Identification of key pathways and biomarkers in sorafenib-resistant hepatocellular carcinoma using bioinformatics analysis.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:30186410", "kind": "science-record", "revision": 5, "content_hash": "sha256:a2d6c10f65e6e7e3c42fa4356d0249ab59d50be490608738d6beb29c11fd1606", "created_at": "2026-11-01T15:40:37Z", "updated_at": "2026-11-01T22:00:01Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Identification of key pathways and biomarkers in sorafenib-resistant hepatocellular carcinoma using bioinformatics analysis.", "doi": "10.3892/etm.2018.6427", "pmid": "30186410", "authors": ["Danping Huang", "Weiqu Yuan", "Hanmin Li", "Shaodong Li", "Zuanguang Chen", "Hongzhi Yang"], "journal": "Experimental and therapeutic medicine", "year": 2018, "abstract": "Hepatocellular carcinoma (HCC) is one of the most common malignant types of cancer, with a high mortality rate. Sorafenib is the sole approved oral clinical therapy against advanced HCC. However, individual patients exhibit varying responses to sorafenib and the development of sorafenib resistance has been a new challenge for its clinical efficacy. The current study identified gene biomarkers and key pathways in sorafenib-resistant HCC using bioinformatics analysis. Gene dataset GSE73571 was obtained from the Gene Expression Omnibus (GEO) database, including four sorafenib-acquired resistant and three sorafenib-sensitive HCC phenotypes. Differentially expressed genes (DEGs) were identified using the web tool GEO2R. Functional and pathway enrichment of DEGs were analyzed using the Database for Annotation, Visualization and Integrated Discovery and the protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape. A total of 1,319 DEGs were selected, which included 593 upregulated and 726 downregulated genes. Functional and pathway enrichment analysis revealed DEGs enriched in negative regulation of endopeptidase activity, cholesterol homeostasis, DNA replication and repair, coagulation cascades, insulin resistance, RNA transport, cell cycle and others. Eight hub genes, including kininogen 1, vascular cell adhesion molecule 1, apolipoprotein C3, alpha 2-HS glycoprotein, erb-b2 receptor tyrosine kinase 2, secreted protein acidic and cysteine rich, vitronectin and vimentin were identified from the PPI network. In conclusion, the present study identified DEGs and key genes in sorafenib-resistant HCC, which further the knowledge of potential mechanisms in the development of sorafenib resistance and may provide potential targets for early diagnosis and new treatments for sorafenib-resistant HCC.", "claims": [{"id": "claim-method", "statement": "DEGs in resistant and sensitive samples were analyzed by GEO2R. |log2FC|≥0.4 and P<0.01 were used as cut-off criteria and defined a statistically significant difference", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:30186410", "locator": "sections[5] \"DEG analysis\" paragraph 2", "quote": "DEGs in resistant and sensitive samples were analyzed by GEO2R. |log2FC|≥0.4 and P<0.01 were used as cut-off criteria and defined a statistically significant difference"}], "state": "complete"}, {"id": "claim-data-access", "statement": "Data and materials have been provided as part of the submitted article.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:30186410", "locator": "sections[17] \"Availability of data and materials\" paragraph 2", "quote": "Data and materials have been provided as part of the submitted article."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": null, "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:30186410"], "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:GSE73571"], "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:GSE73571"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:30186410", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3892/etm.2018.6427", "sha256": "sha256:9bcdc1c67795c0613cb2afbf52a126cae22b98bfe461bbf82bb1121c8db14b53", "bytes": 42474, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3892/etm.2018.6427", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC6122189", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE73571", "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=GSE73571", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE73571", "version": null, "note": "Data and materials have been provided as part of the submitted article.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Data and materials have been provided as part of the submitted article.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM1898056", "GSM1898057", "GSM1898058", "GSM1898059", "GSM1898060", "GSM1898061", "GSM1898062", "GSM1898063", "GSM1898064", "GSM1898065", "GSM1898066", "GSM1898067", "GSM1898068", "GSM1898069", "GSM1898070", "GSM1898071"], "sample_count": 16, "group_sizes": null, "group_sizes_basis": null, "platform": "6244", "taxon": "Homo sapiens", "title": "TUMOR INITIATING CELLS AND IGF/FGF SIGNALING CONTRIBUTE TO SORAFENIB RESISTANCE IN HEPATOCELLULAR CARCINOMA", "resolution_checked_at": "2026-11-01T15:39:55Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "asset:table:pmid:30186410:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:1cbea5afaf188a13bfe48a0a0572725ddfbd9ef484e5dd325167a5467208e0a0", "bytes": 2902, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[11]/table-wrap[1]#tI-etm-0-0-6427", "version": null, "note": "Gene ontology analysis of upregulated and downregulated genes in sorafenib-resistant HCC.", "structure": {"pmcid": "PMC6122189", "section_index": 11, "section_title": "GO enrichment analysis", "row_count": 40, "column_count": 5}, "table": {"label": "Table I.", "caption": "Gene ontology analysis of upregulated and downregulated genes in sorafenib-resistant HCC.", "rows": [["A, Upregulated expression"], [""], ["Category", "Term", "Count", "%", "P-value"], ["GOTERM_CC_DIRECT", "GO:0005615/extracellular space", "110", "16.492", "<0.001"], ["GOTERM_CC_DIRECT", "GO:0070062/extracellular exosome", "177", "26.537", "<0.001"], ["GOTERM_CC_DIRECT", "GO:0005576/extracellular region", "100", "14.993", "<0.001"], ["GOTERM_CC_DIRECT", "GO:0072562/blood microparticle", "21", "3.148", "<0.001"], ["GOTERM_CC_DIRECT", "GO:0016021/integral component of membrane", "235", "35.232", "<0.001"], ["GOTERM_BP_DIRECT", "GO:0010951/negative regulation of endopeptidase activity", "18", "2.699", "<0.001"], ["GOTERM_BP_DIRECT", "GO:0042632/cholesterol homeostasis", "13", "1.949", "<0.001"], ["GOTERM_BP_DIRECT", "GO:0042730/fibrinolysis", "8", "1.199", "<0.001"], ["GOTERM_BP_DIRECT", "GO:0002576/platelet degranulation", "15", "2.249", "<0.001"], ["GOTERM_BP_DIRECT", "GO:0030198/extracellular matrix organization", "20", "2.999", "<0.001"], ["GOTERM_MF_DIRECT", "GO:0005518/collagen binding", "11", "1.649", "<0.001"], ["GOTERM_MF_DIRECT", "GO:0005102/receptor binding", "29", "4.348", "<0.001"], ["GOTERM_MF_DIRECT", "GO:0004252/serine-type endopeptidase activity", "24", "3.598", "<0.001"], ["GOTERM_MF_DIRECT", "GO:0001948/glycoprotein binding", "10", "1.499", "<0.001"], ["GOTERM_MF_DIRECT", "GO:0008131/primary amine oxidase activity", "4", "0.600", "<0.001"], [""], ["Extracellular space means GO enrichment of cellular primarily enriches in the extracellular space."], [""], ["B, downregulated expression"], [""], ["Category", "Term/gene function", "Count", "%", "P-value"], [""], ["GOTERM_MF_DIRECT", "GO:0044822/poly(A) RNA binding", "99", "18.099", "<0.001"], ["GOTERM_MF_DIRECT", "GO:0004386/helicase activity", "20", "3.656", "<0.001"], ["GOTERM_MF_DIRECT", "GO:0005524/ATP binding", "89", "16.271", "<0.001"], ["GOTERM_MF_DIRECT", "GO:0004004/ATP-dependent RNA helicase activity", "14", "2.559", "<0.001"], ["GOTERM_MF_DIRECT", "GO:0008026/ATP-dependent helicase activity", "9", "1.645", "<0.001"], ["GOTERM_CC_DIRECT", "GO:0005730/nucleolus", "75", "13.711", "<0.001"], ["GOTERM_CC_DIRECT", "GO:0005654/nucleoplasm", "152", "27.788", "<0.001"], ["GOTERM_CC_DIRECT", "GO:0005813/centrosome", "43", "7.861", "<0.001"], ["GOTERM_CC_DIRECT", "GO:0005634/nucleus", "199", "36.380", "<0.001"], ["GOTERM_CC_DIRECT", "GO:0005814/centriole", "16", "2.925", "<0.001"], ["GOTERM_BP_DIRECT", "GO:0006260/DNA replication", "25", "4.570", "<0.001"], ["GOTERM_BP_DIRECT", "GO:0006281/DNA repair", "27", "4.936", "<0.001"], ["GOTERM_BP_DIRECT", "GO:0000732/strand displacement", "10", "1.828", "<0.001"], ["GOTERM_BP_DIRECT", "GO:0000731/DNA synthesis involved in DNA repair", "11", "2.011", "<0.001"], ["GOTERM_BP_DIRECT", "GO:0006974/cellular response to DNA damage stimulus", "23", "4.205", "<0.001"]], "row_count": 40, "column_count": 5, "numeric_cells": 120, "header_rows": 3, "locator": "section[11]/table-wrap[1]#tI-etm-0-0-6427"}}, {"id": "asset:table:pmid:30186410:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:a0602d9ed6dbeb3e4d47bea2c7d0aa6ea37083a34f7bb912a2856a2e51277861", "bytes": 2302, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[12]/table-wrap[1]#tII-etm-0-0-6427", "version": null, "note": "KEGG pathway analysis of upregulated and downregulated genes in sorafenib-resistant hepatocellular carcinoma.", "structure": {"pmcid": "PMC6122189", "section_index": 12, "section_title": "KEGG pathway analysis", "row_count": 18, "column_count": 5}, "table": {"label": "Table II.", "caption": "KEGG pathway analysis of upregulated and downregulated genes in sorafenib-resistant hepatocellular carcinoma.", "rows": [["A, Upregulated genes"], [""], ["Name", "Gene count", "%", "P-value", "Genes"], ["hsa04610: Complement and coagulation cascades", "20", "2.999", "<0.001", "KNG1, F12, F10, CFB, C3, C1R, SERPING1, F7, C1S, C8B, FGG, FGB, SERPINF2, KLKB1, SERPINA5, SERPIND1, C2, CFI, PLAU, F2R"], ["hsa04142: Lysosome", "14", "2.099", "0.003047", "TCIRG1, CTSZ, CLTB, ACP5, ACP2, CTSA, CTSS, CTSL, LAPTM5, TPP1, ARSA, CTSE, SMPD1, CTSD"], ["hsa04931: Insulin resistance", "13", "1.949", "0.003298", "SREBF1, NR1H2, PPP1R3C, PPP1R3B, SOCS3, SLC2A2, PRKAG2, PRKAB2, NFKBIA, CREB3L3, SLC27A3, CPT1A, PCK1"], ["hsa01100: Metabolic pathways", "74", "11.094", "0.006009", "TM7SF2, ALAD, OGDHL, ADH1C, ADH1A, AGXT, CKB, PTGIS, P4HA2, ST3GAL5, MAT1A, RGN, DAO, ITPK1, AGPAT3, AGPAT2, GATM, ACADS, SPTLC3, FAXDC2, PISD, PNPLA3, PMM1, ALDH3B1, DGAT2, CYP27A1, HAO2, EXT1, AOC1, AKR1D1, LCT, AOC3, ACAA1, GALNT2, ENPP7, ASS1, HSD17B2, ALDOC, ENPP3, CERS4, PLPP3, PIPOX, THTPA, B3GNT5, DHCR7, PLA2G12B, PEMT, HAAO, ENO3, ETNK2, FUT2, BDH1, GAL3ST1, ACSL5, CYP19A1, TCIRG1, MOGAT3, ST6GAL1, NDUFA2, SI, MAOB, HOGA1, AMPD3, IDNK, PCK1, POLD4, BAAT, HMGCS2, SMPD1, LIPC, PHYKPL, PON3"], ["hsa04975: Fat digestion and absorption", "7", "1.049", "0.007472", "APOA4, ABCG8, MOGAT3, DGAT2, PLA2G12B, PLPP3, AGPAT2"], [""], ["B, Downregulated genes"], [""], ["Name", "Gene count", "%", "P-value", "Genes"], [""], ["hsa03008: Ribosome biogenesis in eukaryotes", "17", "3.108", "<0.001", "XPO1, GTPBP4, UTP6, UTP15, GNL3L, BMS1, DROSHA, WDR36, POP1, WDR3, NOP58, GNL2, MDN1, RBM28, SPATA5, WDR43, GNL3"], ["hsa03013: RNA transport", "17", "3.108", "<0.001", "XPOT, XPO1, XPO5, ALYREF, EIF5B, NUPL2, NUP155, PNN, TRNT1, UPF3B, SEH1L, NUP205, POP1, EIF3J, RANBP2, TPR, GEMIN5"], ["hsa03460: Fanconi anemia pathway", "9", "1.645", "<0.001", "FANCM, BLM, FANCD2, FANCI, BRCA2, BRIP1, ATR, FANCA, BRCA1"], ["hsa04742: Taste transduction", "7", "1.280", "<0.001", "TAS2R13, TAS2R14, TAS2R19, TAS2R46, TAS2R43, TAS2R20, TAS2R10"], ["hsa04110: Cell cycle", "9", "1.645", "0.014438", "CDC7, CDC6, RBL1, PRKDC, ATR, MYC, CDC25A, ATM, STAG1"]], "row_count": 18, "column_count": 5, "numeric_cells": 48, "header_rows": 3, "locator": "section[12]/table-wrap[1]#tII-etm-0-0-6427"}}], "gaps": ["asset:data:geo:GSE73571 not downloaded", "asset:data:geo:GSE73571 licence not read"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "network_analysis", "specific": "ppi_network", "label": "Network / pathway analysis", "dsl_operations": ["build_graph", "centrality_scores", "pathway_enrich"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["edge_list"], "evidence": {"score": 0.7, "band": "medium", "quote": "protein-protein interaction"}}, {"id": "method-2", "family": "network_analysis", "specific": "pathway_enrichment", "label": "Network / pathway analysis", "dsl_operations": ["pathway_enrich"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["edge_list"], "evidence": {"score": 0.7, "band": "medium", "quote": "pathway enrichment"}}, {"id": "method-3", "family": null, "specific": null, "label": "GEO2R", "dsl_operations": [], "missing_operations": [], "expressible": null, "parameters": {}, "data_shapes": [], "evidence": {"score": 1.0, "band": "verbatim", "quote": "DEGs in resistant and sensitive samples were analyzed by GEO2R. |log2FC|≥0.4 and P<0.01 were used as cut-off criteria and defined a statistically significant difference"}}], "targets": [], "gaps": ["method.reader_named_unmapped"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["build_graph", "centrality_scores", "pathway_enrich"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: ppi_network."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE73571"], "resolved_accessions": ["GSE73571"], "statements": ["Data and materials have been provided as part of the submitted article."], "basis": "The paper names GSE73571 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": ["build_graph", "centrality_scores", "pathway_enrich"], "assets": ["source:pmid:30186410", "data:geo:GSE73571", "asset:table:pmid:30186410:1", "asset:table:pmid:30186410:2"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE73571"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:12:12Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 3, "usage": {"prompt_tokens": 36006, "completion_tokens": 786, "cached_tokens": 784}}, "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:30186410", "type": "paper", "label": "pmid:30186410"}, {"id": "source:pmid:30186410", "type": "manuscript", "label": "PMID 30186410 full text"}, {"id": "data:geo:GSE73571", "type": "dataset", "label": "GEO GSE73571"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:30186410", "type": "paper", "label": "pmid:30186410"}, {"id": "source:pmid:30186410", "type": "manuscript", "label": "PMID 30186410 full text"}, {"id": "data:geo:GSE73571", "type": "dataset", "label": "GEO GSE73571"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-30186410", "type": "extraction", "used": ["source:pmid:30186410"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE73571", "type": "accession_resolution", "used": ["data:geo:GSE73571"], "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:30186410", "parent_hash": "sha256:dd066ad41ebe5e0c0c198183c703edabee02074a5e285105f82cc3f3b69d354a", "fork_of": null, "generation": 4}, "gaps": ["asset:data:geo:GSE73571 licence not read", "asset:data:geo:GSE73571 not downloaded", "execution.not_run", "method.reader_named_unmapped", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "analysis", "definition_id": "network_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["build_graph", "centrality_scores", "pathway_enrich"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 0.7, "evidence": ["protein-protein interaction"], "order_basis": "analysis_only", "id": "assay:1"}]}