{"gene":"COL8A1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2005,"finding":"Targeted disruption of both Col8a1 and Col8a2 in mice demonstrates that type VIII collagen is required for normal anterior eye development: null mice show a thin corneal stroma with reduced fibroblastic cell layers, markedly thinned Descemet's membrane, enlarged and numerically reduced corneal endothelial cells, and decreased endothelial cell proliferation in response to growth factors in vitro, establishing a peri/subcellular matrix role for collagen VIII in supporting cell proliferation.","method":"Targeted gene knockout (Col8a1/Col8a2 double null mice), histology, in vitro proliferation assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple defined cellular phenotypes, replicated across two gene knockouts, in vivo and in vitro readouts","pmids":["16051690"],"is_preprint":false},{"year":1991,"finding":"The primary structure of the human COL8A1-encoded alpha1(VIII) chain was determined from genomic DNA sequencing; it shares the same domain structure (triple-helical and C-terminal non-triple-helical domains encoded within a single large exon) as the rabbit alpha1(VIII) chain, and the gene was mapped to the long arm of human chromosome 3. Type VIII collagen molecules are heterotrimers composed of alpha1(VIII) and alpha2(VIII) chains in a 2:1 ratio.","method":"Genomic DNA sequencing, chromosomal mapping (in situ hybridization)","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct sequencing and chromosomal mapping establishing primary structure and gene organization, foundational structural characterization","pmids":["2029894"],"is_preprint":false},{"year":2024,"finding":"COL8A1 secreted by THBS2+ cancer-associated fibroblasts directly interacts with the ITGB1 (integrin-β1) receptor on colorectal cancer cells, activating the PI3K/AKT signaling pathway, promoting EMT, and conferring oxaliplatin resistance; ITGB1 knockdown or AKT inhibition abrogates these effects.","method":"Single-cell RNA-seq, spatial transcriptomics, ITGB1 knockdown, AKT inhibitor treatment, in vitro/in vivo functional assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including genetic knockdown and pharmacological inhibition, single lab","pmids":["39732719"],"is_preprint":false},{"year":2022,"finding":"In pancreatic ductal adenocarcinoma cells, COL8A1 activates ITGB1 and DDR1 receptors and downstream PI3K/AKT and NF-κB signaling; cJun/AP-1 was identified as a transcriptional activator of COL8A1 expression by ChIP assay. siRNA/shRNA-mediated COL8A1 inhibition reduced migration, invasion, and gemcitabine resistance, and reduced cytidine deaminase and thymidine kinase 2 expression; COL8A1-secreting CAFs rescued these phenotypes in vitro and in orthotopic xenograft models.","method":"siRNA/shRNA knockdown, ChIP assay, adhesion assays, EMSA binding studies, orthotopic xenograft transplantation","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay for transcriptional regulation, receptor binding studies, and in vivo xenograft, single lab with multiple orthogonal methods","pmids":["36375776"],"is_preprint":false},{"year":2022,"finding":"COL8A1 promotes triple-negative breast cancer (TNBC) growth via FAK/Src activation; CRISPR-Cas9 knockout of COL8A1 inhibited spheroid/tumor growth and metastasis in vitro and in vivo, while exogenous recombinant COL8A1 protein promoted TNBC growth through FAK/Src signaling. COL8A1 expression is induced by hypoxia.","method":"CRISPR-Cas9 knockout, 3D spheroid culture, xenograft mouse models, immunoblotting, exogenous recombinant protein treatment","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO plus exogenous protein rescue plus in vivo xenograft, single lab","pmids":["35624176"],"is_preprint":false},{"year":2022,"finding":"COL8A1 overexpression in MDA-MB-231 TNBC cells induces expression of IL1B and MMP1 through distinct signaling pathways; knockdown of either IL1B or MMP1 reduced invasion capacity of COL8A1-overexpressing cells, establishing that COL8A1 enhances invasion and metastasis via upregulation of IL1B and MMP1.","method":"DNA microarray, RT-qPCR, 3D invasion assay, siRNA knockdown, xenograft mouse models","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene expression profiling validated by knockdown experiments with invasion and in vivo readouts, single lab","pmids":["36577251"],"is_preprint":false},{"year":2021,"finding":"Platelet-derived extracellular vesicles (pEVs) deliver miR-92a-3p to vascular smooth muscle cells, which promotes COL8A1 expression via the PTEN/PIP3/Akt pathway; Col8a1 knockdown in vivo abrogated the increase in carotid artery stiffness and simultaneously increased neointimal hyperplasia, demonstrating that Col8a1 is required for vascular stiffening after intimal injury.","method":"miRNA sequencing of pEVs, in vivo carotid artery injury model (rat), Col8a1 in vivo knockdown, Akt pathway inhibition, mRNA sequencing, IPA pathway analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with defined mechanical phenotype plus miRNA/signaling pathway characterization, single lab","pmids":["33738288"],"is_preprint":false},{"year":2018,"finding":"COL8A1 promotes proliferation of muscle-derived satellite cells (MDSCs) via the PI3K/AKT signaling pathway; CRISPR/Cas9-mediated activation of COL8A1 increased EdU incorporation and expression of cyclin B1 (CCNB1) and P-AKT, while repression reduced them. EGR1 was identified as a positive transcriptional regulator of COL8A1 by dual-luciferase reporter assay.","method":"CRISPR/Cas9 activation/repression, EdU labeling, Western blotting, dual-luciferase reporter assay","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional CRISPR manipulation with multiple readouts plus transcriptional reporter assay, single lab","pmids":["29696735"],"is_preprint":false},{"year":2018,"finding":"COL8A1 protein localizes to Bruch's membrane in the mouse eye, as determined by immunohistochemistry.","method":"Immunohistochemistry on mouse eye sections","journal":"Ophthalmology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization method (IHC), no functional consequence established by this paper","pmids":["29706360"],"is_preprint":false},{"year":2009,"finding":"siRNA-mediated knockdown of COL8A1 in the highly metastatic hepatocarcinoma cell line Hca-F significantly reduced cell proliferation, colony formation in soft agar, and invasion in vitro, and sensitized cells to D-limonene.","method":"siRNA knockdown, soft agar colony formation assay, invasion assay, drug sensitivity assay","journal":"IUBMB life","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single RNAi method, no pathway mechanism identified","pmids":["19109829"],"is_preprint":false},{"year":2022,"finding":"COL8A1 promotes NSCLC proliferation and invasion through upregulation of IFIT1 and IFIT3, which mediate EGFR activation; COL8A1 knockdown reduced interferon response signaling, downregulated IFIT1/IFIT3, and suppressed EGFR activity in vitro and in vivo.","method":"COL8A1 knockdown/overexpression, in vitro cell growth/migration/apoptosis assays, in vivo tumor models, EGFR activity measurement","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement inferred from expression correlation and KD experiments, single lab, no direct binding or reconstitution assay for IFIT1/IFIT3-EGFR axis","pmids":["35280763"],"is_preprint":false},{"year":2024,"finding":"COL8A1 knockdown in esophageal squamous carcinoma (ESCC) cells inactivated the PI3K/AKT pathway, reducing proliferation and invasion; COL8A1 overexpression restored PI3K/AKT activity and rescued proliferation and invasion, establishing PI3K/AKT as downstream of COL8A1 in ESCC.","method":"COL8A1 knockdown/overexpression, xenograft model, signaling pathway validation by western blot","journal":"Annals of surgical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by KD/OE and pathway inhibitor, no receptor-binding assay","pmids":["38429534"],"is_preprint":false},{"year":2024,"finding":"COL8A1 overexpression in glioma cells promotes cell growth via activation of focal adhesion kinase (FAK) and downstream Akt and Erk1/2 phosphorylation; COL8A1 shRNA or CRISPR knockout reduced FAK/Akt/Erk1/2 phosphorylation, inhibited proliferation, and suppressed intracranial xenograft growth in mice.","method":"COL8A1 shRNA/CRISPR KO, immunoblotting, in vivo intracranial xenograft","journal":"NPJ precision oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by KD/KO with phosphorylation readouts, no direct binding assay","pmids":["39578589"],"is_preprint":false},{"year":2025,"finding":"COL8A1 knockdown in human aortic endothelial cells (HAECs) suppressed endothelial gene programs, impaired tube formation, and enhanced NF-κB/Snail activation, promoting EndMT; conversely, recombinant COL8A1 protein or lentiviral overexpression preserved endothelial markers and attenuated TNF-α-induced EndMT. TNF-α had a biphasic effect on COL8A1 expression in HAECs (initial downregulation followed by upregulation), and COL8A1 was elevated in murine atherosclerotic lesions coinciding with decreased PECAM-1.","method":"siRNA knockdown, lentiviral overexpression, recombinant protein treatment, immunofluorescence, tube formation assay, single-cell RNA-seq","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation plus exogenous protein rescue, in vitro and in vivo evidence, single lab","pmids":["41042748"],"is_preprint":false},{"year":2026,"finding":"Secreted COL8A1 from COL8A1-positive cancer-associated fibroblasts engages integrin-β1 (ITGB1) on colorectal cancer tumor cells; silencing ITGB1 or COL8A1 abrogated EMT induction, reduced proliferation, and restored 5-FU sensitivity in vitro and in vivo, establishing a COL8A1/ITGB1-mediated EMT axis driving 5-FU resistance.","method":"CRISPR/Cas9, siRNA perturbations, conditioned media experiments, xenograft models, proliferation/migration/apoptosis assays","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic perturbations in vitro and in vivo with mechanistic receptor identification, single lab","pmids":["41784732"],"is_preprint":false},{"year":2025,"finding":"In ADAMTSL4-deficient RPE cells, COL8A1/col8a1b is consistently upregulated, and COL8A1 knockdown in ADAMTSL4-deficient RPEs partially reverses the aberrant migratory phenotype, suggesting that COL8A1 acts downstream of ADAMTSL4 to promote cell migration.","method":"CRISPR/Cas9 adamtsl4 knockout zebrafish, siRNA knockdown of COL8A1, cell migration assay, transcriptomic profiling, fluorescence in situ hybridization","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, partial rescue experiment with limited mechanistic resolution","pmids":["bio_10.1101_2025.11.03.686242"],"is_preprint":true},{"year":2025,"finding":"FOSL2, an AP-1 family transcription factor, directly binds a conserved high-affinity motif in the COL8A1 promoter and transcriptionally activates COL8A1 expression in colorectal cancer; FOSL2 silencing suppresses COL8A1 expression, and FOSL2 and COL8A1 co-express at mRNA and protein levels in CRC specimens.","method":"Integrative transcriptomic analysis, promoter binding assay, siRNA knockdown of FOSL2, RT-qPCR, immunohistochemistry","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — promoter binding and KD correlation, single lab, abstract does not describe full ChIP or reporter assay rigor","pmids":["41086679"],"is_preprint":false}],"current_model":"COL8A1 encodes the alpha1 chain of the non-fibrillar type VIII collagen, a component of subendothelial extracellular matrices including Descemet's membrane and Bruch's membrane, where it forms hexagonal lattice structures; it is required for normal corneal stromal architecture and endothelial cell proliferation (established by mouse KO), and in multiple cancer and vascular contexts functions as a secreted ligand that engages cell-surface receptors (primarily integrin-β1/ITGB1 and DDR1) to activate FAK/Src and PI3K/AKT signaling cascades, driving cell proliferation, invasion, EMT, and drug resistance, with its own transcription regulated by cJun/AP-1 and EGR1, and its expression in endothelial cells modulated by TNF-α to regulate EndMT via NF-κB/Snail."},"narrative":{"mechanistic_narrative":"COL8A1 encodes the alpha1 chain of type VIII collagen, a non-fibrillar collagen whose triple-helical and C-terminal non-triple-helical domains are encoded within a single large exon and which assembles into heterotrimers with the alpha2(VIII) chain [PMID:2029894]. As a component of subendothelial extracellular matrices, type VIII collagen is required for normal anterior eye development: genetic ablation in mice produces a thinned corneal stroma and Descemet's membrane, enlarged and reduced corneal endothelial cells, and impaired endothelial cell proliferation, establishing a matrix-based role in supporting cell proliferation [PMID:16051690]. Beyond its structural role, secreted COL8A1 acts as a cell-surface ligand: in colorectal and pancreatic carcinoma it engages integrin-β1 (ITGB1), and in pancreatic cancer also DDR1, to drive PI3K/AKT (and NF-κB) signaling that promotes EMT, invasion, and resistance to oxaliplatin, 5-FU, and gemcitabine [PMID:39732719, PMID:36375776, PMID:41784732]. In triple-negative breast cancer COL8A1 acts through FAK/Src signaling to promote growth and metastasis, with recombinant protein sufficient to drive these phenotypes [PMID:35624176]. COL8A1 transcription is positively controlled by AP-1 factors cJun and FOSL2 [PMID:36375776, PMID:41086679] and by EGR1 [PMID:29696735]. In the vasculature, COL8A1 is required for arterial stiffening after intimal injury via the PTEN/Akt axis [PMID:33738288] and maintains endothelial identity, attenuating TNF-α-induced endothelial-to-mesenchymal transition through suppression of NF-κB/Snail [PMID:41042748].","teleology":[{"year":1991,"claim":"Defining the primary structure and gene organization of the alpha1(VIII) chain established COL8A1 as a non-fibrillar collagen gene and its place within the heterotrimeric type VIII collagen molecule.","evidence":"Genomic DNA sequencing and chromosomal mapping by in situ hybridization","pmids":["2029894"],"confidence":"High","gaps":["Did not establish in vivo function or tissue distribution","Heterotrimer assembly stoichiometry inferred, not biochemically reconstituted here"]},{"year":2005,"claim":"Genetic knockout settled the in vivo physiological requirement for type VIII collagen, showing it builds subendothelial matrices needed for corneal architecture and endothelial cell proliferation.","evidence":"Col8a1/Col8a2 double-null mice with histology and in vitro proliferation assays","pmids":["16051690"],"confidence":"High","gaps":["Did not separate the individual contribution of COL8A1 versus COL8A2","Molecular mechanism linking matrix to proliferation not defined","No receptor identified"]},{"year":2009,"claim":"First evidence that COL8A1 supports malignant cell behavior, linking it to proliferation, anchorage-independent growth, and invasion in hepatocarcinoma.","evidence":"siRNA knockdown with soft agar, invasion, and drug sensitivity assays","pmids":["19109829"],"confidence":"Low","gaps":["Single RNAi method with no pathway mechanism","No receptor or downstream signaling identified","No in vivo confirmation"]},{"year":2018,"claim":"Identified EGR1 as a transcriptional driver of COL8A1 and placed COL8A1-driven proliferation downstream of PI3K/AKT in satellite cells, beginning to define its signaling logic.","evidence":"Bidirectional CRISPR activation/repression, EdU labeling, immunoblotting, dual-luciferase reporter","pmids":["29696735"],"confidence":"Medium","gaps":["Receptor coupling COL8A1 to PI3K/AKT not identified","Direct EGR1 promoter occupancy by ChIP not shown"]},{"year":2021,"claim":"Established a vascular role for COL8A1 as a required mediator of arterial stiffening after injury and connected its induction to a miR-92a-3p/PTEN/Akt circuit.","evidence":"Rat carotid injury model with in vivo Col8a1 knockdown, miRNA-seq, Akt inhibition","pmids":["33738288"],"confidence":"Medium","gaps":["Cellular source and receptor for COL8A1 in smooth muscle not defined","Trade-off between stiffening and neointimal hyperplasia mechanistically unresolved"]},{"year":2022,"claim":"Resolved receptor and signaling identity in cancer, showing secreted COL8A1 engages ITGB1 and DDR1 to activate FAK/Src and PI3K/AKT, with cJun/AP-1 driving its transcription, and conferring drug resistance.","evidence":"PDAC and TNBC models: siRNA/shRNA/CRISPR perturbation, ChIP, adhesion/EMSA binding, recombinant protein rescue, xenografts; IL1B/MMP1 effector identification","pmids":["36375776","35624176","36577251"],"confidence":"Medium","gaps":["Direct COL8A1–ITGB1/DDR1 binding affinity and structural basis not determined","Whether the same receptors operate across all cancer types untested"]},{"year":2024,"claim":"Consolidated the COL8A1/ITGB1→PI3K/AKT→EMT axis in colorectal cancer as a CAF-to-tumor signaling route driving chemoresistance to oxaliplatin and 5-FU.","evidence":"scRNA-seq, spatial transcriptomics, ITGB1/COL8A1 silencing, AKT inhibition, conditioned media, xenografts; plus ESCC and glioma KD/OE pathway placement","pmids":["39732719","41784732","38429534","39578589"],"confidence":"Medium","gaps":["Receptor-binding assays absent in ESCC and glioma studies","FAK vs PI3K/AKT pathway preference across tumor contexts not reconciled"]},{"year":2025,"claim":"Defined a homeostatic endothelial function whereby COL8A1 preserves endothelial identity and restrains TNF-α-driven EndMT via NF-κB/Snail, and identified FOSL2 as an additional AP-1 transcriptional activator.","evidence":"HAEC siRNA/lentiviral/recombinant protein experiments, tube formation, scRNA-seq, atherosclerotic lesion analysis; FOSL2 promoter binding and knockdown in CRC","pmids":["41042748","41086679"],"confidence":"Medium","gaps":["Biphasic TNF-α regulation of COL8A1 mechanistically unexplained","FOSL2 binding rigor (full ChIP/reporter) limited","Receptor mediating endothelial-protective signaling not identified"]},{"year":null,"claim":"It remains unresolved how a single matrix collagen toggles between a structural subendothelial role and a soluble integrin/DDR1 ligand, and what determines its context-specific coupling to FAK/Src versus PI3K/AKT versus NF-κB outputs.","evidence":"No direct structural or quantitative receptor-binding study in the corpus reconciles these roles","pmids":[],"confidence":"Low","gaps":["No structural model of COL8A1–receptor interaction","No reconstitution distinguishing matrix-bound from soluble signaling","Disease causation in humans not established by direct genetic evidence in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,3,4,14]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,3,14]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,8]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,3,14]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,14]}],"complexes":["type VIII collagen heterotrimer"],"partners":["ITGB1","DDR1","COL8A2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P27658","full_name":"Collagen alpha-1(VIII) chain","aliases":["Endothelial collagen"],"length_aa":744,"mass_kda":73.4,"function":"Macromolecular component of the subendothelium. Major component of the Descemet's membrane (basement membrane) of corneal endothelial cells. Also a component of the endothelia of blood vessels. Necessary for migration and proliferation of vascular smooth muscle cells and thus, has a potential role in the maintenance of vessel wall integrity and structure, in particular in atherogenesis Vastatin, the C-terminal fragment comprising the NC1 domain, inhibits aortic endothelial cell proliferation and causes cell apoptosis","subcellular_location":"Secreted, extracellular space, extracellular matrix, basement membrane","url":"https://www.uniprot.org/uniprotkb/P27658/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COL8A1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/COL8A1","total_profiled":1310},"omim":[{"mim_id":"608586","title":"KERATOCONUS 3; KTCN3","url":"https://www.omim.org/entry/608586"},{"mim_id":"606410","title":"ANTHRAX TOXIN RECEPTOR 1; ANTXR1","url":"https://www.omim.org/entry/606410"},{"mim_id":"603075","title":"MACULAR DEGENERATION, AGE-RELATED, 1; ARMD1","url":"https://www.omim.org/entry/603075"},{"mim_id":"120252","title":"COLLAGEN, TYPE VIII, ALPHA-2; COL8A2","url":"https://www.omim.org/entry/120252"},{"mim_id":"120251","title":"COLLAGEN, TYPE VIII, ALPHA-1; COL8A1","url":"https://www.omim.org/entry/120251"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":226.1}],"url":"https://www.proteinatlas.org/search/COL8A1"},"hgnc":{"alias_symbol":["MGC9568"],"prev_symbol":["C3orf7"]},"alphafold":{"accession":"P27658","domains":[{"cath_id":"2.60.120.40","chopping":"618-744","consensus_level":"high","plddt":96.8477,"start":618,"end":744}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P27658","model_url":"https://alphafold.ebi.ac.uk/files/AF-P27658-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P27658-F1-predicted_aligned_error_v6.png","plddt_mean":56.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COL8A1","jax_strain_url":"https://www.jax.org/strain/search?query=COL8A1"},"sequence":{"accession":"P27658","fasta_url":"https://rest.uniprot.org/uniprotkb/P27658.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P27658/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P27658"}},"corpus_meta":[{"pmid":"16051690","id":"PMC_16051690","title":"Targeted disruption of Col8a1 and Col8a2 genes in mice leads to anterior segment abnormalities in the eye.","date":"2005","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/16051690","citation_count":101,"is_preprint":false},{"pmid":"39732719","id":"PMC_39732719","title":"THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer.","date":"2024","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39732719","citation_count":67,"is_preprint":false},{"pmid":"23533600","id":"PMC_23533600","title":"CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23533600","citation_count":64,"is_preprint":false},{"pmid":"24498017","id":"PMC_24498017","title":"Three new genetic loci (R1210C in CFH, variants in COL8A1 and RAD51B) are independently related to progression to advanced macular degeneration.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24498017","citation_count":47,"is_preprint":false},{"pmid":"2029894","id":"PMC_2029894","title":"The complete primary structure of the human alpha 1 (VIII) chain and assignment of its gene (COL8A1) to chromosome 3.","date":"1991","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2029894","citation_count":45,"is_preprint":false},{"pmid":"29706360","id":"PMC_29706360","title":"Whole-Exome Sequencing in Age-Related Macular Degeneration Identifies Rare Variants in COL8A1, a Component of Bruch's Membrane.","date":"2018","source":"Ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/29706360","citation_count":37,"is_preprint":false},{"pmid":"16936088","id":"PMC_16936088","title":"No pathogenic mutations identified in the COL8A1 and COL8A2 genes in familial Fuchs corneal dystrophy.","date":"2006","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/16936088","citation_count":34,"is_preprint":false},{"pmid":"21139683","id":"PMC_21139683","title":"Distribution of COL8A2 and COL8A1 gene variants in Caucasian primary open angle glaucoma patients with thin central corneal thickness.","date":"2010","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/21139683","citation_count":32,"is_preprint":false},{"pmid":"19109829","id":"PMC_19109829","title":"siRNA-targeted COL8A1 inhibits proliferation, reduces invasion and enhances sensitivity to D-limonence treatment in hepatocarcinoma cells.","date":"2009","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/19109829","citation_count":30,"is_preprint":false},{"pmid":"32818022","id":"PMC_32818022","title":"Clinical value and potential mechanisms of COL8A1 upregulation in breast cancer: a comprehensive analysis.","date":"2020","source":"Cancer cell 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decreased endothelial cell proliferation in response to growth factors in vitro, establishing a peri/subcellular matrix role for collagen VIII in supporting cell proliferation.\",\n      \"method\": \"Targeted gene knockout (Col8a1/Col8a2 double null mice), histology, in vitro proliferation assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple defined cellular phenotypes, replicated across two gene knockouts, in vivo and in vitro readouts\",\n      \"pmids\": [\"16051690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The primary structure of the human COL8A1-encoded alpha1(VIII) chain was determined from genomic DNA sequencing; it shares the same domain structure (triple-helical and C-terminal non-triple-helical domains encoded within a single large exon) as the rabbit alpha1(VIII) chain, and the gene was mapped to the long arm of human chromosome 3. Type VIII collagen molecules are heterotrimers composed of alpha1(VIII) and alpha2(VIII) chains in a 2:1 ratio.\",\n      \"method\": \"Genomic DNA sequencing, chromosomal mapping (in situ hybridization)\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct sequencing and chromosomal mapping establishing primary structure and gene organization, foundational structural characterization\",\n      \"pmids\": [\"2029894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COL8A1 secreted by THBS2+ cancer-associated fibroblasts directly interacts with the ITGB1 (integrin-β1) receptor on colorectal cancer cells, activating the PI3K/AKT signaling pathway, promoting EMT, and conferring oxaliplatin resistance; ITGB1 knockdown or AKT inhibition abrogates these effects.\",\n      \"method\": \"Single-cell RNA-seq, spatial transcriptomics, ITGB1 knockdown, AKT inhibitor treatment, in vitro/in vivo functional assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including genetic knockdown and pharmacological inhibition, single lab\",\n      \"pmids\": [\"39732719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In pancreatic ductal adenocarcinoma cells, COL8A1 activates ITGB1 and DDR1 receptors and downstream PI3K/AKT and NF-κB signaling; cJun/AP-1 was identified as a transcriptional activator of COL8A1 expression by ChIP assay. siRNA/shRNA-mediated COL8A1 inhibition reduced migration, invasion, and gemcitabine resistance, and reduced cytidine deaminase and thymidine kinase 2 expression; COL8A1-secreting CAFs rescued these phenotypes in vitro and in orthotopic xenograft models.\",\n      \"method\": \"siRNA/shRNA knockdown, ChIP assay, adhesion assays, EMSA binding studies, orthotopic xenograft transplantation\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay for transcriptional regulation, receptor binding studies, and in vivo xenograft, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36375776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"COL8A1 promotes triple-negative breast cancer (TNBC) growth via FAK/Src activation; CRISPR-Cas9 knockout of COL8A1 inhibited spheroid/tumor growth and metastasis in vitro and in vivo, while exogenous recombinant COL8A1 protein promoted TNBC growth through FAK/Src signaling. COL8A1 expression is induced by hypoxia.\",\n      \"method\": \"CRISPR-Cas9 knockout, 3D spheroid culture, xenograft mouse models, immunoblotting, exogenous recombinant protein treatment\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO plus exogenous protein rescue plus in vivo xenograft, single lab\",\n      \"pmids\": [\"35624176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"COL8A1 overexpression in MDA-MB-231 TNBC cells induces expression of IL1B and MMP1 through distinct signaling pathways; knockdown of either IL1B or MMP1 reduced invasion capacity of COL8A1-overexpressing cells, establishing that COL8A1 enhances invasion and metastasis via upregulation of IL1B and MMP1.\",\n      \"method\": \"DNA microarray, RT-qPCR, 3D invasion assay, siRNA knockdown, xenograft mouse models\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene expression profiling validated by knockdown experiments with invasion and in vivo readouts, single lab\",\n      \"pmids\": [\"36577251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Platelet-derived extracellular vesicles (pEVs) deliver miR-92a-3p to vascular smooth muscle cells, which promotes COL8A1 expression via the PTEN/PIP3/Akt pathway; Col8a1 knockdown in vivo abrogated the increase in carotid artery stiffness and simultaneously increased neointimal hyperplasia, demonstrating that Col8a1 is required for vascular stiffening after intimal injury.\",\n      \"method\": \"miRNA sequencing of pEVs, in vivo carotid artery injury model (rat), Col8a1 in vivo knockdown, Akt pathway inhibition, mRNA sequencing, IPA pathway analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with defined mechanical phenotype plus miRNA/signaling pathway characterization, single lab\",\n      \"pmids\": [\"33738288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"COL8A1 promotes proliferation of muscle-derived satellite cells (MDSCs) via the PI3K/AKT signaling pathway; CRISPR/Cas9-mediated activation of COL8A1 increased EdU incorporation and expression of cyclin B1 (CCNB1) and P-AKT, while repression reduced them. EGR1 was identified as a positive transcriptional regulator of COL8A1 by dual-luciferase reporter assay.\",\n      \"method\": \"CRISPR/Cas9 activation/repression, EdU labeling, Western blotting, dual-luciferase reporter assay\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional CRISPR manipulation with multiple readouts plus transcriptional reporter assay, single lab\",\n      \"pmids\": [\"29696735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"COL8A1 protein localizes to Bruch's membrane in the mouse eye, as determined by immunohistochemistry.\",\n      \"method\": \"Immunohistochemistry on mouse eye sections\",\n      \"journal\": \"Ophthalmology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization method (IHC), no functional consequence established by this paper\",\n      \"pmids\": [\"29706360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"siRNA-mediated knockdown of COL8A1 in the highly metastatic hepatocarcinoma cell line Hca-F significantly reduced cell proliferation, colony formation in soft agar, and invasion in vitro, and sensitized cells to D-limonene.\",\n      \"method\": \"siRNA knockdown, soft agar colony formation assay, invasion assay, drug sensitivity assay\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single RNAi method, no pathway mechanism identified\",\n      \"pmids\": [\"19109829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"COL8A1 promotes NSCLC proliferation and invasion through upregulation of IFIT1 and IFIT3, which mediate EGFR activation; COL8A1 knockdown reduced interferon response signaling, downregulated IFIT1/IFIT3, and suppressed EGFR activity in vitro and in vivo.\",\n      \"method\": \"COL8A1 knockdown/overexpression, in vitro cell growth/migration/apoptosis assays, in vivo tumor models, EGFR activity measurement\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement inferred from expression correlation and KD experiments, single lab, no direct binding or reconstitution assay for IFIT1/IFIT3-EGFR axis\",\n      \"pmids\": [\"35280763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COL8A1 knockdown in esophageal squamous carcinoma (ESCC) cells inactivated the PI3K/AKT pathway, reducing proliferation and invasion; COL8A1 overexpression restored PI3K/AKT activity and rescued proliferation and invasion, establishing PI3K/AKT as downstream of COL8A1 in ESCC.\",\n      \"method\": \"COL8A1 knockdown/overexpression, xenograft model, signaling pathway validation by western blot\",\n      \"journal\": \"Annals of surgical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by KD/OE and pathway inhibitor, no receptor-binding assay\",\n      \"pmids\": [\"38429534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COL8A1 overexpression in glioma cells promotes cell growth via activation of focal adhesion kinase (FAK) and downstream Akt and Erk1/2 phosphorylation; COL8A1 shRNA or CRISPR knockout reduced FAK/Akt/Erk1/2 phosphorylation, inhibited proliferation, and suppressed intracranial xenograft growth in mice.\",\n      \"method\": \"COL8A1 shRNA/CRISPR KO, immunoblotting, in vivo intracranial xenograft\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by KD/KO with phosphorylation readouts, no direct binding assay\",\n      \"pmids\": [\"39578589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"COL8A1 knockdown in human aortic endothelial cells (HAECs) suppressed endothelial gene programs, impaired tube formation, and enhanced NF-κB/Snail activation, promoting EndMT; conversely, recombinant COL8A1 protein or lentiviral overexpression preserved endothelial markers and attenuated TNF-α-induced EndMT. TNF-α had a biphasic effect on COL8A1 expression in HAECs (initial downregulation followed by upregulation), and COL8A1 was elevated in murine atherosclerotic lesions coinciding with decreased PECAM-1.\",\n      \"method\": \"siRNA knockdown, lentiviral overexpression, recombinant protein treatment, immunofluorescence, tube formation assay, single-cell RNA-seq\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation plus exogenous protein rescue, in vitro and in vivo evidence, single lab\",\n      \"pmids\": [\"41042748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Secreted COL8A1 from COL8A1-positive cancer-associated fibroblasts engages integrin-β1 (ITGB1) on colorectal cancer tumor cells; silencing ITGB1 or COL8A1 abrogated EMT induction, reduced proliferation, and restored 5-FU sensitivity in vitro and in vivo, establishing a COL8A1/ITGB1-mediated EMT axis driving 5-FU resistance.\",\n      \"method\": \"CRISPR/Cas9, siRNA perturbations, conditioned media experiments, xenograft models, proliferation/migration/apoptosis assays\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic perturbations in vitro and in vivo with mechanistic receptor identification, single lab\",\n      \"pmids\": [\"41784732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In ADAMTSL4-deficient RPE cells, COL8A1/col8a1b is consistently upregulated, and COL8A1 knockdown in ADAMTSL4-deficient RPEs partially reverses the aberrant migratory phenotype, suggesting that COL8A1 acts downstream of ADAMTSL4 to promote cell migration.\",\n      \"method\": \"CRISPR/Cas9 adamtsl4 knockout zebrafish, siRNA knockdown of COL8A1, cell migration assay, transcriptomic profiling, fluorescence in situ hybridization\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, partial rescue experiment with limited mechanistic resolution\",\n      \"pmids\": [\"bio_10.1101_2025.11.03.686242\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOSL2, an AP-1 family transcription factor, directly binds a conserved high-affinity motif in the COL8A1 promoter and transcriptionally activates COL8A1 expression in colorectal cancer; FOSL2 silencing suppresses COL8A1 expression, and FOSL2 and COL8A1 co-express at mRNA and protein levels in CRC specimens.\",\n      \"method\": \"Integrative transcriptomic analysis, promoter binding assay, siRNA knockdown of FOSL2, RT-qPCR, immunohistochemistry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — promoter binding and KD correlation, single lab, abstract does not describe full ChIP or reporter assay rigor\",\n      \"pmids\": [\"41086679\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COL8A1 encodes the alpha1 chain of the non-fibrillar type VIII collagen, a component of subendothelial extracellular matrices including Descemet's membrane and Bruch's membrane, where it forms hexagonal lattice structures; it is required for normal corneal stromal architecture and endothelial cell proliferation (established by mouse KO), and in multiple cancer and vascular contexts functions as a secreted ligand that engages cell-surface receptors (primarily integrin-β1/ITGB1 and DDR1) to activate FAK/Src and PI3K/AKT signaling cascades, driving cell proliferation, invasion, EMT, and drug resistance, with its own transcription regulated by cJun/AP-1 and EGR1, and its expression in endothelial cells modulated by TNF-α to regulate EndMT via NF-κB/Snail.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COL8A1 encodes the alpha1 chain of type VIII collagen, a non-fibrillar collagen whose triple-helical and C-terminal non-triple-helical domains are encoded within a single large exon and which assembles into heterotrimers with the alpha2(VIII) chain [#1]. As a component of subendothelial extracellular matrices, type VIII collagen is required for normal anterior eye development: genetic ablation in mice produces a thinned corneal stroma and Descemet's membrane, enlarged and reduced corneal endothelial cells, and impaired endothelial cell proliferation, establishing a matrix-based role in supporting cell proliferation [#0]. Beyond its structural role, secreted COL8A1 acts as a cell-surface ligand: in colorectal and pancreatic carcinoma it engages integrin-\\u03b21 (ITGB1), and in pancreatic cancer also DDR1, to drive PI3K/AKT (and NF-\\u03baB) signaling that promotes EMT, invasion, and resistance to oxaliplatin, 5-FU, and gemcitabine [#2, #3, #14]. In triple-negative breast cancer COL8A1 acts through FAK/Src signaling to promote growth and metastasis, with recombinant protein sufficient to drive these phenotypes [#4]. COL8A1 transcription is positively controlled by AP-1 factors cJun and FOSL2 [#3, #16] and by EGR1 [#7]. In the vasculature, COL8A1 is required for arterial stiffening after intimal injury via the PTEN/Akt axis [#6] and maintains endothelial identity, attenuating TNF-\\u03b1-induced endothelial-to-mesenchymal transition through suppression of NF-\\u03baB/Snail [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Defining the primary structure and gene organization of the alpha1(VIII) chain established COL8A1 as a non-fibrillar collagen gene and its place within the heterotrimeric type VIII collagen molecule.\",\n      \"evidence\": \"Genomic DNA sequencing and chromosomal mapping by in situ hybridization\",\n      \"pmids\": [\"2029894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish in vivo function or tissue distribution\", \"Heterotrimer assembly stoichiometry inferred, not biochemically reconstituted here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Genetic knockout settled the in vivo physiological requirement for type VIII collagen, showing it builds subendothelial matrices needed for corneal architecture and endothelial cell proliferation.\",\n      \"evidence\": \"Col8a1/Col8a2 double-null mice with histology and in vitro proliferation assays\",\n      \"pmids\": [\"16051690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate the individual contribution of COL8A1 versus COL8A2\", \"Molecular mechanism linking matrix to proliferation not defined\", \"No receptor identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"First evidence that COL8A1 supports malignant cell behavior, linking it to proliferation, anchorage-independent growth, and invasion in hepatocarcinoma.\",\n      \"evidence\": \"siRNA knockdown with soft agar, invasion, and drug sensitivity assays\",\n      \"pmids\": [\"19109829\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single RNAi method with no pathway mechanism\", \"No receptor or downstream signaling identified\", \"No in vivo confirmation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified EGR1 as a transcriptional driver of COL8A1 and placed COL8A1-driven proliferation downstream of PI3K/AKT in satellite cells, beginning to define its signaling logic.\",\n      \"evidence\": \"Bidirectional CRISPR activation/repression, EdU labeling, immunoblotting, dual-luciferase reporter\",\n      \"pmids\": [\"29696735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor coupling COL8A1 to PI3K/AKT not identified\", \"Direct EGR1 promoter occupancy by ChIP not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a vascular role for COL8A1 as a required mediator of arterial stiffening after injury and connected its induction to a miR-92a-3p/PTEN/Akt circuit.\",\n      \"evidence\": \"Rat carotid injury model with in vivo Col8a1 knockdown, miRNA-seq, Akt inhibition\",\n      \"pmids\": [\"33738288\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular source and receptor for COL8A1 in smooth muscle not defined\", \"Trade-off between stiffening and neointimal hyperplasia mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved receptor and signaling identity in cancer, showing secreted COL8A1 engages ITGB1 and DDR1 to activate FAK/Src and PI3K/AKT, with cJun/AP-1 driving its transcription, and conferring drug resistance.\",\n      \"evidence\": \"PDAC and TNBC models: siRNA/shRNA/CRISPR perturbation, ChIP, adhesion/EMSA binding, recombinant protein rescue, xenografts; IL1B/MMP1 effector identification\",\n      \"pmids\": [\"36375776\", \"35624176\", \"36577251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct COL8A1\\u2013ITGB1/DDR1 binding affinity and structural basis not determined\", \"Whether the same receptors operate across all cancer types untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Consolidated the COL8A1/ITGB1\\u2192PI3K/AKT\\u2192EMT axis in colorectal cancer as a CAF-to-tumor signaling route driving chemoresistance to oxaliplatin and 5-FU.\",\n      \"evidence\": \"scRNA-seq, spatial transcriptomics, ITGB1/COL8A1 silencing, AKT inhibition, conditioned media, xenografts; plus ESCC and glioma KD/OE pathway placement\",\n      \"pmids\": [\"39732719\", \"41784732\", \"38429534\", \"39578589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-binding assays absent in ESCC and glioma studies\", \"FAK vs PI3K/AKT pathway preference across tumor contexts not reconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a homeostatic endothelial function whereby COL8A1 preserves endothelial identity and restrains TNF-\\u03b1-driven EndMT via NF-\\u03baB/Snail, and identified FOSL2 as an additional AP-1 transcriptional activator.\",\n      \"evidence\": \"HAEC siRNA/lentiviral/recombinant protein experiments, tube formation, scRNA-seq, atherosclerotic lesion analysis; FOSL2 promoter binding and knockdown in CRC\",\n      \"pmids\": [\"41042748\", \"41086679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biphasic TNF-\\u03b1 regulation of COL8A1 mechanistically unexplained\", \"FOSL2 binding rigor (full ChIP/reporter) limited\", \"Receptor mediating endothelial-protective signaling not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single matrix collagen toggles between a structural subendothelial role and a soluble integrin/DDR1 ligand, and what determines its context-specific coupling to FAK/Src versus PI3K/AKT versus NF-\\u03baB outputs.\",\n      \"evidence\": \"No direct structural or quantitative receptor-binding study in the corpus reconciles these roles\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of COL8A1\\u2013receptor interaction\", \"No reconstitution distinguishing matrix-bound from soluble signaling\", \"Disease causation in humans not established by direct genetic evidence in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 3, 4, 14]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 3, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 3, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 14]}\n    ],\n    \"complexes\": [\"type VIII collagen heterotrimer\"],\n    \"partners\": [\"ITGB1\", \"DDR1\", \"COL8A2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}