{"gene":"NID2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2016,"finding":"NID2 re-expression in NPC and ESCC cells suppresses clonogenic survival, migration, and liver metastasis, and mechanistic studies confirm that NID2 suppresses the EGFR/Akt and integrin/FAK/PLCγ metastasis-related signaling pathways.","method":"Re-expression/transduction of NID2 in cancer cell lines, clonogenic and migration assays, in vivo liver metastasis model, signaling pathway analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function/gain-of-function with defined cellular phenotypes and pathway placement; single lab, multiple functional assays but no in vitro reconstitution or structural validation","pmids":["27793011"],"is_preprint":false},{"year":2019,"finding":"NID2 overexpression or demethylation in lung cancer cells decreases cell viability, proliferation, migration, and invasion, increases apoptosis, and inhibits tumorigenesis in nude mouse xenograft models, establishing NID2 as a tumor suppressor whose silencing by promoter hypermethylation promotes lung cancer development.","method":"NID2 overexpression and demethylation in cancer cell lines, CCK-8, colony formation, transwell, wound-healing, flow cytometry, nude mouse xenograft","journal":"Pathology oncology research : POR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/OE with defined cellular and in vivo phenotypes, multiple orthogonal assays; single lab","pmids":["30826972"],"is_preprint":false},{"year":2025,"finding":"In vascular smooth muscle cells, NID2 overexpression promotes osteogenic transdifferentiation via activation of the downstream IGF2-ERK1/2 signaling pathway; sEH gene deletion reduces NID2 expression (through elevated EETs) and thereby inhibits diabetic vascular calcification, and NID2 overexpression (via AAV9) abolishes this protective effect.","method":"sEH gene knockout mouse model, siRNA knockdown, pharmacologic inhibition, NID2 overexpression via AAV9, Western blotting, alizarin red staining, Von Kossa staining, immunohistochemistry, immunofluorescence","journal":"Chinese medical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Ephx2 KO + NID2 OE rescue experiment) with multiple orthogonal readouts; single lab","pmids":["40937642"],"is_preprint":false}],"current_model":"NID2 (Nidogen-2) is a basement membrane component that functions as a tumor/metastasis suppressor by inhibiting EGFR/Akt and integrin/FAK/PLCγ signaling in epithelial cancers; its promoter is frequently silenced by hypermethylation across multiple cancer types, and in vascular smooth muscle cells it promotes osteogenic transdifferentiation by activating an IGF2-ERK1/2 signaling pathway downstream of EET levels."},"narrative":{"mechanistic_narrative":"NID2 (Nidogen-2) functions as a context-dependent regulator of cell signaling whose re-expression suppresses tumor progression in epithelial cancers while its overexpression drives pathological osteogenic transdifferentiation in vascular smooth muscle cells [PMID:27793011, PMID:40937642]. In nasopharyngeal and esophageal squamous carcinoma cells, NID2 re-expression suppresses clonogenic survival, migration, and liver metastasis by inhibiting the EGFR/Akt and integrin/FAK/PLCγ signaling pathways [PMID:27793011], and in lung cancer cells NID2 overexpression or promoter demethylation reduces viability, proliferation, migration, and invasion while increasing apoptosis and blocking xenograft tumorigenesis, identifying promoter hypermethylation as the mechanism of its silencing [PMID:30826972]. In a distinct vascular context, NID2 overexpression promotes osteogenic transdifferentiation of smooth muscle cells through activation of an IGF2-ERK1/2 signaling axis, and its induction downstream of reduced soluble epoxide hydrolase activity (via elevated EETs) drives diabetic vascular calcification [PMID:40937642]. Beyond these signaling phenotypes, no structural or biochemical reconstitution of NID2 function has been characterized in the available corpus.","teleology":[{"year":2016,"claim":"Established NID2 as a metastasis suppressor in squamous carcinomas and placed it upstream of defined oncogenic signaling, answering whether its loss has a causal role in tumor spread.","evidence":"NID2 re-expression in NPC and ESCC cell lines with clonogenic/migration assays, in vivo liver metastasis model, and pathway analysis","pmids":["27793011"],"confidence":"Medium","gaps":["No direct biochemical demonstration of how NID2 engages EGFR or integrin to inhibit signaling","Single lab; no reciprocal loss-of-function in patient-derived models","Mechanism of NID2 silencing not addressed in this study"]},{"year":2019,"claim":"Extended the tumor-suppressor model to lung cancer and linked NID2 silencing causally to promoter hypermethylation, addressing why NID2 is lost in epithelial tumors.","evidence":"NID2 overexpression and demethylation in lung cancer cell lines with CCK-8, colony formation, transwell, wound-healing, flow cytometry, and nude mouse xenografts","pmids":["30826972"],"confidence":"Medium","gaps":["Downstream effector pathways in lung cancer not mechanistically dissected","Direct demethylation-driven re-expression not shown at the endogenous promoter in vivo","Single lab"]},{"year":2025,"claim":"Revealed a context-opposite, pro-pathogenic role for NID2 in vascular calcification and connected it to an upstream EET/sEH input and downstream IGF2-ERK1/2 output, answering how NID2 contributes to diabetic vascular disease.","evidence":"Ephx2 (sEH) knockout mouse with siRNA, pharmacologic inhibition, AAV9-mediated NID2 overexpression rescue, alizarin red/Von Kossa staining, and Western blotting","pmids":["40937642"],"confidence":"Medium","gaps":["How NID2 activates IGF2-ERK1/2 is not biochemically defined","Mechanism by which EETs lower NID2 expression unknown","Single lab; reconciliation with the tumor-suppressor context not addressed"]},{"year":null,"claim":"How NID2 produces opposite outcomes (signaling suppression in epithelial cancers versus osteogenic signaling activation in vascular smooth muscle) at the molecular level remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or reconstituted biochemical mechanism for NID2 signaling modulation","No identified direct receptor or matrix partner mediating its effects","Cell-type determinants of NID2's opposite roles undefined"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,2]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14112","full_name":"Nidogen-2","aliases":["Osteonidogen"],"length_aa":1375,"mass_kda":151.3,"function":"Cell adhesion glycoprotein which is widely distributed in basement membranes. Binds to collagens I and IV, to perlecan and to laminin 1. Does not bind fibulins. It probably has a role in cell-extracellular matrix interactions","subcellular_location":"Secreted, extracellular space, extracellular matrix, basement membrane","url":"https://www.uniprot.org/uniprotkb/Q14112/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NID2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NID2","total_profiled":1310},"omim":[{"mim_id":"605399","title":"NIDOGEN 2; NID2","url":"https://www.omim.org/entry/605399"},{"mim_id":"604633","title":"EGF-CONTAINING FIBULIN-LIKE EXTRACELLULAR MATRIX PROTEIN 2; EFEMP2","url":"https://www.omim.org/entry/604633"},{"mim_id":"131390","title":"NIDOGEN 1; NID1","url":"https://www.omim.org/entry/131390"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"ovary","ntpm":57.9},{"tissue":"placenta","ntpm":57.1}],"url":"https://www.proteinatlas.org/search/NID2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q14112","domains":[{"cath_id":"-","chopping":"34-169_177-282","consensus_level":"high","plddt":84.9721,"start":34,"end":282},{"cath_id":"2.40.155.10","chopping":"516-751","consensus_level":"high","plddt":88.7235,"start":516,"end":751},{"cath_id":"2.10.25.10","chopping":"762-803","consensus_level":"medium","plddt":80.7067,"start":762,"end":803},{"cath_id":"2.10.25,2.10.25","chopping":"809-845","consensus_level":"high","plddt":78.1911,"start":809,"end":845},{"cath_id":"-","chopping":"968-1004","consensus_level":"medium","plddt":82.157,"start":968,"end":1004},{"cath_id":"4.10.800.10","chopping":"1018-1087","consensus_level":"medium","plddt":78.8389,"start":1018,"end":1087},{"cath_id":"2.120.10.30","chopping":"1110-1367","consensus_level":"medium","plddt":91.2048,"start":1110,"end":1367}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14112","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14112-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14112-F1-predicted_aligned_error_v6.png","plddt_mean":73.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NID2","jax_strain_url":"https://www.jax.org/strain/search?query=NID2"},"sequence":{"accession":"Q14112","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14112.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14112/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14112"}},"corpus_meta":[{"pmid":"19674832","id":"PMC_19674832","title":"Identification and validation of the methylated TWIST1 and NID2 genes through real-time methylation-specific polymerase chain reaction assays for the noninvasive detection of primary bladder cancer in urine samples.","date":"2009","source":"European urology","url":"https://pubmed.ncbi.nlm.nih.gov/19674832","citation_count":125,"is_preprint":false},{"pmid":"21558411","id":"PMC_21558411","title":"NID2 and HOXA9 promoter hypermethylation as biomarkers for prevention and early detection in oral cavity squamous cell carcinoma tissues and saliva.","date":"2011","source":"Cancer prevention research (Philadelphia, Pa.)","url":"https://pubmed.ncbi.nlm.nih.gov/21558411","citation_count":110,"is_preprint":false},{"pmid":"23682613","id":"PMC_23682613","title":"Hypermethylation of TWIST1 and NID2 in tumor tissues and voided urine in urinary bladder cancer patients.","date":"2013","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23682613","citation_count":38,"is_preprint":false},{"pmid":"27793011","id":"PMC_27793011","title":"Metastasis-suppressing NID2, an epigenetically-silenced gene, in the pathogenesis of nasopharyngeal carcinoma and esophageal squamous cell carcinoma.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27793011","citation_count":31,"is_preprint":false},{"pmid":"26027762","id":"PMC_26027762","title":"Multi-institutional external validation of urinary TWIST1 and NID2 methylation as a diagnostic test for bladder cancer.","date":"2015","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26027762","citation_count":29,"is_preprint":false},{"pmid":"23083854","id":"PMC_23083854","title":"Detecting DNA methylation of the BCL2, CDKN2A and NID2 genes in urine using a nested methylation specific polymerase chain reaction assay to predict bladder cancer.","date":"2012","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/23083854","citation_count":29,"is_preprint":false},{"pmid":"28106542","id":"PMC_28106542","title":"Urinary NID2 and TWIST1 methylation to augment conventional urine cytology for the detection of bladder cancer.","date":"2017","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/28106542","citation_count":23,"is_preprint":false},{"pmid":"22741015","id":"PMC_22741015","title":"Methylation status of NEUROG2 and NID2 improves the diagnosis of stage I NSCLC.","date":"2012","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/22741015","citation_count":22,"is_preprint":false},{"pmid":"32171289","id":"PMC_32171289","title":"Evaluation of NID2 promoter methylation for screening of Oral squamous cell carcinoma.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32171289","citation_count":19,"is_preprint":false},{"pmid":"30826972","id":"PMC_30826972","title":"Silencing NID2 by DNA Hypermethylation Promotes Lung Cancer.","date":"2019","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/30826972","citation_count":16,"is_preprint":false},{"pmid":"34922269","id":"PMC_34922269","title":"Evaluation of DNA methylation in promoter regions of hTERT, TWIST1, VIM and NID2 genes in Moroccan bladder cancer patients.","date":"2021","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34922269","citation_count":14,"is_preprint":false},{"pmid":"36908806","id":"PMC_36908806","title":"Nidogen-2 (NID2) is a Key Factor in Collagen Causing Poor Response to Immunotherapy in Melanoma.","date":"2023","source":"Pharmacogenomics and personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36908806","citation_count":2,"is_preprint":false},{"pmid":"40937642","id":"PMC_40937642","title":"Diabetic vascular calcification inhibited by soluble epoxide hydrolase gene deletion via regressing NID2-mediated IGF2-ERK1/2 signaling pathway.","date":"2025","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/40937642","citation_count":1,"is_preprint":false},{"pmid":"42057892","id":"PMC_42057892","title":"Evaluation of NID2 and CDO1 methylation for ovarian cancer screening.","date":"2026","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/42057892","citation_count":0,"is_preprint":false},{"pmid":"42239723","id":"PMC_42239723","title":"Integrative omics identify NID2 as a therapeutic target linking depression and colorectal cancer in humans.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/42239723","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.20.671189","title":"Primary Cilium-dependent Humoral Bioactive Factors Acts in a Paracrine Manner to Control Fibroblast Cell Migration","date":"2025-08-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.20.671189","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10697,"output_tokens":878,"usd":0.022631,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7354,"output_tokens":1698,"usd":0.03961,"stage2_stop_reason":"end_turn"},"total_usd":0.062241,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"NID2 re-expression in NPC and ESCC cells suppresses clonogenic survival, migration, and liver metastasis, and mechanistic studies confirm that NID2 suppresses the EGFR/Akt and integrin/FAK/PLCγ metastasis-related signaling pathways.\",\n      \"method\": \"Re-expression/transduction of NID2 in cancer cell lines, clonogenic and migration assays, in vivo liver metastasis model, signaling pathway analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function/gain-of-function with defined cellular phenotypes and pathway placement; single lab, multiple functional assays but no in vitro reconstitution or structural validation\",\n      \"pmids\": [\"27793011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NID2 overexpression or demethylation in lung cancer cells decreases cell viability, proliferation, migration, and invasion, increases apoptosis, and inhibits tumorigenesis in nude mouse xenograft models, establishing NID2 as a tumor suppressor whose silencing by promoter hypermethylation promotes lung cancer development.\",\n      \"method\": \"NID2 overexpression and demethylation in cancer cell lines, CCK-8, colony formation, transwell, wound-healing, flow cytometry, nude mouse xenograft\",\n      \"journal\": \"Pathology oncology research : POR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/OE with defined cellular and in vivo phenotypes, multiple orthogonal assays; single lab\",\n      \"pmids\": [\"30826972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In vascular smooth muscle cells, NID2 overexpression promotes osteogenic transdifferentiation via activation of the downstream IGF2-ERK1/2 signaling pathway; sEH gene deletion reduces NID2 expression (through elevated EETs) and thereby inhibits diabetic vascular calcification, and NID2 overexpression (via AAV9) abolishes this protective effect.\",\n      \"method\": \"sEH gene knockout mouse model, siRNA knockdown, pharmacologic inhibition, NID2 overexpression via AAV9, Western blotting, alizarin red staining, Von Kossa staining, immunohistochemistry, immunofluorescence\",\n      \"journal\": \"Chinese medical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Ephx2 KO + NID2 OE rescue experiment) with multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"40937642\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NID2 (Nidogen-2) is a basement membrane component that functions as a tumor/metastasis suppressor by inhibiting EGFR/Akt and integrin/FAK/PLCγ signaling in epithelial cancers; its promoter is frequently silenced by hypermethylation across multiple cancer types, and in vascular smooth muscle cells it promotes osteogenic transdifferentiation by activating an IGF2-ERK1/2 signaling pathway downstream of EET levels.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NID2 (Nidogen-2) functions as a context-dependent regulator of cell signaling whose re-expression suppresses tumor progression in epithelial cancers while its overexpression drives pathological osteogenic transdifferentiation in vascular smooth muscle cells [#0, #2]. In nasopharyngeal and esophageal squamous carcinoma cells, NID2 re-expression suppresses clonogenic survival, migration, and liver metastasis by inhibiting the EGFR/Akt and integrin/FAK/PLCγ signaling pathways [#0], and in lung cancer cells NID2 overexpression or promoter demethylation reduces viability, proliferation, migration, and invasion while increasing apoptosis and blocking xenograft tumorigenesis, identifying promoter hypermethylation as the mechanism of its silencing [#1]. In a distinct vascular context, NID2 overexpression promotes osteogenic transdifferentiation of smooth muscle cells through activation of an IGF2-ERK1/2 signaling axis, and its induction downstream of reduced soluble epoxide hydrolase activity (via elevated EETs) drives diabetic vascular calcification [#2]. Beyond these signaling phenotypes, no structural or biochemical reconstitution of NID2 function has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established NID2 as a metastasis suppressor in squamous carcinomas and placed it upstream of defined oncogenic signaling, answering whether its loss has a causal role in tumor spread.\",\n      \"evidence\": \"NID2 re-expression in NPC and ESCC cell lines with clonogenic/migration assays, in vivo liver metastasis model, and pathway analysis\",\n      \"pmids\": [\"27793011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct biochemical demonstration of how NID2 engages EGFR or integrin to inhibit signaling\",\n        \"Single lab; no reciprocal loss-of-function in patient-derived models\",\n        \"Mechanism of NID2 silencing not addressed in this study\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the tumor-suppressor model to lung cancer and linked NID2 silencing causally to promoter hypermethylation, addressing why NID2 is lost in epithelial tumors.\",\n      \"evidence\": \"NID2 overexpression and demethylation in lung cancer cell lines with CCK-8, colony formation, transwell, wound-healing, flow cytometry, and nude mouse xenografts\",\n      \"pmids\": [\"30826972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream effector pathways in lung cancer not mechanistically dissected\",\n        \"Direct demethylation-driven re-expression not shown at the endogenous promoter in vivo\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a context-opposite, pro-pathogenic role for NID2 in vascular calcification and connected it to an upstream EET/sEH input and downstream IGF2-ERK1/2 output, answering how NID2 contributes to diabetic vascular disease.\",\n      \"evidence\": \"Ephx2 (sEH) knockout mouse with siRNA, pharmacologic inhibition, AAV9-mediated NID2 overexpression rescue, alizarin red/Von Kossa staining, and Western blotting\",\n      \"pmids\": [\"40937642\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How NID2 activates IGF2-ERK1/2 is not biochemically defined\",\n        \"Mechanism by which EETs lower NID2 expression unknown\",\n        \"Single lab; reconciliation with the tumor-suppressor context not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NID2 produces opposite outcomes (signaling suppression in epithelial cancers versus osteogenic signaling activation in vascular smooth muscle) at the molecular level remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural or reconstituted biochemical mechanism for NID2 signaling modulation\",\n        \"No identified direct receptor or matrix partner mediating its effects\",\n        \"Cell-type determinants of NID2's opposite roles undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}