{"gene":"CLDN1","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1999,"finding":"CLDN1 (initially named SEMP1) encodes a tight junction-associated transmembrane protein with high identity to mouse claudin-1, functioning as a component of epithelial tight junctions involved in maintenance of cell polarity and paracellular permeability regulation.","method":"cDNA cloning, differential display, amino acid sequence analysis, tissue expression profiling","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — original cloning and structural characterization, single lab but multiple methods","pmids":["9931503"],"is_preprint":false},{"year":2002,"finding":"CLDN1 protein localizes to cell-cell contact sites (tight junctions) in breast epithelial cells and, when re-expressed in CLDN1-negative breast tumor cells, reconstitutes paracellular flux inhibition independently of occludin, indicating CLDN1 alone is sufficient for gate function of tight junctions.","method":"Retroviral transduction, immunofluorescence, quantitative RT-PCR, Western blot, paracellular flux assay with fluorescent dextran","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 1-2 — functional reconstitution in cells with multiple orthogonal readouts, replicated in two cell lines","pmids":["11920682"],"is_preprint":false},{"year":2004,"finding":"CLDN1 membrane localization in breast tumor spheroids induces apoptosis; cytosolic versus membrane distribution determines apoptotic outcome, and membrane-localized CLDN1 inhibits paracellular flux, suggesting CLDN1 restricts nutrient/growth factor supply in 3D tumor cultures.","method":"Retroviral transduction, FACS sorting, 3D spheroid culture, cellular immunofluorescence, apoptosis assays, paracellular flux measurement","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — functional loss/gain with defined phenotypic readout, multiple assays, single lab","pmids":["14648703"],"is_preprint":false},{"year":2013,"finding":"miR-155 directly targets the 3' UTR of CLDN1 mRNA, suppressing CLDN1 protein expression and reducing invasion and proliferation of ovarian cancer-initiating cells.","method":"Luciferase reporter assay, Western blot, RT-PCR, Transwell migration assay, xenograft tumor model","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3'UTR targeting validated by luciferase, multiple functional assays","pmids":["23523916"],"is_preprint":false},{"year":2013,"finding":"Phospho-ΔNp63α (ATM-phosphorylated) regulates CLDN1 expression through dual mechanisms: direct binding to the CLDN1 promoter to control transcription, and upregulation of miR-185-5p/downregulation of let7-5p which post-transcriptionally modulate CLDN1 via its 3'-UTR.","method":"Promoter reporter assay, miRNA transfection, 3'-UTR reporter assay, chromatin binding analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — dual mechanism validated with promoter and 3'UTR reporters, single lab","pmids":["24070899"],"is_preprint":false},{"year":2016,"finding":"CLDN1 induces EMT in cervical cancer cells by interacting with SNAI1, leading to downregulation of E-cadherin and upregulation of vimentin, promoting invasion and metastasis.","method":"Overexpression in SiHa cells, Western blot, co-immunoprecipitation (CLDN1–SNAI1 interaction), Transwell invasion, xenograft model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 — protein interaction demonstrated, functional phenotype validated in vitro and in vivo","pmids":["27974683"],"is_preprint":false},{"year":2016,"finding":"Nm23H1 regulates CLDN1 expression via AKT signaling in esophageal squamous cell carcinoma: Nm23H1 silencing activates AKT phosphorylation, which reduces CLDN1 expression and enhances cell invasiveness; AKT inhibitor MK2206 rescues CLDN1 expression and suppresses invasion.","method":"siRNA knockdown, overexpression, Western blot, AKT inhibitor treatment, migration/invasion assays, immunofluorescence","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established by genetic and pharmacological manipulation, multiple orthogonal methods","pmids":["27376780"],"is_preprint":false},{"year":2016,"finding":"miR-142-5p directly targets CLDN1 (validated by luciferase assay), and its overexpression in thyrocytes reduces claudin-1 mRNA and protein levels and increases thyrocyte monolayer permeability.","method":"Luciferase reporter assay, Western blot, RT-PCR, permeability assay","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct targeting validated by luciferase plus functional permeability readout","pmids":["27277258"],"is_preprint":false},{"year":2017,"finding":"CLDN1 promotes EMT and migration in human bronchial epithelial cells via the Notch signaling pathway: CLDN1 knockdown reduces Notch intracellular domain (NICD) and Hes-1 levels, and Notch activator Jagged-1 reverses the protective effects of CLDN1 silencing.","method":"siRNA knockdown, Western blot, RT-PCR, Transwell assay, Notch pathway manipulation","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — pathway position established by epistasis using Notch activator rescue experiment","pmids":["28316062"],"is_preprint":false},{"year":2017,"finding":"miR-29a directly targets the 3'UTR of CLDN1 mRNA (validated by dual-luciferase assay), suppressing CLDN1 expression; CLDN1 knockdown reduces HCC cell growth and migration, and overexpression of CLDN1 reverses miR-29a-mediated suppression.","method":"Dual-luciferase reporter assay, siRNA knockdown, overexpression rescue, proliferation and migration assays, in vivo tumor model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3'UTR targeting validated, rescue experiments performed","pmids":["28342862"],"is_preprint":false},{"year":2017,"finding":"CLDN1 promotes cisplatin drug resistance in NSCLC by activating autophagy through upregulation of ULK1 phosphorylation.","method":"Western blot, CCK-8 assay, confocal microscopy for autophagosomes, Transwell assay, siRNA knockdown","journal":"Medical science monitor","confidence":"Medium","confidence_rationale":"Tier 2-3 — mechanistic link to ULK1 phosphorylation shown by Western blot with functional drug resistance readout","pmids":["28614291"],"is_preprint":false},{"year":2017,"finding":"TMPRSS4 regulates CLDN1 expression via ERK1/2 signaling pathway in HCC cells, and CLDN1 promotes cancer stem cell traits including tumorsphere formation.","method":"Western blot, ERK1/2 pathway inhibition, sphere formation assay, overexpression and knockdown experiments","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — signaling connection inferred from Western blot correlations, single lab","pmids":["28651932"],"is_preprint":false},{"year":2018,"finding":"IL-33 downregulates CLDN1 expression in keratinocytes through the ERK/STAT3 pathway; STAT3 directly binds to the CLDN1 promoter to suppress its transcription, impairing epithelial barrier function.","method":"MAPK inhibitors, siRNA, Western blot, RT-PCR, TEER measurement, FITC-dextran flux assay, EMSA for STAT3 binding to CLDN1 promoter","journal":"Journal of dermatological science","confidence":"High","confidence_rationale":"Tier 1-2 — EMSA directly demonstrates STAT3 binding to CLDN1 promoter; ERK/STAT3 pathway confirmed pharmacologically and genetically with functional barrier readout","pmids":["29534857"],"is_preprint":false},{"year":2018,"finding":"BHLHE40 suppresses CLDN1 transcription by interacting with SP1 (not by binding E-box motifs); BHLHE40 prevents SP1 from binding to a specific motif at -233 to -61 bp upstream of the CLDN1 transcription start site. The BHLH and Orange domains of BHLHE40 are essential for this interaction with SP1.","method":"Reporter assays, co-immunoprecipitation, co-localization, siRNA, deletion mutant analysis, ChIP-like binding analysis","journal":"Molecular carcinogenesis","confidence":"High","confidence_rationale":"Tier 1-2 — promoter dissection with deletion mutants plus co-IP of BHLHE40-SP1 and epistasis (BHLHE40 cannot suppress CLDN1 after SP1 knockdown)","pmids":["29704436"],"is_preprint":false},{"year":2019,"finding":"CLDN1 acts as a metastasis suppressor in lung adenocarcinoma through a feedback loop: CLDN1 upregulates EPHB6 and enhances its activation, suppressing ERK1/2 signaling, which in turn represses SLUG (a negative regulator of CLDN1). DNA hypermethylation of the CLDN1 promoter disrupts this loop.","method":"Immunoprecipitation, immunoblots, methylation-specific PCR, pyrosequencing, chromatin immunoprecipitation, reporter assay, migration assay, sphere assay, aldefluor assay, xenograft experiments","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (Co-IP, ChIP, reporter, functional assays) in single study establishing the CLDN1-EPHB6-ERK1/2-SLUG axis","pmids":["32754286"],"is_preprint":false},{"year":2019,"finding":"Peptides derived from the first extracellular loop of CLDN1 transiently disrupt tight junctions in human lung epithelial cells and delay TJ formation in primary human keratinocytes, increasing transepithelial water loss and enabling epicutaneous antigen delivery.","method":"Peptide design, TEER measurement, FITC-Dextran permeability assay, live cell imaging, mouse epicutaneous immunization, antibody titer measurement","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — extracellular loop peptides validated functionally with barrier and immunization assays","pmids":["31381894"],"is_preprint":false},{"year":2019,"finding":"CLDN1 promotes autophagy and tumor proliferation/metastasis in esophageal squamous cell carcinoma via the AMPK/STAT1/ULK1 signaling pathway, and notably localizes predominantly to the nucleus in ESCC tumor cells.","method":"Western blot, immunohistochemistry, in vitro proliferation/migration/invasion assays, in vivo xenograft, immunofluorescence for nuclear distribution, pathway analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — AMPK/STAT1/ULK1 pathway validated in vitro and in vivo, nuclear localization confirmed by multiple methods","pmids":["31498437"],"is_preprint":false},{"year":2020,"finding":"hsa-miR-31-3p directly targets the 3'UTR of CLDN1 (confirmed by dual-luciferase assay), is induced by UVB and UVA irradiation, and its overexpression increases keratinocyte permeability and reduces claudin-1 expression, impairing skin barrier function.","method":"Dual-luciferase reporter assay, Western blot, FITC-Dextran permeability assay, UV irradiation, RT-PCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3'UTR targeting confirmed, functional barrier consequence demonstrated","pmids":["32907715"],"is_preprint":false},{"year":2021,"finding":"EZH2-mediated H3K27me3 histone modification accumulates at the CLDN1 transcription start site to suppress CLDN1 transcription; EZH2 inhibition with GSK126 restores CLDN1 expression and barrier function in esophageal epithelium.","method":"ChIP-qPCR, Western blot, RNA sequencing, TEER measurement, FITC-dextran flux assay, EGDA rat model, EZH2 inhibitor treatment","journal":"Digestive and liver disease","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP-qPCR directly demonstrates H3K27me3 at CLDN1 TSS, pharmacological rescue in rat model provides in vivo validation","pmids":["34789399"],"is_preprint":false},{"year":2021,"finding":"LIN28B directly binds to CLDN1 mRNA (via RNA immunoprecipitation) and posttranscriptionally upregulates CLDN1, which enhances collective invasion, migration, and metastatic liver tumor formation; NOTCH3 acts downstream of the LIN28B/CLDN1 axis.","method":"RNA immunoprecipitation, siRNA knockdown, overexpression, in vitro invasion/migration assays, murine CRC metastasis model, bulk RNA sequencing, pharmacological NOTCH3 inhibition","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 — RNA immunoprecipitation directly demonstrates LIN28B-CLDN1 mRNA binding, validated in vivo with metastasis model and NOTCH3 epistasis","pmids":["37318881"],"is_preprint":false},{"year":2022,"finding":"A missense variant p.Arg81His in CLDN1 causes decreased protein expression and mislocation of CLDN1 away from the membrane (confirmed in transfected HaCaT cells), with 3D protein modeling predicting deleterious conformational changes, resulting in autosomal recessive congenital ichthyosis.","method":"Whole exome sequencing, Sanger sequencing, 3D protein modeling, Western blot, immunofluorescence confocal microscopy in transfected cells","journal":"American journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — functional consequence of mutation validated by protein expression and localization in transfected cells plus structural modeling","pmids":["35920354"],"is_preprint":false},{"year":2023,"finding":"CLDN1 loss in keratinocytes (CRISPR/Cas9 KO) results in significantly reduced barrier function, decreased filaggrin and cytokeratin-10 expression, diminished stratification/stratum granulosum formation, and increased proliferative keratinocytes in the basal layer.","method":"CRISPR/Cas9 knockout, monolayer and organotypic culture barrier assays, gene expression analysis, histological analysis","journal":"Experimental dermatology","confidence":"High","confidence_rationale":"Tier 1-2 — clean genetic KO with multiple orthogonal phenotypic readouts in both 2D and 3D organotypic models","pmids":["38711223"],"is_preprint":false},{"year":2023,"finding":"CLDN1 promotes proliferation and migration of airway smooth muscle cells by directly interacting with MMP14 (co-immunoprecipitation) and positively regulating MMP14 expression; MMP14 overexpression rescues the inhibitory effects of CLDN1 silencing.","method":"Co-immunoprecipitation, Western blot, siRNA knockdown, overexpression, CCK-8 assay, EdU assay, Transwell assay, ELISA","journal":"Autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct CLDN1-MMP14 interaction shown by Co-IP, functional rescue confirms pathway position","pmids":["37964516"],"is_preprint":false},{"year":2023,"finding":"CLDN1 promotes trophoblast invasion and endovascular trophoblast differentiation by regulating VIM, SNAIL, IL1B, and PECAM1; knockdown suppresses invasion/migration and tube penetration while overexpression promotes these functions in HTR8/SVneo cells.","method":"siRNA knockdown, overexpression, Western blot, RT-PCR, invasion/migration assay, tube formation assay, EOPE mouse model","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 — loss and gain of function with defined molecular markers, validated in mouse model","pmids":["37523840"],"is_preprint":false},{"year":2023,"finding":"WNT7A stimulated by cancer-associated fibroblasts activates AKT signaling in oral squamous cell carcinoma cells, which downregulates CLDN1 expression, promoting cancer cell migration; AKT inhibitor MK2206 rescues CLDN1 expression and suppresses migration.","method":"Transwell coculture, microarray, knockdown, phosphokinase array, AKT inhibitor treatment, immunohistochemistry","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 — WNT7A/AKT/CLDN1 axis confirmed by pharmacological AKT inhibition rescuing CLDN1 with functional migration readout","pmids":["37541622"],"is_preprint":false},{"year":2023,"finding":"Oxaliplatin-induced CLDN1 overexpression in colorectal cancer cells is mediated at least in part by activation of the MAPKp38/GSK3β/Wnt/β-catenin pathway; overexpressed CLDN1 confers resistance to apoptosis.","method":"Flow cytometry, immunofluorescence, Western blot, phosphoproteome analysis, proximity ligation assay, luciferase reporter assay, RNAseq, xenograft model","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (phosphoproteomics, proximity ligation, luciferase) identifying pathway, single lab","pmids":["37041570"],"is_preprint":false},{"year":2022,"finding":"LncRNA WAKMAR2 directly binds c-Fos protein and recruits this complex to the CLDN1 promoter to enhance CLDN1 transcription; loss of WAKMAR2 reduces CLDN1 expression and impairs keratinocyte barrier function.","method":"RNA pulldown, promoter-reporter assay, chromatin isolation by RNA purification-sequencing (ChIRP-seq), AP-1 inhibitor treatment, in vivo mouse UV model","journal":"Contact dermatitis","confidence":"High","confidence_rationale":"Tier 1-2 — RNA pulldown identifies WAKMAR2-c-Fos binding, ChIRP-seq maps lncRNA to CLDN1 promoter, AP-1 inhibitor reversal establishes mechanism, in vivo validation","pmids":["36461623"],"is_preprint":false},{"year":2014,"finding":"CLDN1 knockdown in mouse osteoblasts (MC3T3-E1) reduces cell proliferation, alkaline phosphatase activity, cyclinD1, ALP, Runx-2, osterix, and β-catenin levels, identifying CLDN1 as a positive regulator of osteoblast differentiation linked to the Wnt/β-catenin pathway.","method":"Lentiviral shRNA knockdown, proliferation assay, ALP activity assay, RT-PCR, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic KO with multiple differentiation markers, pathway placement via β-catenin measurement","pmids":["25479235"],"is_preprint":false},{"year":2021,"finding":"CLDN1 regulates trophoblast apoptosis via BIRC3: CLDN1 knockdown reduces BIRC3 expression and increases cleaved PARP, while BIRC3 overexpression rescues the apoptotic effect of CLDN1 knockdown.","method":"siRNA knockdown, overexpression rescue, RNA-seq, Western blot, RT-PCR, immunohistochemistry, flow cytometry","journal":"Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis demonstrated by BIRC3 rescue of CLDN1 KD phenotype, RNA-seq identifies downstream target","pmids":["33784242"],"is_preprint":false},{"year":2023,"finding":"In the ILVASC syndrome, the CLDN1 p.Arg81His variant causes distorted tight junction architecture (confirmed by transmission electron microscopy of patient skin), providing direct ultrastructural evidence that CLDN1 is essential for normal TJ assembly in human epidermis.","method":"Transmission electron microscopy, haplotype analysis, immunofluorescence","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — TEM of patient skin directly demonstrates TJ architecture disruption caused by CLDN1 loss of function","pmids":["37814412"],"is_preprint":false}],"current_model":"CLDN1 is a four-transmembrane tight junction protein whose first extracellular loop mediates paracellular barrier function independently of occludin; it is transcriptionally regulated by STAT3 (downstream of IL-33/ERK), EZH2-mediated H3K27me3, SP1/BHLHE40, RUNX3, and lncRNA-c-Fos complexes, and post-transcriptionally by multiple miRNAs (miR-155, miR-29a, miR-142-5p, miR-31-3p); in cancer contexts CLDN1 activates autophagy via AMPK/STAT1/ULK1, interacts with SNAI1 to drive EMT, is posttranscriptionally stabilized by LIN28B to activate NOTCH3-mediated metastasis, acts as a metastasis suppressor in lung adenocarcinoma through the CLDN1-EPHB6-ERK1/2-SLUG feedback axis, directly binds MMP14, and its membrane versus nuclear localization determines context-specific oncogenic or tumor-suppressive outcomes."},"narrative":{"teleology":[{"year":1999,"claim":"Identification of CLDN1 as a tight junction transmembrane protein established it as a structural component of the epithelial paracellular barrier, opening the question of whether it had autonomous barrier-forming activity.","evidence":"cDNA cloning, sequence analysis, and tissue expression profiling of the human gene initially named SEMP1","pmids":["9931503"],"confidence":"Medium","gaps":["No functional data demonstrating barrier activity","Relationship to other claudin family members at TJs unknown"]},{"year":2002,"claim":"Reconstitution experiments showed CLDN1 alone is sufficient for paracellular gate function independently of occludin, establishing its autonomous role in barrier formation.","evidence":"Retroviral re-expression in CLDN1-negative breast tumor cells with paracellular flux assays and immunofluorescence","pmids":["11920682"],"confidence":"High","gaps":["Which extracellular domain mediates barrier activity not yet mapped","Mechanism of CLDN1 homotypic or heterotypic interactions unknown"]},{"year":2004,"claim":"The finding that membrane-localized CLDN1 induces apoptosis in 3D tumor spheroids while cytosolic CLDN1 does not revealed that subcellular localization determines CLDN1's functional output, introducing the concept of context-dependent pro- versus anti-tumorigenic roles.","evidence":"3D spheroid culture of breast cancer cells with retroviral CLDN1 transduction, apoptosis assays, and immunofluorescence","pmids":["14648703"],"confidence":"Medium","gaps":["Mechanism of CLDN1 mislocalization to cytosol unresolved","Whether nuclear localization (later observed) has distinct functions not yet addressed"]},{"year":2013,"claim":"Identification of miR-155 and phospho-ΔNp63α/miR-185-5p as direct post-transcriptional regulators of CLDN1 via its 3′-UTR established that CLDN1 expression is tightly controlled at the mRNA level, explaining how barrier function and invasion can be dynamically tuned.","evidence":"Luciferase 3′-UTR reporter assays, miRNA transfection, and promoter reporter assays in ovarian cancer and epithelial cells","pmids":["23523916","24070899"],"confidence":"Medium","gaps":["Full repertoire of miRNAs targeting CLDN1 not defined","Relative contribution of transcriptional vs. post-transcriptional regulation in specific tissues unknown"]},{"year":2016,"claim":"Demonstration that CLDN1 interacts with SNAI1 to drive EMT and that Nm23H1/AKT signaling regulates CLDN1 expression linked CLDN1 to invasion/metastasis signaling networks beyond its structural barrier role.","evidence":"Co-immunoprecipitation of CLDN1–SNAI1 with functional EMT readouts in cervical cancer cells; AKT inhibitor rescue of CLDN1 in esophageal cancer cells","pmids":["27974683","27376780"],"confidence":"Medium","gaps":["CLDN1–SNAI1 interaction domain not mapped","Whether CLDN1 directly activates SNAI1 transcriptional activity or sequesters it is unknown","Reciprocal Co-IP for CLDN1–SNAI1 not reported"]},{"year":2017,"claim":"Multiple studies converged on CLDN1's signaling capacity: it activates Notch (NICD/Hes-1) in bronchial epithelium and promotes autophagy via ULK1 phosphorylation in NSCLC, revealing CLDN1 as a signal transducer beyond its structural role.","evidence":"siRNA knockdown with Notch activator rescue in bronchial cells; ULK1 phosphorylation and autophagosome analysis in NSCLC lines","pmids":["28316062","28614291"],"confidence":"Medium","gaps":["How CLDN1 activates Notch cleavage mechanistically is unknown","Whether autophagy activation requires membrane or nuclear CLDN1 not tested"]},{"year":2018,"claim":"Identification of STAT3 direct binding to the CLDN1 promoter (via IL-33/ERK) and BHLHE40–SP1 interaction blocking SP1-dependent transcription defined two distinct transcriptional repression mechanisms, explaining how inflammatory and developmental cues silence CLDN1.","evidence":"EMSA showing STAT3 binding to CLDN1 promoter in keratinocytes; Co-IP plus deletion mutant analysis of BHLHE40–SP1 with CLDN1 promoter reporters","pmids":["29534857","29704436"],"confidence":"High","gaps":["Whether STAT3 and BHLHE40/SP1 act on the same or distinct CLDN1 promoter elements not resolved","Combinatorial transcriptional regulation in vivo not tested"]},{"year":2019,"claim":"The CLDN1–EPHB6–ERK1/2–SLUG feedback axis was delineated as a metastasis-suppressive circuit in lung adenocarcinoma disrupted by promoter hypermethylation, establishing CLDN1 as a bona fide metastasis suppressor in this context and reconciling its dual role in cancer.","evidence":"Co-IP, ChIP, methylation-specific PCR, pyrosequencing, reporter assays, and xenograft experiments in lung adenocarcinoma models","pmids":["32754286"],"confidence":"High","gaps":["Whether this feedback loop operates in other carcinoma types unknown","Direct structural basis for CLDN1–EPHB6 interaction not determined"]},{"year":2019,"claim":"Functional demonstration that first extracellular loop peptides transiently open tight junctions mapped the barrier-mediating domain and enabled translational application for transepithelial drug/antigen delivery.","evidence":"Peptide design from ECL1, TEER and FITC-dextran assays in lung epithelial cells and primary keratinocytes, mouse epicutaneous immunization","pmids":["31381894"],"confidence":"Medium","gaps":["Whether peptides disrupt CLDN1 homotypic or heterotypic claudin interactions not distinguished","Long-term safety of barrier disruption not assessed"]},{"year":2021,"claim":"EZH2-mediated H3K27me3 at the CLDN1 TSS was shown to epigenetically silence CLDN1 in esophageal epithelium, and LIN28B was found to directly bind and stabilize CLDN1 mRNA to activate NOTCH3-dependent metastasis, adding epigenetic and RNA-binding protein layers to CLDN1 regulation.","evidence":"ChIP-qPCR for H3K27me3 at CLDN1 TSS with EZH2 inhibitor rescue in rat model; RNA immunoprecipitation of LIN28B–CLDN1 mRNA with in vivo CRC metastasis model","pmids":["34789399","37318881"],"confidence":"High","gaps":["Whether EZH2 and DNA methylation cooperate to silence CLDN1 not tested","How LIN28B binding stabilizes CLDN1 mRNA (e.g., polyA tail protection) mechanistically unclear"]},{"year":2022,"claim":"The lncRNA WAKMAR2–c-Fos complex was shown to bind the CLDN1 promoter and activate transcription, identifying a non-coding RNA–transcription factor mechanism that maintains barrier function in keratinocytes.","evidence":"RNA pulldown, ChIRP-seq mapping WAKMAR2 to CLDN1 promoter, AP-1 inhibitor reversal, in vivo UV mouse model","pmids":["36461623"],"confidence":"High","gaps":["Whether other AP-1 family members substitute for c-Fos at the CLDN1 promoter unknown","Relative importance of WAKMAR2 vs. direct c-Fos binding not quantified"]},{"year":2022,"claim":"The CLDN1 p.Arg81His variant was shown to cause protein mislocalization and reduced expression, directly linking CLDN1 loss of function to autosomal recessive congenital ichthyosis (ILVASC), with ultrastructural TEM confirmation of disrupted tight junction architecture in patient skin.","evidence":"WES/Sanger sequencing, Western blot and immunofluorescence in transfected HaCaT cells, TEM of patient skin biopsies","pmids":["35920354","37814412"],"confidence":"Medium","gaps":["Only one causative variant functionally characterized; allelic spectrum of CLDN1-associated disease not fully defined","Mechanism by which Arg81His disrupts folding/trafficking not resolved at atomic level"]},{"year":2023,"claim":"CRISPR knockout of CLDN1 in keratinocytes definitively demonstrated its requirement for epidermal stratification, stratum granulosum formation, and differentiation marker expression, establishing CLDN1 as essential for keratinocyte terminal differentiation beyond barrier function.","evidence":"CRISPR/Cas9 knockout in keratinocytes with monolayer barrier assays and 3D organotypic culture histology","pmids":["38711223"],"confidence":"High","gaps":["Whether CLDN1 signals to promote differentiation or acts indirectly via barrier-dependent paracrine cues unresolved","Compensatory roles of other claudins in CLDN1-null epidermis not assessed"]},{"year":2023,"claim":"CLDN1 was found to directly interact with MMP14 and to regulate trophoblast invasion through VIM/SNAIL/IL1B/PECAM1, expanding its non-barrier functions to extracellular matrix remodeling and placental biology.","evidence":"Co-immunoprecipitation of CLDN1–MMP14 in airway smooth muscle cells; knockdown/overexpression in HTR8/SVneo trophoblast cells with invasion and tube formation assays","pmids":["37964516","37523840"],"confidence":"Medium","gaps":["CLDN1–MMP14 interaction domain not mapped","Whether CLDN1 directly modulates MMP14 enzymatic activity or only its expression not distinguished","Reciprocal validation of CLDN1–MMP14 interaction needed"]},{"year":null,"claim":"Key unresolved questions include: what determines CLDN1 membrane vs. nuclear routing and how nuclear CLDN1 mechanistically activates signaling cascades (AMPK/STAT1, Notch); whether CLDN1 functions as a signaling receptor or scaffold; and the structural basis for its diverse protein interactions (SNAI1, EPHB6, MMP14).","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CLDN1 in complex with any binding partner","Nuclear import mechanism and nuclear CLDN1 interactome undefined","Relative contributions of barrier vs. signaling functions in vivo not genetically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,15,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,8,14,16]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,15,21]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,15,20,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1,15,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,8,12,14,24,25,27]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10,16]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[12,13,18,26]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,25,28]}],"complexes":[],"partners":["SNAI1","EPHB6","MMP14","LIN28B","SP1","BHLHE40"],"other_free_text":[]},"mechanistic_narrative":"CLDN1 is a four-transmembrane tight junction protein that establishes paracellular barrier function in epithelia and whose subcellular localization, transcriptional regulation, and protein interactions determine context-dependent roles in tissue homeostasis, differentiation, and cancer. CLDN1 alone is sufficient to reconstitute paracellular flux inhibition at tight junctions independently of occludin, and its first extracellular loop mediates this barrier activity; CRISPR knockout in keratinocytes abolishes barrier function, impairs stratification, and reduces differentiation markers including filaggrin [PMID:11920682, PMID:38711223, PMID:31381894]. CLDN1 transcription is suppressed by STAT3 (downstream of IL-33/ERK), BHLHE40–SP1 interaction, and EZH2-mediated H3K27me3 at its promoter, and positively regulated by a WAKMAR2–c-Fos complex; post-transcriptionally, CLDN1 mRNA is directly targeted by miR-155, miR-29a, miR-142-5p, and miR-31-3p, and stabilized by LIN28B binding [PMID:29534857, PMID:29704436, PMID:34789399, PMID:36461623, PMID:37318881]. In cancer, CLDN1 exerts context-dependent effects: it promotes EMT through SNAI1 interaction and Notch signaling, drives autophagy and drug resistance via AMPK/STAT1/ULK1, and acts as a metastasis suppressor in lung adenocarcinoma through the CLDN1–EPHB6–ERK1/2–SLUG feedback axis, with membrane versus nuclear localization determining oncogenic or tumor-suppressive outcomes [PMID:27974683, PMID:31498437, PMID:32754286, PMID:28614291]. Biallelic loss-of-function mutations in CLDN1, including the p.Arg81His variant that causes protein mislocalization and disrupted tight junction ultrastructure, cause autosomal recessive ichthyosis-associated syndromes (ILVASC/neonatal ichthyosis-sclerosing cholangitis) [PMID:35920354, PMID:37814412]."},"prefetch_data":{"uniprot":{"accession":"O95832","full_name":"Claudin-1","aliases":["Senescence-associated epithelial membrane protein"],"length_aa":211,"mass_kda":22.7,"function":"Claudins function as major constituents of the tight junction complexes that regulate the permeability of epithelia. While some claudin family members play essential roles in the formation of impermeable barriers, others mediate the permeability to ions and small molecules. Often, several claudin family members are coexpressed and interact with each other, and this determines the overall permeability. CLDN1 is required to prevent the paracellular diffusion of small molecules through tight junctions in the epidermis and is required for the normal barrier function of the skin. Required for normal water homeostasis and to prevent excessive water loss through the skin, probably via an indirect effect on the expression levels of other proteins, since CLDN1 itself seems to be dispensable for water barrier formation in keratinocyte tight junctions (PubMed:23407391) (Microbial infection) Acts as a co-receptor for hepatitis C virus (HCV) in hepatocytes (PubMed:17325668, PubMed:20375010, PubMed:24038151). Associates with CD81 and the CLDN1-CD81 receptor complex is essential for HCV entry into host cell (PubMed:20375010). Acts as a receptor for dengue virus (PubMed:24074594)","subcellular_location":"Cell junction, tight junction; Cell membrane; Basolateral cell membrane","url":"https://www.uniprot.org/uniprotkb/O95832/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLDN1","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/CLDN1","total_profiled":1310},"omim":[{"mim_id":"619677","title":"CLAUDIN DOMAIN-CONTAINING PROTEIN 1; CLDND1","url":"https://www.omim.org/entry/619677"},{"mim_id":"619658","title":"CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 7, WITH OR WITHOUT HEARING LOSS; PFIC7","url":"https://www.omim.org/entry/619658"},{"mim_id":"617579","title":"CLAUDIN 10; CLDN10","url":"https://www.omim.org/entry/617579"},{"mim_id":"616671","title":"KERATIN 76, TYPE II; KRT76","url":"https://www.omim.org/entry/616671"},{"mim_id":"615878","title":"CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 4; PFIC4","url":"https://www.omim.org/entry/615878"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":289.7},{"tissue":"skin 1","ntpm":275.6}],"url":"https://www.proteinatlas.org/search/CLDN1"},"hgnc":{"alias_symbol":["SEMP1","ILVASC"],"prev_symbol":[]},"alphafold":{"accession":"O95832","domains":[{"cath_id":"1.20.140.150","chopping":"1-29_74-187","consensus_level":"medium","plddt":90.5959,"start":1,"end":187}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95832","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95832-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95832-F1-predicted_aligned_error_v6.png","plddt_mean":84.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLDN1","jax_strain_url":"https://www.jax.org/strain/search?query=CLDN1"},"sequence":{"accession":"O95832","fasta_url":"https://rest.uniprot.org/uniprotkb/O95832.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95832/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95832"}},"corpus_meta":[{"pmid":"23523916","id":"PMC_23523916","title":"MicroRNA-155 is a novel 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cytosolic versus membrane distribution determines apoptotic outcome, and membrane-localized CLDN1 inhibits paracellular flux, suggesting CLDN1 restricts nutrient/growth factor supply in 3D tumor cultures.\",\n      \"method\": \"Retroviral transduction, FACS sorting, 3D spheroid culture, cellular immunofluorescence, apoptosis assays, paracellular flux measurement\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional loss/gain with defined phenotypic readout, multiple assays, single lab\",\n      \"pmids\": [\"14648703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-155 directly targets the 3' UTR of CLDN1 mRNA, suppressing CLDN1 protein expression and reducing invasion and proliferation of ovarian cancer-initiating cells.\",\n      \"method\": \"Luciferase reporter assay, Western blot, RT-PCR, Transwell migration assay, xenograft tumor model\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'UTR targeting validated by luciferase, multiple functional assays\",\n      \"pmids\": [\"23523916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Phospho-ΔNp63α (ATM-phosphorylated) regulates CLDN1 expression through dual mechanisms: direct binding to the CLDN1 promoter to control transcription, and upregulation of miR-185-5p/downregulation of let7-5p which post-transcriptionally modulate CLDN1 via its 3'-UTR.\",\n      \"method\": \"Promoter reporter assay, miRNA transfection, 3'-UTR reporter assay, chromatin binding analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual mechanism validated with promoter and 3'UTR reporters, single lab\",\n      \"pmids\": [\"24070899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CLDN1 induces EMT in cervical cancer cells by interacting with SNAI1, leading to downregulation of E-cadherin and upregulation of vimentin, promoting invasion and metastasis.\",\n      \"method\": \"Overexpression in SiHa cells, Western blot, co-immunoprecipitation (CLDN1–SNAI1 interaction), Transwell invasion, xenograft model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — protein interaction demonstrated, functional phenotype validated in vitro and in vivo\",\n      \"pmids\": [\"27974683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nm23H1 regulates CLDN1 expression via AKT signaling in esophageal squamous cell carcinoma: Nm23H1 silencing activates AKT phosphorylation, which reduces CLDN1 expression and enhances cell invasiveness; AKT inhibitor MK2206 rescues CLDN1 expression and suppresses invasion.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blot, AKT inhibitor treatment, migration/invasion assays, immunofluorescence\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by genetic and pharmacological manipulation, multiple orthogonal methods\",\n      \"pmids\": [\"27376780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-142-5p directly targets CLDN1 (validated by luciferase assay), and its overexpression in thyrocytes reduces claudin-1 mRNA and protein levels and increases thyrocyte monolayer permeability.\",\n      \"method\": \"Luciferase reporter assay, Western blot, RT-PCR, permeability assay\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct targeting validated by luciferase plus functional permeability readout\",\n      \"pmids\": [\"27277258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CLDN1 promotes EMT and migration in human bronchial epithelial cells via the Notch signaling pathway: CLDN1 knockdown reduces Notch intracellular domain (NICD) and Hes-1 levels, and Notch activator Jagged-1 reverses the protective effects of CLDN1 silencing.\",\n      \"method\": \"siRNA knockdown, Western blot, RT-PCR, Transwell assay, Notch pathway manipulation\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway position established by epistasis using Notch activator rescue experiment\",\n      \"pmids\": [\"28316062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-29a directly targets the 3'UTR of CLDN1 mRNA (validated by dual-luciferase assay), suppressing CLDN1 expression; CLDN1 knockdown reduces HCC cell growth and migration, and overexpression of CLDN1 reverses miR-29a-mediated suppression.\",\n      \"method\": \"Dual-luciferase reporter assay, siRNA knockdown, overexpression rescue, proliferation and migration assays, in vivo tumor model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'UTR targeting validated, rescue experiments performed\",\n      \"pmids\": [\"28342862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CLDN1 promotes cisplatin drug resistance in NSCLC by activating autophagy through upregulation of ULK1 phosphorylation.\",\n      \"method\": \"Western blot, CCK-8 assay, confocal microscopy for autophagosomes, Transwell assay, siRNA knockdown\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic link to ULK1 phosphorylation shown by Western blot with functional drug resistance readout\",\n      \"pmids\": [\"28614291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TMPRSS4 regulates CLDN1 expression via ERK1/2 signaling pathway in HCC cells, and CLDN1 promotes cancer stem cell traits including tumorsphere formation.\",\n      \"method\": \"Western blot, ERK1/2 pathway inhibition, sphere formation assay, overexpression and knockdown experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — signaling connection inferred from Western blot correlations, single lab\",\n      \"pmids\": [\"28651932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-33 downregulates CLDN1 expression in keratinocytes through the ERK/STAT3 pathway; STAT3 directly binds to the CLDN1 promoter to suppress its transcription, impairing epithelial barrier function.\",\n      \"method\": \"MAPK inhibitors, siRNA, Western blot, RT-PCR, TEER measurement, FITC-dextran flux assay, EMSA for STAT3 binding to CLDN1 promoter\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — EMSA directly demonstrates STAT3 binding to CLDN1 promoter; ERK/STAT3 pathway confirmed pharmacologically and genetically with functional barrier readout\",\n      \"pmids\": [\"29534857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BHLHE40 suppresses CLDN1 transcription by interacting with SP1 (not by binding E-box motifs); BHLHE40 prevents SP1 from binding to a specific motif at -233 to -61 bp upstream of the CLDN1 transcription start site. The BHLH and Orange domains of BHLHE40 are essential for this interaction with SP1.\",\n      \"method\": \"Reporter assays, co-immunoprecipitation, co-localization, siRNA, deletion mutant analysis, ChIP-like binding analysis\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — promoter dissection with deletion mutants plus co-IP of BHLHE40-SP1 and epistasis (BHLHE40 cannot suppress CLDN1 after SP1 knockdown)\",\n      \"pmids\": [\"29704436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CLDN1 acts as a metastasis suppressor in lung adenocarcinoma through a feedback loop: CLDN1 upregulates EPHB6 and enhances its activation, suppressing ERK1/2 signaling, which in turn represses SLUG (a negative regulator of CLDN1). DNA hypermethylation of the CLDN1 promoter disrupts this loop.\",\n      \"method\": \"Immunoprecipitation, immunoblots, methylation-specific PCR, pyrosequencing, chromatin immunoprecipitation, reporter assay, migration assay, sphere assay, aldefluor assay, xenograft experiments\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Co-IP, ChIP, reporter, functional assays) in single study establishing the CLDN1-EPHB6-ERK1/2-SLUG axis\",\n      \"pmids\": [\"32754286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Peptides derived from the first extracellular loop of CLDN1 transiently disrupt tight junctions in human lung epithelial cells and delay TJ formation in primary human keratinocytes, increasing transepithelial water loss and enabling epicutaneous antigen delivery.\",\n      \"method\": \"Peptide design, TEER measurement, FITC-Dextran permeability assay, live cell imaging, mouse epicutaneous immunization, antibody titer measurement\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — extracellular loop peptides validated functionally with barrier and immunization assays\",\n      \"pmids\": [\"31381894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CLDN1 promotes autophagy and tumor proliferation/metastasis in esophageal squamous cell carcinoma via the AMPK/STAT1/ULK1 signaling pathway, and notably localizes predominantly to the nucleus in ESCC tumor cells.\",\n      \"method\": \"Western blot, immunohistochemistry, in vitro proliferation/migration/invasion assays, in vivo xenograft, immunofluorescence for nuclear distribution, pathway analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — AMPK/STAT1/ULK1 pathway validated in vitro and in vivo, nuclear localization confirmed by multiple methods\",\n      \"pmids\": [\"31498437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"hsa-miR-31-3p directly targets the 3'UTR of CLDN1 (confirmed by dual-luciferase assay), is induced by UVB and UVA irradiation, and its overexpression increases keratinocyte permeability and reduces claudin-1 expression, impairing skin barrier function.\",\n      \"method\": \"Dual-luciferase reporter assay, Western blot, FITC-Dextran permeability assay, UV irradiation, RT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'UTR targeting confirmed, functional barrier consequence demonstrated\",\n      \"pmids\": [\"32907715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EZH2-mediated H3K27me3 histone modification accumulates at the CLDN1 transcription start site to suppress CLDN1 transcription; EZH2 inhibition with GSK126 restores CLDN1 expression and barrier function in esophageal epithelium.\",\n      \"method\": \"ChIP-qPCR, Western blot, RNA sequencing, TEER measurement, FITC-dextran flux assay, EGDA rat model, EZH2 inhibitor treatment\",\n      \"journal\": \"Digestive and liver disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP-qPCR directly demonstrates H3K27me3 at CLDN1 TSS, pharmacological rescue in rat model provides in vivo validation\",\n      \"pmids\": [\"34789399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LIN28B directly binds to CLDN1 mRNA (via RNA immunoprecipitation) and posttranscriptionally upregulates CLDN1, which enhances collective invasion, migration, and metastatic liver tumor formation; NOTCH3 acts downstream of the LIN28B/CLDN1 axis.\",\n      \"method\": \"RNA immunoprecipitation, siRNA knockdown, overexpression, in vitro invasion/migration assays, murine CRC metastasis model, bulk RNA sequencing, pharmacological NOTCH3 inhibition\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — RNA immunoprecipitation directly demonstrates LIN28B-CLDN1 mRNA binding, validated in vivo with metastasis model and NOTCH3 epistasis\",\n      \"pmids\": [\"37318881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A missense variant p.Arg81His in CLDN1 causes decreased protein expression and mislocation of CLDN1 away from the membrane (confirmed in transfected HaCaT cells), with 3D protein modeling predicting deleterious conformational changes, resulting in autosomal recessive congenital ichthyosis.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, 3D protein modeling, Western blot, immunofluorescence confocal microscopy in transfected cells\",\n      \"journal\": \"American journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional consequence of mutation validated by protein expression and localization in transfected cells plus structural modeling\",\n      \"pmids\": [\"35920354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CLDN1 loss in keratinocytes (CRISPR/Cas9 KO) results in significantly reduced barrier function, decreased filaggrin and cytokeratin-10 expression, diminished stratification/stratum granulosum formation, and increased proliferative keratinocytes in the basal layer.\",\n      \"method\": \"CRISPR/Cas9 knockout, monolayer and organotypic culture barrier assays, gene expression analysis, histological analysis\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — clean genetic KO with multiple orthogonal phenotypic readouts in both 2D and 3D organotypic models\",\n      \"pmids\": [\"38711223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CLDN1 promotes proliferation and migration of airway smooth muscle cells by directly interacting with MMP14 (co-immunoprecipitation) and positively regulating MMP14 expression; MMP14 overexpression rescues the inhibitory effects of CLDN1 silencing.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, siRNA knockdown, overexpression, CCK-8 assay, EdU assay, Transwell assay, ELISA\",\n      \"journal\": \"Autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct CLDN1-MMP14 interaction shown by Co-IP, functional rescue confirms pathway position\",\n      \"pmids\": [\"37964516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CLDN1 promotes trophoblast invasion and endovascular trophoblast differentiation by regulating VIM, SNAIL, IL1B, and PECAM1; knockdown suppresses invasion/migration and tube penetration while overexpression promotes these functions in HTR8/SVneo cells.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blot, RT-PCR, invasion/migration assay, tube formation assay, EOPE mouse model\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss and gain of function with defined molecular markers, validated in mouse model\",\n      \"pmids\": [\"37523840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WNT7A stimulated by cancer-associated fibroblasts activates AKT signaling in oral squamous cell carcinoma cells, which downregulates CLDN1 expression, promoting cancer cell migration; AKT inhibitor MK2206 rescues CLDN1 expression and suppresses migration.\",\n      \"method\": \"Transwell coculture, microarray, knockdown, phosphokinase array, AKT inhibitor treatment, immunohistochemistry\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — WNT7A/AKT/CLDN1 axis confirmed by pharmacological AKT inhibition rescuing CLDN1 with functional migration readout\",\n      \"pmids\": [\"37541622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Oxaliplatin-induced CLDN1 overexpression in colorectal cancer cells is mediated at least in part by activation of the MAPKp38/GSK3β/Wnt/β-catenin pathway; overexpressed CLDN1 confers resistance to apoptosis.\",\n      \"method\": \"Flow cytometry, immunofluorescence, Western blot, phosphoproteome analysis, proximity ligation assay, luciferase reporter assay, RNAseq, xenograft model\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (phosphoproteomics, proximity ligation, luciferase) identifying pathway, single lab\",\n      \"pmids\": [\"37041570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LncRNA WAKMAR2 directly binds c-Fos protein and recruits this complex to the CLDN1 promoter to enhance CLDN1 transcription; loss of WAKMAR2 reduces CLDN1 expression and impairs keratinocyte barrier function.\",\n      \"method\": \"RNA pulldown, promoter-reporter assay, chromatin isolation by RNA purification-sequencing (ChIRP-seq), AP-1 inhibitor treatment, in vivo mouse UV model\",\n      \"journal\": \"Contact dermatitis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — RNA pulldown identifies WAKMAR2-c-Fos binding, ChIRP-seq maps lncRNA to CLDN1 promoter, AP-1 inhibitor reversal establishes mechanism, in vivo validation\",\n      \"pmids\": [\"36461623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CLDN1 knockdown in mouse osteoblasts (MC3T3-E1) reduces cell proliferation, alkaline phosphatase activity, cyclinD1, ALP, Runx-2, osterix, and β-catenin levels, identifying CLDN1 as a positive regulator of osteoblast differentiation linked to the Wnt/β-catenin pathway.\",\n      \"method\": \"Lentiviral shRNA knockdown, proliferation assay, ALP activity assay, RT-PCR, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with multiple differentiation markers, pathway placement via β-catenin measurement\",\n      \"pmids\": [\"25479235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CLDN1 regulates trophoblast apoptosis via BIRC3: CLDN1 knockdown reduces BIRC3 expression and increases cleaved PARP, while BIRC3 overexpression rescues the apoptotic effect of CLDN1 knockdown.\",\n      \"method\": \"siRNA knockdown, overexpression rescue, RNA-seq, Western blot, RT-PCR, immunohistochemistry, flow cytometry\",\n      \"journal\": \"Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis demonstrated by BIRC3 rescue of CLDN1 KD phenotype, RNA-seq identifies downstream target\",\n      \"pmids\": [\"33784242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In the ILVASC syndrome, the CLDN1 p.Arg81His variant causes distorted tight junction architecture (confirmed by transmission electron microscopy of patient skin), providing direct ultrastructural evidence that CLDN1 is essential for normal TJ assembly in human epidermis.\",\n      \"method\": \"Transmission electron microscopy, haplotype analysis, immunofluorescence\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — TEM of patient skin directly demonstrates TJ architecture disruption caused by CLDN1 loss of function\",\n      \"pmids\": [\"37814412\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CLDN1 is a four-transmembrane tight junction protein whose first extracellular loop mediates paracellular barrier function independently of occludin; it is transcriptionally regulated by STAT3 (downstream of IL-33/ERK), EZH2-mediated H3K27me3, SP1/BHLHE40, RUNX3, and lncRNA-c-Fos complexes, and post-transcriptionally by multiple miRNAs (miR-155, miR-29a, miR-142-5p, miR-31-3p); in cancer contexts CLDN1 activates autophagy via AMPK/STAT1/ULK1, interacts with SNAI1 to drive EMT, is posttranscriptionally stabilized by LIN28B to activate NOTCH3-mediated metastasis, acts as a metastasis suppressor in lung adenocarcinoma through the CLDN1-EPHB6-ERK1/2-SLUG feedback axis, directly binds MMP14, and its membrane versus nuclear localization determines context-specific oncogenic or tumor-suppressive outcomes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CLDN1 is a four-transmembrane tight junction protein that establishes paracellular barrier function in epithelia and whose subcellular localization, transcriptional regulation, and protein interactions determine context-dependent roles in tissue homeostasis, differentiation, and cancer. CLDN1 alone is sufficient to reconstitute paracellular flux inhibition at tight junctions independently of occludin, and its first extracellular loop mediates this barrier activity; CRISPR knockout in keratinocytes abolishes barrier function, impairs stratification, and reduces differentiation markers including filaggrin [PMID:11920682, PMID:38711223, PMID:31381894]. CLDN1 transcription is suppressed by STAT3 (downstream of IL-33/ERK), BHLHE40–SP1 interaction, and EZH2-mediated H3K27me3 at its promoter, and positively regulated by a WAKMAR2–c-Fos complex; post-transcriptionally, CLDN1 mRNA is directly targeted by miR-155, miR-29a, miR-142-5p, and miR-31-3p, and stabilized by LIN28B binding [PMID:29534857, PMID:29704436, PMID:34789399, PMID:36461623, PMID:37318881]. In cancer, CLDN1 exerts context-dependent effects: it promotes EMT through SNAI1 interaction and Notch signaling, drives autophagy and drug resistance via AMPK/STAT1/ULK1, and acts as a metastasis suppressor in lung adenocarcinoma through the CLDN1–EPHB6–ERK1/2–SLUG feedback axis, with membrane versus nuclear localization determining oncogenic or tumor-suppressive outcomes [PMID:27974683, PMID:31498437, PMID:32754286, PMID:28614291]. Biallelic loss-of-function mutations in CLDN1, including the p.Arg81His variant that causes protein mislocalization and disrupted tight junction ultrastructure, cause autosomal recessive ichthyosis-associated syndromes (ILVASC/neonatal ichthyosis-sclerosing cholangitis) [PMID:35920354, PMID:37814412].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of CLDN1 as a tight junction transmembrane protein established it as a structural component of the epithelial paracellular barrier, opening the question of whether it had autonomous barrier-forming activity.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and tissue expression profiling of the human gene initially named SEMP1\",\n      \"pmids\": [\"9931503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional data demonstrating barrier activity\", \"Relationship to other claudin family members at TJs unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Reconstitution experiments showed CLDN1 alone is sufficient for paracellular gate function independently of occludin, establishing its autonomous role in barrier formation.\",\n      \"evidence\": \"Retroviral re-expression in CLDN1-negative breast tumor cells with paracellular flux assays and immunofluorescence\",\n      \"pmids\": [\"11920682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which extracellular domain mediates barrier activity not yet mapped\", \"Mechanism of CLDN1 homotypic or heterotypic interactions unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The finding that membrane-localized CLDN1 induces apoptosis in 3D tumor spheroids while cytosolic CLDN1 does not revealed that subcellular localization determines CLDN1's functional output, introducing the concept of context-dependent pro- versus anti-tumorigenic roles.\",\n      \"evidence\": \"3D spheroid culture of breast cancer cells with retroviral CLDN1 transduction, apoptosis assays, and immunofluorescence\",\n      \"pmids\": [\"14648703\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of CLDN1 mislocalization to cytosol unresolved\", \"Whether nuclear localization (later observed) has distinct functions not yet addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of miR-155 and phospho-ΔNp63α/miR-185-5p as direct post-transcriptional regulators of CLDN1 via its 3′-UTR established that CLDN1 expression is tightly controlled at the mRNA level, explaining how barrier function and invasion can be dynamically tuned.\",\n      \"evidence\": \"Luciferase 3′-UTR reporter assays, miRNA transfection, and promoter reporter assays in ovarian cancer and epithelial cells\",\n      \"pmids\": [\"23523916\", \"24070899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full repertoire of miRNAs targeting CLDN1 not defined\", \"Relative contribution of transcriptional vs. post-transcriptional regulation in specific tissues unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that CLDN1 interacts with SNAI1 to drive EMT and that Nm23H1/AKT signaling regulates CLDN1 expression linked CLDN1 to invasion/metastasis signaling networks beyond its structural barrier role.\",\n      \"evidence\": \"Co-immunoprecipitation of CLDN1–SNAI1 with functional EMT readouts in cervical cancer cells; AKT inhibitor rescue of CLDN1 in esophageal cancer cells\",\n      \"pmids\": [\"27974683\", \"27376780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CLDN1–SNAI1 interaction domain not mapped\", \"Whether CLDN1 directly activates SNAI1 transcriptional activity or sequesters it is unknown\", \"Reciprocal Co-IP for CLDN1–SNAI1 not reported\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple studies converged on CLDN1's signaling capacity: it activates Notch (NICD/Hes-1) in bronchial epithelium and promotes autophagy via ULK1 phosphorylation in NSCLC, revealing CLDN1 as a signal transducer beyond its structural role.\",\n      \"evidence\": \"siRNA knockdown with Notch activator rescue in bronchial cells; ULK1 phosphorylation and autophagosome analysis in NSCLC lines\",\n      \"pmids\": [\"28316062\", \"28614291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CLDN1 activates Notch cleavage mechanistically is unknown\", \"Whether autophagy activation requires membrane or nuclear CLDN1 not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of STAT3 direct binding to the CLDN1 promoter (via IL-33/ERK) and BHLHE40–SP1 interaction blocking SP1-dependent transcription defined two distinct transcriptional repression mechanisms, explaining how inflammatory and developmental cues silence CLDN1.\",\n      \"evidence\": \"EMSA showing STAT3 binding to CLDN1 promoter in keratinocytes; Co-IP plus deletion mutant analysis of BHLHE40–SP1 with CLDN1 promoter reporters\",\n      \"pmids\": [\"29534857\", \"29704436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAT3 and BHLHE40/SP1 act on the same or distinct CLDN1 promoter elements not resolved\", \"Combinatorial transcriptional regulation in vivo not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The CLDN1–EPHB6–ERK1/2–SLUG feedback axis was delineated as a metastasis-suppressive circuit in lung adenocarcinoma disrupted by promoter hypermethylation, establishing CLDN1 as a bona fide metastasis suppressor in this context and reconciling its dual role in cancer.\",\n      \"evidence\": \"Co-IP, ChIP, methylation-specific PCR, pyrosequencing, reporter assays, and xenograft experiments in lung adenocarcinoma models\",\n      \"pmids\": [\"32754286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this feedback loop operates in other carcinoma types unknown\", \"Direct structural basis for CLDN1–EPHB6 interaction not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Functional demonstration that first extracellular loop peptides transiently open tight junctions mapped the barrier-mediating domain and enabled translational application for transepithelial drug/antigen delivery.\",\n      \"evidence\": \"Peptide design from ECL1, TEER and FITC-dextran assays in lung epithelial cells and primary keratinocytes, mouse epicutaneous immunization\",\n      \"pmids\": [\"31381894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether peptides disrupt CLDN1 homotypic or heterotypic claudin interactions not distinguished\", \"Long-term safety of barrier disruption not assessed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"EZH2-mediated H3K27me3 at the CLDN1 TSS was shown to epigenetically silence CLDN1 in esophageal epithelium, and LIN28B was found to directly bind and stabilize CLDN1 mRNA to activate NOTCH3-dependent metastasis, adding epigenetic and RNA-binding protein layers to CLDN1 regulation.\",\n      \"evidence\": \"ChIP-qPCR for H3K27me3 at CLDN1 TSS with EZH2 inhibitor rescue in rat model; RNA immunoprecipitation of LIN28B–CLDN1 mRNA with in vivo CRC metastasis model\",\n      \"pmids\": [\"34789399\", \"37318881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EZH2 and DNA methylation cooperate to silence CLDN1 not tested\", \"How LIN28B binding stabilizes CLDN1 mRNA (e.g., polyA tail protection) mechanistically unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The lncRNA WAKMAR2–c-Fos complex was shown to bind the CLDN1 promoter and activate transcription, identifying a non-coding RNA–transcription factor mechanism that maintains barrier function in keratinocytes.\",\n      \"evidence\": \"RNA pulldown, ChIRP-seq mapping WAKMAR2 to CLDN1 promoter, AP-1 inhibitor reversal, in vivo UV mouse model\",\n      \"pmids\": [\"36461623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other AP-1 family members substitute for c-Fos at the CLDN1 promoter unknown\", \"Relative importance of WAKMAR2 vs. direct c-Fos binding not quantified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The CLDN1 p.Arg81His variant was shown to cause protein mislocalization and reduced expression, directly linking CLDN1 loss of function to autosomal recessive congenital ichthyosis (ILVASC), with ultrastructural TEM confirmation of disrupted tight junction architecture in patient skin.\",\n      \"evidence\": \"WES/Sanger sequencing, Western blot and immunofluorescence in transfected HaCaT cells, TEM of patient skin biopsies\",\n      \"pmids\": [\"35920354\", \"37814412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only one causative variant functionally characterized; allelic spectrum of CLDN1-associated disease not fully defined\", \"Mechanism by which Arg81His disrupts folding/trafficking not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"CRISPR knockout of CLDN1 in keratinocytes definitively demonstrated its requirement for epidermal stratification, stratum granulosum formation, and differentiation marker expression, establishing CLDN1 as essential for keratinocyte terminal differentiation beyond barrier function.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in keratinocytes with monolayer barrier assays and 3D organotypic culture histology\",\n      \"pmids\": [\"38711223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CLDN1 signals to promote differentiation or acts indirectly via barrier-dependent paracrine cues unresolved\", \"Compensatory roles of other claudins in CLDN1-null epidermis not assessed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"CLDN1 was found to directly interact with MMP14 and to regulate trophoblast invasion through VIM/SNAIL/IL1B/PECAM1, expanding its non-barrier functions to extracellular matrix remodeling and placental biology.\",\n      \"evidence\": \"Co-immunoprecipitation of CLDN1–MMP14 in airway smooth muscle cells; knockdown/overexpression in HTR8/SVneo trophoblast cells with invasion and tube formation assays\",\n      \"pmids\": [\"37964516\", \"37523840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CLDN1–MMP14 interaction domain not mapped\", \"Whether CLDN1 directly modulates MMP14 enzymatic activity or only its expression not distinguished\", \"Reciprocal validation of CLDN1–MMP14 interaction needed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: what determines CLDN1 membrane vs. nuclear routing and how nuclear CLDN1 mechanistically activates signaling cascades (AMPK/STAT1, Notch); whether CLDN1 functions as a signaling receptor or scaffold; and the structural basis for its diverse protein interactions (SNAI1, EPHB6, MMP14).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of CLDN1 in complex with any binding partner\", \"Nuclear import mechanism and nuclear CLDN1 interactome undefined\", \"Relative contributions of barrier vs. signaling functions in vivo not genetically dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 15, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 8, 14, 16]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 15, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 15, 20, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 15, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8, 12, 14, 24, 25, 27]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10, 16]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [12, 13, 18, 26]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 25, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SNAI1\",\n      \"EPHB6\",\n      \"MMP14\",\n      \"LIN28B\",\n      \"SP1\",\n      \"BHLHE40\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}