Hypoxia-related signatures predicts survival, immunosuppression and PARP inhibitor resistance in HCC.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:40518504", "kind": "science-record", "revision": 2, "content_hash": "sha256:6b4837a316562353a2b0f7de342efc760836c0c6eb0d4569c04dc8c056d8de88", "created_at": "2026-11-01T20:30:37Z", "updated_at": "2026-11-01T21:35:18Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Hypoxia-related signatures predicts survival, immunosuppression and PARP inhibitor resistance in HCC.", "doi": "10.1007/s12672-025-02923-3", "pmid": "40518504", "authors": ["Min Su", "Haibo Duan", "Yu Gu", "Jianfu Zhao"], "journal": "Discover oncology", "year": 2025, "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.\nMETHODS: 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.\nRESULTS: 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.\nCONCLUSION: 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.", "claims": [{"id": "claim-method", "statement": "Based on the univariate Cox regression results, this study constructed a LASSO-Cox proportional hazards model by R glmnet package for variable selection and model optimization [21].", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40518504", "locator": "sections[9] \"LASSO-cox model construction\" paragraph 2", "quote": "Based on the univariate Cox regression results, this study constructed a LASSO-Cox proportional hazards model by R glmnet package for variable selection and model optimization [21]."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The datasets analyzed in this study are publicly accessible through three platforms: (1) Gene Expression Omnibus (GEO) for transcriptomic profiles, under accession numbers GSE185969 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE185969) and GSE20140 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE20140); (2) UCSC Xena (https://xenabrowser.net/datapages/?cohort=GDC TCGA Liver Cancer (LIHC)&removeHub=https%3 A%2 F%2Fxena.treehouse.gi.ucsc.edu%3A443) for TCGA-LIHC multi-omics data, including survival analysis and somatic mutation annotations; and (3) Biosino (https://www.biosino.org/node/project/detail/OEP000321) for CHCC liver cancer multi-omics integration. All data are openly available under the terms of their respective repositories.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40518504", "locator": "sections[26] \"notes\" paragraph 1", "quote": "The datasets analyzed in this study are publicly accessible through three platforms: (1) Gene Expression Omnibus (GEO) for transcriptomic profiles, under accession numbers GSE185969 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE185969) and GSE20140 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE20140); (2) UCSC Xena (https://xenabrowser.net/datapages/?cohort=GDC TCGA Liver Cancer (LIHC)&removeHub=https%3 A%2 F%2Fxena.treehouse.gi.ucsc.edu%3A443) for TCGA-LIHC multi-omics data, including survival analysis and somatic mutation annotations; and (3) Biosino (https://www.biosino.org/node/project/detail/OEP000321) for CHCC liver cancer multi-omics integration. All data are openly available under the terms of their respective repositories."}], "state": "complete"}, {"id": "claim-target-result", "statement": "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.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:40518504", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "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."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "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.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:40518504"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE185969"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE185969"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:40518504", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1007/s12672-025-02923-3", "sha256": "sha256:ca06817d22fb5616c3536c30115ff52a9236c1128040107ba80ac9ca60a62efc", "bytes": 32009, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1007/s12672-025-02923-3", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC12167732", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE185969", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE185969", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE185969", "version": null, "note": "The datasets analyzed in this study are publicly accessible through three platforms: (1) Gene Expression Omnibus (GEO) for transcriptomic profiles, under accession numbers GSE185969 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE185969) and GSE20140 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE20140); (2) UCSC Xena (https://xenabrowser.net/datapages/?cohort=GDC TCGA Liver Cancer (LIHC)&removeHub=https%3 A%2 F%2Fxena.treehouse.gi.ucsc.edu%3A443) for TCGA-LIHC multi-omics data, including survival analysis and somatic mutation annotations; and (3) Biosino (https://www.biosino.org/node/project/detail/OEP000321) for CHCC liver cancer multi-omics integration. All data are openly available under the terms of their respective repositories.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The datasets analyzed in this study are publicly accessible through three platforms: (1) Gene Expression Omnibus (GEO) for transcriptomic profiles, under accession numbers GSE185969 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE185969) and GSE20140 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE20140); (2) UCSC Xena (https://xenabrowser.net/datapages/?cohort=GDC TCGA Liver Cancer (LIHC)&removeHub=https%3 A%2 F%2Fxena.treehouse.gi.ucsc.edu%3A443) for TCGA-LIHC multi-omics data, including survival analysis and somatic mutation annotations; and (3) Biosino (https://www.biosino.org/node/project/detail/OEP000321) for CHCC liver cancer multi-omics integration. 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The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE185969", "GSE20140"], "resolved_accessions": ["GSE185969", "GSE20140"], "statements": ["The datasets analyzed in this study are publicly accessible through three platforms: (1) Gene Expression Omnibus (GEO) for transcriptomic profiles, under accession numbers GSE185969 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE185969) and GSE20140 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE20140); (2) UCSC Xena (https://xenabrowser.net/datapages/?cohort=GDC TCGA Liver Cancer (LIHC)&removeHub=https%3 A%2 F%2Fxena.treehouse.gi.ucsc.edu%3A443) for TCGA-LIHC multi-omics data, including survival analysis and somatic mutation annotations; and (3) Biosino (https://www.biosino.org/node/project/detail/OEP000321) for CHCC liver cancer multi-omics integration. All data are openly available under the terms of their respective repositories."], "basis": "The paper names GSE185969, GSE20140 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["cox_ph"], "assets": ["source:pmid:40518504", "data:geo:GSE185969"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE185969"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T19:54:22Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 8980, "completion_tokens": 2331, "cached_tokens": 256}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:40518504", "type": "paper", "label": "pmid:40518504"}, {"id": "source:pmid:40518504", "type": "manuscript", "label": "PMID 40518504 full text"}, {"id": "data:geo:GSE185969", "type": "dataset", "label": "GEO GSE185969"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:40518504", "type": "paper", "label": "pmid:40518504"}, {"id": "source:pmid:40518504", "type": "manuscript", "label": "PMID 40518504 full text"}, {"id": "data:geo:GSE185969", "type": "dataset", "label": "GEO GSE185969"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-40518504", "type": "extraction", "used": ["source:pmid:40518504"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE185969", "type": "accession_resolution", "used": ["data:geo:GSE185969"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:40518504", "parent_hash": "sha256:3f6a0d5fa30d587bd4b1ca65ad239fb2f5b919ff45c3979e9cb19d44e2c36ee6", "fork_of": null, "generation": 1}, "gaps": ["asset:data:geo:GSE185969 licence not read", "asset:data:geo:GSE185969 not downloaded", "asset:data:geo:GSE20140 licence not read", "asset:data:geo:GSE20140 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["cox_ph"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Based on the univariate Cox regression results, this study constructed a LASSO-Cox proportional hazards model by R glmnet package for variable selection and model optimization [21]."], "order_basis": "analysis_only", "id": "assay:1"}]}