Affinage

COL8A1

Collagen alpha-1(VIII) chain · UniProt P27658

Length
744 aa
Mass
73.4 kDa
Annotated
2026-06-09
35 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1991 High

    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

    PMID:2029894

    Open questions at the time
    • Did not establish in vivo function or tissue distribution
    • Heterotrimer assembly stoichiometry inferred, not biochemically reconstituted here
  2. 2005 High

    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

    PMID:16051690

    Open questions at the time
    • Did not separate the individual contribution of COL8A1 versus COL8A2
    • Molecular mechanism linking matrix to proliferation not defined
    • No receptor identified
  3. 2009 Low

    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

    PMID:19109829

    Open questions at the time
    • Single RNAi method with no pathway mechanism
    • No receptor or downstream signaling identified
    • No in vivo confirmation
  4. 2018 Medium

    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

    PMID:29696735

    Open questions at the time
    • Receptor coupling COL8A1 to PI3K/AKT not identified
    • Direct EGR1 promoter occupancy by ChIP not shown
  5. 2021 Medium

    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

    PMID:33738288

    Open questions at the time
    • Cellular source and receptor for COL8A1 in smooth muscle not defined
    • Trade-off between stiffening and neointimal hyperplasia mechanistically unresolved
  6. 2022 Medium

    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

    PMID:35624176 PMID:36375776 PMID:36577251

    Open questions at the time
    • Direct COL8A1–ITGB1/DDR1 binding affinity and structural basis not determined
    • Whether the same receptors operate across all cancer types untested
  7. 2024 Medium

    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

    PMID:38429534 PMID:39578589 PMID:39732719 PMID:41784732

    Open questions at the time
    • Receptor-binding assays absent in ESCC and glioma studies
    • FAK vs PI3K/AKT pathway preference across tumor contexts not reconciled
  8. 2025 Medium

    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

    PMID:41042748 PMID:41086679

    Open questions at the time
    • Biphasic TNF-α regulation of COL8A1 mechanistically unexplained
    • FOSL2 binding rigor (full ChIP/reporter) limited
    • Receptor mediating endothelial-protective signaling not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098631 cell adhesion mediator activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
Complex memberships
type VIII collagen heterotrimer

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 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. Targeted gene knockout (Col8a1/Col8a2 double null mice), histology, in vitro proliferation assays FASEB journal High 16051690
1991 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. Genomic DNA sequencing, chromosomal mapping (in situ hybridization) European journal of biochemistry High 2029894
2024 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. Single-cell RNA-seq, spatial transcriptomics, ITGB1 knockdown, AKT inhibitor treatment, in vitro/in vivo functional assays Molecular cancer Medium 39732719
2022 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. siRNA/shRNA knockdown, ChIP assay, adhesion assays, EMSA binding studies, orthotopic xenograft transplantation Matrix biology Medium 36375776
2022 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. CRISPR-Cas9 knockout, 3D spheroid culture, xenograft mouse models, immunoblotting, exogenous recombinant protein treatment Breast cancer research and treatment Medium 35624176
2022 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. DNA microarray, RT-qPCR, 3D invasion assay, siRNA knockdown, xenograft mouse models Biochemical and biophysical research communications Medium 36577251
2021 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. miRNA sequencing of pEVs, in vivo carotid artery injury model (rat), Col8a1 in vivo knockdown, Akt pathway inhibition, mRNA sequencing, IPA pathway analysis Frontiers in cell and developmental biology Medium 33738288
2018 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. CRISPR/Cas9 activation/repression, EdU labeling, Western blotting, dual-luciferase reporter assay Cell biology international Medium 29696735
2018 COL8A1 protein localizes to Bruch's membrane in the mouse eye, as determined by immunohistochemistry. Immunohistochemistry on mouse eye sections Ophthalmology Low 29706360
2009 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. siRNA knockdown, soft agar colony formation assay, invasion assay, drug sensitivity assay IUBMB life Low 19109829
2022 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. COL8A1 knockdown/overexpression, in vitro cell growth/migration/apoptosis assays, in vivo tumor models, EGFR activity measurement Frontiers in oncology Low 35280763
2024 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. COL8A1 knockdown/overexpression, xenograft model, signaling pathway validation by western blot Annals of surgical oncology Low 38429534
2024 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. COL8A1 shRNA/CRISPR KO, immunoblotting, in vivo intracranial xenograft NPJ precision oncology Low 39578589
2025 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. siRNA knockdown, lentiviral overexpression, recombinant protein treatment, immunofluorescence, tube formation assay, single-cell RNA-seq American journal of physiology. Heart and circulatory physiology Medium 41042748
2026 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. CRISPR/Cas9, siRNA perturbations, conditioned media experiments, xenograft models, proliferation/migration/apoptosis assays Apoptosis Medium 41784732
2025 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. CRISPR/Cas9 adamtsl4 knockout zebrafish, siRNA knockdown of COL8A1, cell migration assay, transcriptomic profiling, fluorescence in situ hybridization bioRxivpreprint Low bio_10.1101_2025.11.03.686242
2025 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. Integrative transcriptomic analysis, promoter binding assay, siRNA knockdown of FOSL2, RT-qPCR, immunohistochemistry Biochemical and biophysical research communications Low 41086679

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Targeted disruption of Col8a1 and Col8a2 genes in mice leads to anterior segment abnormalities in the eye. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 101 16051690
2024 THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer. Molecular cancer 67 39732719
2013 CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1. PloS one 64 23533600
2014 Three new genetic loci (R1210C in CFH, variants in COL8A1 and RAD51B) are independently related to progression to advanced macular degeneration. PloS one 47 24498017
1991 The complete primary structure of the human alpha 1 (VIII) chain and assignment of its gene (COL8A1) to chromosome 3. European journal of biochemistry 45 2029894
2018 Whole-Exome Sequencing in Age-Related Macular Degeneration Identifies Rare Variants in COL8A1, a Component of Bruch's Membrane. Ophthalmology 37 29706360
2006 No pathogenic mutations identified in the COL8A1 and COL8A2 genes in familial Fuchs corneal dystrophy. Investigative ophthalmology & visual science 34 16936088
2010 Distribution of COL8A2 and COL8A1 gene variants in Caucasian primary open angle glaucoma patients with thin central corneal thickness. Molecular vision 32 21139683
2009 siRNA-targeted COL8A1 inhibits proliferation, reduces invasion and enhances sensitivity to D-limonence treatment in hepatocarcinoma cells. IUBMB life 30 19109829
2020 Clinical value and potential mechanisms of COL8A1 upregulation in breast cancer: a comprehensive analysis. Cancer cell international 27 32818022
2021 Platelet-Derived Extracellular Vesicles Increase Col8a1 Secretion and Vascular Stiffness in Intimal Injury. Frontiers in cell and developmental biology 26 33738288
2007 Keratoconus is not associated with mutations in COL8A1 and COL8A2. Cornea 24 17721297
2022 Tumor and stroma COL8A1 secretion induces autocrine and paracrine progression signaling in pancreatic ductal adenocarcinoma. Matrix biology : journal of the International Society for Matrix Biology 23 36375776
2018 Effects of COL8A1 on the proliferation of muscle-derived satellite cells. Cell biology international 19 29696735
2022 COL8A1 Promotes NSCLC Progression Through IFIT1/IFIT3-Mediated EGFR Activation. Frontiers in oncology 18 35280763
2022 COL8A1 facilitates the growth of triple-negative breast cancer via FAK/Src activation. Breast cancer research and treatment 18 35624176
2020 RNAseq-Based Prioritization Revealed COL6A5, COL8A1, COL10A1 and MIR146A as Common and Differential Susceptibility Biomarkers for Psoriasis and Psoriatic Arthritis: Confirmation from Genotyping Analysis of 1417 Italian Subjects. International journal of molecular sciences 17 32326527
2012 Effect of enhanced expression of COL8A1 on lymphatic metastasis of hepatocellular carcinoma in mice. Experimental and therapeutic medicine 13 23170115
2022 COL8A1 enhances the invasion/metastasis in MDA-MB-231 cells via the induction of IL1B and MMP1 expression. Biochemical and biophysical research communications 12 36577251
2019 RAD51B (rs8017304 and rs2588809), TRIB1 (rs6987702, rs4351379, and rs4351376), COL8A1 (rs13095226), and COL10A1 (rs1064583) Gene Variants with Predisposition to Age-Related Macular Degeneration. Disease markers 9 31191752
2025 LPAR3 and COL8A1, as matrix stiffness-related biomarkers, promote nasopharyngeal carcinoma metastasis by triggering EMT and angiogenesis. Cellular signalling 8 40049264
2021 Serum Levels of ARMS2, COL8A1, RAD51B, and VEGF and their Correlations in Age-related Macular Degeneration. Current neurovascular research 8 34060991
2015 COL8A1 rs13095226 polymorphism shows no association with neovascular age-related macular degeneration or polypoidal choroidal vasculopathy in Chinese subjects. International journal of clinical and experimental pathology 6 26617902
2024 COL8A1 Regulates Esophageal Squamous Carcinoma Proliferation and Invasion Through PI3K/AKT Pathway. Annals of surgical oncology 4 38429534
2024 Two patients with Knobloch syndrome due to mutation in COL8A1 gene: case report and review of the literature. BMC ophthalmology 4 38575892
2025 COL8A1 regulates endothelial phenotype in inflammatory endothelial-to-mesenchymal transition. American journal of physiology. Heart and circulatory physiology 3 41042748
2024 KDM3A knockdown regulates COMP, LOX, COL8A1 and ACOT1 genes in myocardial fibrosis. Bioinformation 3 38854759
2024 COL8A1 overexpression promotes glioma cell growth by activating focal adhesion kinase signaling cascade. NPJ precision oncology 3 39578589
2026 [Retracted] Effect of enhanced expression of COL8A1 on lymphatic metastasis of hepatocellular carcinoma in mice. Experimental and therapeutic medicine 0 41756350
2026 COL8A1-positive cancer-associated fibroblasts are drivers of 5-fluorouracil resistance in colorectal cancer. Apoptosis : an international journal on programmed cell death 0 41784732
2026 F2R Promotes Prostate Cancer Progression via COL8A1-Dependent Activation of the FAK/PI3K/AKT Signaling Axis. The journal of gene medicine 0 42126351
2026 LRRC46 regulates bovine granulosa cell functions via the COL8A1-mediated EGFR/PI3K/AKT signaling pathway. Theriogenology 0 42224836
2025 Integrative multi-omics analysis uncovers a novel FOSL2-COL8A1-EMT regulatory axis driving colorectal cancer progression. Biochemical and biophysical research communications 0 41086679
2025 COL8A1 as a pro-inflammatory mediator bridges immune evasion and therapy resistance in glioma. Frontiers in immunology 0 41451204
2024 Exudative Age-Related Macular Degeneration: Association between Treatment Efficacy and Single-Nucleotide Variants in RAD51B, TRIB1, COL8A1, COL10A1, IL-9, IL-10, and VEGFA Genes. International journal of molecular sciences 0 38999967

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