel target for HCC treatment.

Keywords: Hepatocellular carcinoma; Hypoxia; Immune; Prognostic; Risk score; TCGA.

Abstract

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