Hypoxia-related signatures predicts survival, immunosuppression and PARP inhibitor resistance in HCC
Abstract Background Despite extensive research on hypoxia in hepatocellular carcinoma (HCC), previous studies have relied on pre-existing hypoxia gene sets, limiting their specificity. We developed a novel approach using direct comparison of hypoxic versus normoxic HCC cell lines to establish a more...
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| Format: | Article |
| Language: | English |
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Springer
2025-06-01
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| Series: | Discover Oncology |
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| Online Access: | https://doi.org/10.1007/s12672-025-02923-3 |
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| author | Min Su Haibo Duan Yu Gu Jianfu Zhao |
| author_facet | Min Su Haibo Duan Yu Gu Jianfu Zhao |
| author_sort | Min Su |
| collection | DOAJ |
| description | Abstract Background Despite extensive research on hypoxia in hepatocellular carcinoma (HCC), previous studies have relied on pre-existing hypoxia gene sets, limiting their specificity. We developed a novel approach using direct comparison of hypoxic versus normoxic HCC cell lines to establish a more precise hypoxia signature. Methods Through differential gene expression analysis of HCC cells under controlled oxygen conditions (GSE185969) and integration with TCGA-LIHC data, we identified and validated a highly specific 29-gene hypoxia signature. We performed comprehensive immune profiling and genomic instability analyses using multi-omics approaches. Results Our HCC-specific hypoxia signature demonstrated superior prognostic value (AUC: 0.805, 0.805, 0.748 at 1/3/5 years) compared to conventional hypoxia markers. High-risk tumors showed distinct immunosuppressive features including reduced CD8 + T cells and elevated Th2 cells, along with significantly increased expression of immune checkpoints CD274 (PD-1, p < 0.05) and CD276 (B7-H3, r = 0.62, p < 0.001). Notably, we uncovered an unexpected inverse relationship between hypoxia-induced genomic instability and PARP inhibitor sensitivity, challenging current therapeutic paradigms. Conclusion Our methodology establishes a more precise hypoxia signature specific to HCC, advancing beyond traditional approaches. The paradoxical finding of reduced PARP inhibitor sensitivity in genomically unstable tumors reveals new complexities in hypoxia-driven treatment resistance, suggesting the need for alternative therapeutic strategies in hypoxic HCC. |
| format | Article |
| id | doaj-art-ecf1a7c334eb42ad8febc43d1184df5b |
| institution | DOAJ |
| issn | 2730-6011 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj-art-ecf1a7c334eb42ad8febc43d1184df5b2025-08-20T03:22:50ZengSpringerDiscover Oncology2730-60112025-06-0116111410.1007/s12672-025-02923-3Hypoxia-related signatures predicts survival, immunosuppression and PARP inhibitor resistance in HCCMin Su0Haibo Duan1Yu Gu2Jianfu Zhao3Department of Oncology, Cancer Diagnosis and Therapy Research Center, The First Affiliated Hospital of Jinan UniversityDepartment of Oncology, Cancer Diagnosis and Therapy Research Center, The First Affiliated Hospital of Jinan UniversityGuangzhou Institute of Cancer Research, Affiliated Cancer Hospital,Guangzhou Medical UniversityDepartment of Oncology, Cancer Diagnosis and Therapy Research Center, The First Affiliated Hospital of Jinan UniversityAbstract Background Despite extensive research on hypoxia in hepatocellular carcinoma (HCC), previous studies have relied on pre-existing hypoxia gene sets, limiting their specificity. We developed a novel approach using direct comparison of hypoxic versus normoxic HCC cell lines to establish a more precise hypoxia signature. Methods Through differential gene expression analysis of HCC cells under controlled oxygen conditions (GSE185969) and integration with TCGA-LIHC data, we identified and validated a highly specific 29-gene hypoxia signature. We performed comprehensive immune profiling and genomic instability analyses using multi-omics approaches. Results Our HCC-specific hypoxia signature demonstrated superior prognostic value (AUC: 0.805, 0.805, 0.748 at 1/3/5 years) compared to conventional hypoxia markers. High-risk tumors showed distinct immunosuppressive features including reduced CD8 + T cells and elevated Th2 cells, along with significantly increased expression of immune checkpoints CD274 (PD-1, p < 0.05) and CD276 (B7-H3, r = 0.62, p < 0.001). Notably, we uncovered an unexpected inverse relationship between hypoxia-induced genomic instability and PARP inhibitor sensitivity, challenging current therapeutic paradigms. Conclusion Our methodology establishes a more precise hypoxia signature specific to HCC, advancing beyond traditional approaches. The paradoxical finding of reduced PARP inhibitor sensitivity in genomically unstable tumors reveals new complexities in hypoxia-driven treatment resistance, suggesting the need for alternative therapeutic strategies in hypoxic HCC.https://doi.org/10.1007/s12672-025-02923-3Hepatocellular carcinomaHypoxiaGenomic instabilityTumor immune microenvironmentPrognostic signature |
| spellingShingle | Min Su Haibo Duan Yu Gu Jianfu Zhao Hypoxia-related signatures predicts survival, immunosuppression and PARP inhibitor resistance in HCC Discover Oncology Hepatocellular carcinoma Hypoxia Genomic instability Tumor immune microenvironment Prognostic signature |
| title | Hypoxia-related signatures predicts survival, immunosuppression and PARP inhibitor resistance in HCC |
| title_full | Hypoxia-related signatures predicts survival, immunosuppression and PARP inhibitor resistance in HCC |
| title_fullStr | Hypoxia-related signatures predicts survival, immunosuppression and PARP inhibitor resistance in HCC |
| title_full_unstemmed | Hypoxia-related signatures predicts survival, immunosuppression and PARP inhibitor resistance in HCC |
| title_short | Hypoxia-related signatures predicts survival, immunosuppression and PARP inhibitor resistance in HCC |
| title_sort | hypoxia related signatures predicts survival immunosuppression and parp inhibitor resistance in hcc |
| topic | Hepatocellular carcinoma Hypoxia Genomic instability Tumor immune microenvironment Prognostic signature |
| url | https://doi.org/10.1007/s12672-025-02923-3 |
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