{"gene":"KRT7","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2016,"finding":"KRT7-AS lncRNA forms an RNA-RNA hybrid with KRT7 mRNA and controls KRT7 expression at both the mRNA and post-transcriptional levels; forced overexpression of the KRT7-overlapping region (but not non-overlapping portions) of KRT7-AS increased keratin 7 protein levels, promoting gastric cancer cell proliferation and migration.","method":"RNA sequencing, RNA-RNA hybrid assay, forced overexpression of full-length vs. truncated KRT7-AS constructs, cell proliferation and migration assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping overexpression experiments with orthogonal functional readouts in a single lab","pmids":["26876208"],"is_preprint":false},{"year":2021,"finding":"m6A methyltransferase METTL3 methylates KRT7-AS at A877, stabilizing a KRT7-AS/KRT7 mRNA duplex via IGF2BP1/HuR complexes; additionally, YTHDF1/eEF-1 mediates FTO-regulated translational elongation of KRT7 mRNA with methylated A950 in KRT7 exon 6 as the key site, together promoting breast cancer lung metastasis.","method":"Epi-transcriptome and transcriptome analyses, m6A site-specific mutagenesis (A877, A950), RIP/pulldown for IGF2BP1/HuR and YTHDF1/eEF-1 complexes, in vivo lung metastasis model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — site-specific mutagenesis plus complex pulldowns plus in vivo validation, single lab","pmids":["33795252"],"is_preprint":false},{"year":2020,"finding":"KRT7 overexpression promotes epithelial-mesenchymal transition (EMT), migration, and proliferation of ovarian cancer cells via the TGF-β/Smad2/3 signaling pathway, and also regulates cell-matrix adhesion through integrin-β1-focal adhesion kinase signaling; KRT7 siRNA knockdown reversed these effects and inhibited tumor growth in vivo.","method":"CCK8 proliferation assay, wound healing and transwell migration assays, KRT7 siRNA knockdown, Western blotting for TGF-β/Smad2/3 and integrin-β1/FAK pathway components, in vivo xenograft model","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined pathway readouts and in vivo confirmation, single lab, multiple orthogonal methods","pmids":["33416175"],"is_preprint":false},{"year":2019,"finding":"FOXA1 transcriptionally activates KRT7 in gastric cancer cells, as demonstrated by dual luciferase reporter assay; FOXA1 exerts its pro-proliferative, migratory, and invasive functions through KRT7 activation, and knockdown of either FOXA1 or KRT7 increased chemosensitivity to 5-fluorouracil.","method":"Dual luciferase reporter assay, gain- and loss-of-function experiments (siRNA/overexpression), cell proliferation/migration/invasion assays, 5-FU sensitivity assay","journal":"Journal of biological regulators and homeostatic agents","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcriptional activation confirmed by reporter assay plus functional epistasis, single lab","pmids":["31317696"],"is_preprint":false},{"year":2010,"finding":"FOXA1 siRNA treatment of esophageal cancer cells reduced KRT7 mRNA levels, placing KRT7 downstream of FOXA1 in a transcriptional pathway; FOXA1 and LOXL2 siRNAs also reduced invasion and migration of esophageal squamous cell carcinoma (ESCC) cells, suggesting KRT7-expressing ESCCs with lymph node metastasis are driven in part by FOXA1.","method":"siRNA knockdown of FOXA1 and LOXL2, RT-PCR for KRT7 mRNA, invasion and migration assays, gene expression profiling of 24 ESCCs","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA knockdown with mRNA readout and functional assays, no direct KRT7 mechanism tested","pmids":["20043065"],"is_preprint":false},{"year":2020,"finding":"FoxM1 binds a consensus AP-2 cis element to regulate KRT7 (and KRT5) gene expression in ovarian cancer; KRT7 deficiency specifically prevented cell migration but not proliferation of SK-OV-3 cells.","method":"ChIP-seq, RNA-seq, qPCR, Western blot for FoxM1 knockdown effect on KRT7, migration and proliferation assays with KRT7 siRNA knockdown","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq identifies direct binding plus loss-of-function with specific phenotypic readout, single lab","pmids":["32659254"],"is_preprint":false},{"year":2021,"finding":"miR-216a suppresses WT1 expression, and WT1 promotes KRT7 transcription; silencing KRT7 diminished the oncogenic role of WT1 in pancreatic cancer, and the miR-216a/WT1/KRT7 axis influenced PI3K/AKT pathway activity.","method":"miRNA microarray, transcription reporter assay for WT1→KRT7, siRNA/overexpression of miR-216a and WT1, KRT7 knockdown functional assays (proliferation, invasion), in vivo tumor model","journal":"IUBMB life","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway epistasis established by knockdown/overexpression cascade, single lab, indirect mechanism for KRT7","pmids":["33759343"],"is_preprint":false},{"year":2022,"finding":"KRT7 knockdown in pancreatic cancer cell lines significantly suppressed cell-in-cell (CIC) formation, cell cluster formation, cell proliferation, migration, and invasion.","method":"KRT7 siRNA knockdown, CIC formation assay, cell cluster assay, proliferation/migration/invasion assays, qRT-PCR/Western blot/IHC for KRT7 validation","journal":"BMC cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss-of-function with multiple cellular phenotype readouts but no defined downstream mechanism, single lab","pmids":["35974300"],"is_preprint":false},{"year":2025,"finding":"KRT7 overexpression in pancreatic ductal adenocarcinoma cells promotes liver metastasis by stimulating FGF2 secretion, which inhibits cancer-associated fibroblast (CAF) proliferation and ECM-related gene transcription through the Wnt/β-catenin pathway, creating a prometastatic niche with reduced ECM deposition; FGF2 targeting decreased liver metastasis in vivo.","method":"KRT7 overexpression in PDAC cells, orthotopic tumor model, scRNA-seq analysis of CAF infiltration, FGF2 secretion measurement, Wnt/β-catenin pathway analysis in CAFs, in vivo FGF2 targeting experiment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic crosstalk demonstrated with in vivo rescue experiment plus scRNA-seq, single lab, multiple orthogonal approaches","pmids":["40011455"],"is_preprint":false},{"year":2020,"finding":"Fusobacterium nucleatum infection upregulates KRT7-AS and KRT7 expression in colorectal cancer cells via NF-κB signaling; KRT7-AS facilitates CRC cell migration by upregulating KRT7, and Fn-induced CRC lung metastasis was attenuated by depletion of KRT7-AS.","method":"RNA sequencing, RT-PCR validation, NF-κB pathway analysis, KRT7-AS depletion (siRNA), transwell/wound healing migration assays, in vivo tail-vein lung metastasis model","journal":"Gut microbes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KRT7 is downstream effector of KRT7-AS, mechanism for KRT7 protein itself not directly tested, single lab","pmids":["31910722"],"is_preprint":false},{"year":2009,"finding":"A rabbit monoclonal antibody (clone BC1) raised against the C-terminus peptide of CK7 was validated to specifically recognize KRT7 protein by Western blotting on HeLa cell lysates and immunohistochemistry on formalin-fixed paraffin-embedded tissues, with staining pattern concordant with the established mouse monoclonal OV-TL 12/30 clone.","method":"ELISA peptide screening, Western blotting on HeLa lysates, IHC on FFPE tissues, comparison with reference antibody OV-TL 12/30","journal":"Applied immunohistochemistry & molecular morphology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — antibody characterization confirming protein identity, no functional mechanistic insight","pmids":["19098679"],"is_preprint":false}],"current_model":"KRT7 (Keratin 7) is a type II intermediate filament protein expressed in simple epithelial cells; its transcription is directly activated by FOXA1 and FoxM1 (via an AP-2 cis element), and its mRNA is post-transcriptionally stabilized by a KRT7-AS lncRNA duplex regulated by m6A methylation (METTL3/IGF2BP1/HuR) while its translation is elongation-regulated by YTHDF1/eEF-1 downstream of FTO; KRT7 promotes cell migration and EMT through TGF-β/Smad2/3 and integrin-β1/FAK signaling, and drives pancreatic cancer liver metastasis by stimulating FGF2 secretion that remodels the CAF-ECM niche via Wnt/β-catenin signaling."},"narrative":{"mechanistic_narrative":"KRT7 (Keratin 7) is a type II keratin whose expression promotes epithelial cancer cell migration, invasion, and epithelial-mesenchymal transition across multiple tumor types [PMID:33416175, PMID:32659254]. In ovarian cancer, KRT7 overexpression drives EMT, migration, and proliferation through TGF-β/Smad2/3 signaling and regulates cell-matrix adhesion via integrin-β1/FAK signaling, with knockdown reversing these effects and inhibiting tumor growth in vivo [PMID:33416175]. KRT7 transcription is directly activated by forkhead transcription factors: FOXA1 confers pro-proliferative, migratory, and invasive activity and modulates 5-fluorouracil chemosensitivity through KRT7 [PMID:31317696], and FoxM1 binds an AP-2 consensus cis element to regulate KRT7 expression, where KRT7 loss selectively blocks migration without affecting proliferation [PMID:32659254]. KRT7 expression is further controlled by a KRT7-AS antisense lncRNA that forms an RNA-RNA hybrid with KRT7 mRNA to raise keratin 7 protein levels and promote proliferation and migration [PMID:26876208]; this duplex is stabilized by METTL3-deposited m6A at A877 via IGF2BP1/HuR, while YTHDF1/eEF-1 mediates FTO-regulated translational elongation of KRT7 mRNA methylated at A950, together driving metastasis [PMID:33795252]. In pancreatic ductal adenocarcinoma, KRT7 overexpression promotes liver metastasis by stimulating FGF2 secretion, which suppresses cancer-associated fibroblast proliferation and ECM gene transcription through Wnt/β-catenin signaling to establish a prometastatic, ECM-depleted niche [PMID:40011455].","teleology":[{"year":2016,"claim":"Established that KRT7 expression is set post-transcriptionally by an antisense lncRNA, revealing a non-canonical layer of control over a structural keratin.","evidence":"RNA-seq, RNA-RNA hybrid assay, and domain-mapped overexpression of KRT7-AS in gastric cancer cells with proliferation/migration readouts","pmids":["26876208"],"confidence":"Medium","gaps":["Did not define how the KRT7-AS/KRT7 duplex mechanistically stabilizes the mRNA","Limited to gastric cancer context"]},{"year":2010,"claim":"Placed KRT7 downstream of FOXA1 in a transcriptional program, framing the keratin as an effector of a forkhead factor in epithelial cancer invasion.","evidence":"FOXA1 siRNA knockdown with RT-PCR readout of KRT7 mRNA and invasion/migration assays in esophageal squamous cell carcinoma","pmids":["20043065"],"confidence":"Low","gaps":["Direct KRT7-driven mechanism not tested—only mRNA correlation with FOXA1","Functional phenotypes attributed to FOXA1, not isolated KRT7"]},{"year":2019,"claim":"Confirmed FOXA1 directly transactivates KRT7 and that KRT7 mediates FOXA1's oncogenic and chemoresistance functions, converting correlation into a causal transcriptional axis.","evidence":"Dual luciferase reporter assay plus gain/loss-of-function epistasis and 5-FU sensitivity assays in gastric cancer cells","pmids":["31317696"],"confidence":"Medium","gaps":["FOXA1 binding site on the KRT7 promoter not mapped","Mechanism by which KRT7 protein alters chemosensitivity unresolved"]},{"year":2020,"claim":"Defined the downstream signaling through which KRT7 drives EMT and adhesion, linking the keratin to TGF-β/Smad2/3 and integrin-β1/FAK pathways.","evidence":"KRT7 siRNA knockdown with pathway Western blots, migration/proliferation assays, and xenograft model in ovarian cancer","pmids":["33416175"],"confidence":"Medium","gaps":["Whether KRT7 acts upstream of or in parallel to TGF-β signaling not resolved","Direct molecular partners connecting KRT7 to integrin-β1/FAK not identified"]},{"year":2020,"claim":"Identified a second forkhead activator (FoxM1) acting through an AP-2 cis element and showed KRT7 loss selectively blocks migration, separating its migratory from proliferative roles.","evidence":"ChIP-seq, RNA-seq, qPCR, and KRT7 siRNA knockdown phenotyping in ovarian cancer cells","pmids":["32659254"],"confidence":"Medium","gaps":["Relationship between FoxM1 and FOXA1 regulation of KRT7 not reconciled","Mechanistic basis of migration-specific dependence unexplained"]},{"year":2020,"claim":"Connected an external stimulus to KRT7 induction, showing bacterial infection upregulates KRT7-AS/KRT7 via NF-κB to promote metastasis.","evidence":"RNA-seq, NF-κB pathway analysis, KRT7-AS siRNA depletion, and in vivo lung metastasis model in colorectal cancer with Fusobacterium nucleatum","pmids":["31910722"],"confidence":"Low","gaps":["KRT7 protein function not directly tested—effects attributed to KRT7-AS","Direct NF-κB target locus not mapped"]},{"year":2021,"claim":"Resolved the m6A logic governing KRT7, mapping methylation sites and reader complexes that stabilize the KRT7-AS/KRT7 duplex and tune KRT7 translation.","evidence":"Epi-transcriptome analysis, site-specific mutagenesis (A877, A950), RIP/pulldown for IGF2BP1/HuR and YTHDF1/eEF-1, and in vivo lung metastasis in breast cancer","pmids":["33795252"],"confidence":"Medium","gaps":["Relative contribution of duplex stabilization versus translational elongation to phenotype not dissected","Single lab; reader-complex assignments not orthogonally confirmed"]},{"year":2021,"claim":"Extended upstream regulation to a miR-216a/WT1 cascade feeding into KRT7 in pancreatic cancer linked to PI3K/AKT activity.","evidence":"miRNA microarray, transcription reporter for WT1→KRT7, knockdown/overexpression cascade, and in vivo pancreatic tumor model","pmids":["33759343"],"confidence":"Low","gaps":["KRT7's mechanistic contribution is indirect within the axis","WT1 binding to the KRT7 promoter not directly mapped"]},{"year":2022,"claim":"Showed KRT7 is required for cell-in-cell and cell cluster formation in pancreatic cancer, implicating it in collective cellular organization beyond single-cell migration.","evidence":"KRT7 siRNA knockdown with CIC, cluster, proliferation, migration, and invasion assays in PDAC cell lines","pmids":["35974300"],"confidence":"Low","gaps":["No downstream molecular mechanism for CIC formation defined","In vivo relevance of cluster formation not tested"]},{"year":2025,"claim":"Revealed a non-cell-autonomous mechanism whereby KRT7 reshapes the metastatic microenvironment through FGF2-driven CAF and ECM remodeling.","evidence":"KRT7 overexpression in PDAC, orthotopic model, scRNA-seq of CAFs, FGF2 secretion measurement, Wnt/β-catenin analysis, and in vivo FGF2 targeting","pmids":["40011455"],"confidence":"Medium","gaps":["Mechanism linking intracellular KRT7 to FGF2 secretion not defined","Whether this niche remodeling generalizes beyond PDAC liver metastasis unknown"]},{"year":null,"claim":"How KRT7's structural filament role mechanistically connects to its diverse signaling outputs (TGF-β/Smad, integrin/FAK, FGF2/Wnt) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biophysical link between keratin filament assembly and signaling activation established","No direct protein interactors of KRT7 mapped in the corpus","Whether signaling effects require filament integrity vs. soluble KRT7 untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,10]}],"localization":[],"pathway":[],"complexes":[],"partners":["KRT7-AS","METTL3","IGF2BP1","HUR","YTHDF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P08729","full_name":"Keratin, type II cytoskeletal 7","aliases":["Cytokeratin-7","CK-7","Keratin-7","K7","Sarcolectin","Type-II keratin Kb7"],"length_aa":469,"mass_kda":51.4,"function":"Blocks interferon-dependent interphase and stimulates DNA synthesis in cells. Involved in the translational regulation of the human papillomavirus type 16 E7 mRNA (HPV16 E7)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P08729/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRT7","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KRT7","total_profiled":1310},"omim":[{"mim_id":"608246","title":"KERATIN 72, TYPE II; KRT72","url":"https://www.omim.org/entry/608246"},{"mim_id":"148059","title":"KERATIN 7, TYPE II; KRT7","url":"https://www.omim.org/entry/148059"},{"mim_id":"139350","title":"KERATIN 1, TYPE II; KRT1","url":"https://www.omim.org/entry/139350"},{"mim_id":"122000","title":"CORNEAL DYSTROPHY, POSTERIOR POLYMORPHOUS, 1; PPCD1","url":"https://www.omim.org/entry/122000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Intermediate filaments","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":341.9},{"tissue":"salivary gland","ntpm":952.4},{"tissue":"thyroid gland","ntpm":405.5}],"url":"https://www.proteinatlas.org/search/KRT7"},"hgnc":{"alias_symbol":["K7","CK7","CK-7","K2C7","SCL"],"prev_symbol":[]},"alphafold":{"accession":"P08729","domains":[{"cath_id":"-","chopping":"95-129_149-238_262-403","consensus_level":"medium","plddt":94.189,"start":95,"end":403}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08729","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08729-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08729-F1-predicted_aligned_error_v6.png","plddt_mean":73.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRT7","jax_strain_url":"https://www.jax.org/strain/search?query=KRT7"},"sequence":{"accession":"P08729","fasta_url":"https://rest.uniprot.org/uniprotkb/P08729.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08729/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08729"}},"corpus_meta":[{"pmid":"31910722","id":"PMC_31910722","title":"Fusobacterium 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KRT7 mRNA and controls KRT7 expression at both the mRNA and post-transcriptional levels; forced overexpression of the KRT7-overlapping region (but not non-overlapping portions) of KRT7-AS increased keratin 7 protein levels, promoting gastric cancer cell proliferation and migration.\",\n      \"method\": \"RNA sequencing, RNA-RNA hybrid assay, forced overexpression of full-length vs. truncated KRT7-AS constructs, cell proliferation and migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping overexpression experiments with orthogonal functional readouts in a single lab\",\n      \"pmids\": [\"26876208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"m6A methyltransferase METTL3 methylates KRT7-AS at A877, stabilizing a KRT7-AS/KRT7 mRNA duplex via IGF2BP1/HuR complexes; additionally, YTHDF1/eEF-1 mediates FTO-regulated translational elongation of KRT7 mRNA with methylated A950 in KRT7 exon 6 as the key site, together promoting breast cancer lung metastasis.\",\n      \"method\": \"Epi-transcriptome and transcriptome analyses, m6A site-specific mutagenesis (A877, A950), RIP/pulldown for IGF2BP1/HuR and YTHDF1/eEF-1 complexes, in vivo lung metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-specific mutagenesis plus complex pulldowns plus in vivo validation, single lab\",\n      \"pmids\": [\"33795252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KRT7 overexpression promotes epithelial-mesenchymal transition (EMT), migration, and proliferation of ovarian cancer cells via the TGF-β/Smad2/3 signaling pathway, and also regulates cell-matrix adhesion through integrin-β1-focal adhesion kinase signaling; KRT7 siRNA knockdown reversed these effects and inhibited tumor growth in vivo.\",\n      \"method\": \"CCK8 proliferation assay, wound healing and transwell migration assays, KRT7 siRNA knockdown, Western blotting for TGF-β/Smad2/3 and integrin-β1/FAK pathway components, in vivo xenograft model\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined pathway readouts and in vivo confirmation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33416175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FOXA1 transcriptionally activates KRT7 in gastric cancer cells, as demonstrated by dual luciferase reporter assay; FOXA1 exerts its pro-proliferative, migratory, and invasive functions through KRT7 activation, and knockdown of either FOXA1 or KRT7 increased chemosensitivity to 5-fluorouracil.\",\n      \"method\": \"Dual luciferase reporter assay, gain- and loss-of-function experiments (siRNA/overexpression), cell proliferation/migration/invasion assays, 5-FU sensitivity assay\",\n      \"journal\": \"Journal of biological regulators and homeostatic agents\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional activation confirmed by reporter assay plus functional epistasis, single lab\",\n      \"pmids\": [\"31317696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FOXA1 siRNA treatment of esophageal cancer cells reduced KRT7 mRNA levels, placing KRT7 downstream of FOXA1 in a transcriptional pathway; FOXA1 and LOXL2 siRNAs also reduced invasion and migration of esophageal squamous cell carcinoma (ESCC) cells, suggesting KRT7-expressing ESCCs with lymph node metastasis are driven in part by FOXA1.\",\n      \"method\": \"siRNA knockdown of FOXA1 and LOXL2, RT-PCR for KRT7 mRNA, invasion and migration assays, gene expression profiling of 24 ESCCs\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA knockdown with mRNA readout and functional assays, no direct KRT7 mechanism tested\",\n      \"pmids\": [\"20043065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FoxM1 binds a consensus AP-2 cis element to regulate KRT7 (and KRT5) gene expression in ovarian cancer; KRT7 deficiency specifically prevented cell migration but not proliferation of SK-OV-3 cells.\",\n      \"method\": \"ChIP-seq, RNA-seq, qPCR, Western blot for FoxM1 knockdown effect on KRT7, migration and proliferation assays with KRT7 siRNA knockdown\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq identifies direct binding plus loss-of-function with specific phenotypic readout, single lab\",\n      \"pmids\": [\"32659254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-216a suppresses WT1 expression, and WT1 promotes KRT7 transcription; silencing KRT7 diminished the oncogenic role of WT1 in pancreatic cancer, and the miR-216a/WT1/KRT7 axis influenced PI3K/AKT pathway activity.\",\n      \"method\": \"miRNA microarray, transcription reporter assay for WT1→KRT7, siRNA/overexpression of miR-216a and WT1, KRT7 knockdown functional assays (proliferation, invasion), in vivo tumor model\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway epistasis established by knockdown/overexpression cascade, single lab, indirect mechanism for KRT7\",\n      \"pmids\": [\"33759343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KRT7 knockdown in pancreatic cancer cell lines significantly suppressed cell-in-cell (CIC) formation, cell cluster formation, cell proliferation, migration, and invasion.\",\n      \"method\": \"KRT7 siRNA knockdown, CIC formation assay, cell cluster assay, proliferation/migration/invasion assays, qRT-PCR/Western blot/IHC for KRT7 validation\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss-of-function with multiple cellular phenotype readouts but no defined downstream mechanism, single lab\",\n      \"pmids\": [\"35974300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KRT7 overexpression in pancreatic ductal adenocarcinoma cells promotes liver metastasis by stimulating FGF2 secretion, which inhibits cancer-associated fibroblast (CAF) proliferation and ECM-related gene transcription through the Wnt/β-catenin pathway, creating a prometastatic niche with reduced ECM deposition; FGF2 targeting decreased liver metastasis in vivo.\",\n      \"method\": \"KRT7 overexpression in PDAC cells, orthotopic tumor model, scRNA-seq analysis of CAF infiltration, FGF2 secretion measurement, Wnt/β-catenin pathway analysis in CAFs, in vivo FGF2 targeting experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic crosstalk demonstrated with in vivo rescue experiment plus scRNA-seq, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"40011455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fusobacterium nucleatum infection upregulates KRT7-AS and KRT7 expression in colorectal cancer cells via NF-κB signaling; KRT7-AS facilitates CRC cell migration by upregulating KRT7, and Fn-induced CRC lung metastasis was attenuated by depletion of KRT7-AS.\",\n      \"method\": \"RNA sequencing, RT-PCR validation, NF-κB pathway analysis, KRT7-AS depletion (siRNA), transwell/wound healing migration assays, in vivo tail-vein lung metastasis model\",\n      \"journal\": \"Gut microbes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KRT7 is downstream effector of KRT7-AS, mechanism for KRT7 protein itself not directly tested, single lab\",\n      \"pmids\": [\"31910722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A rabbit monoclonal antibody (clone BC1) raised against the C-terminus peptide of CK7 was validated to specifically recognize KRT7 protein by Western blotting on HeLa cell lysates and immunohistochemistry on formalin-fixed paraffin-embedded tissues, with staining pattern concordant with the established mouse monoclonal OV-TL 12/30 clone.\",\n      \"method\": \"ELISA peptide screening, Western blotting on HeLa lysates, IHC on FFPE tissues, comparison with reference antibody OV-TL 12/30\",\n      \"journal\": \"Applied immunohistochemistry & molecular morphology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — antibody characterization confirming protein identity, no functional mechanistic insight\",\n      \"pmids\": [\"19098679\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT7 (Keratin 7) is a type II intermediate filament protein expressed in simple epithelial cells; its transcription is directly activated by FOXA1 and FoxM1 (via an AP-2 cis element), and its mRNA is post-transcriptionally stabilized by a KRT7-AS lncRNA duplex regulated by m6A methylation (METTL3/IGF2BP1/HuR) while its translation is elongation-regulated by YTHDF1/eEF-1 downstream of FTO; KRT7 promotes cell migration and EMT through TGF-β/Smad2/3 and integrin-β1/FAK signaling, and drives pancreatic cancer liver metastasis by stimulating FGF2 secretion that remodels the CAF-ECM niche via Wnt/β-catenin signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KRT7 (Keratin 7) is a type II keratin whose expression promotes epithelial cancer cell migration, invasion, and epithelial-mesenchymal transition across multiple tumor types [#2, #5]. In ovarian cancer, KRT7 overexpression drives EMT, migration, and proliferation through TGF-\\u03b2/Smad2/3 signaling and regulates cell-matrix adhesion via integrin-\\u03b21/FAK signaling, with knockdown reversing these effects and inhibiting tumor growth in vivo [#2]. KRT7 transcription is directly activated by forkhead transcription factors: FOXA1 confers pro-proliferative, migratory, and invasive activity and modulates 5-fluorouracil chemosensitivity through KRT7 [#3], and FoxM1 binds an AP-2 consensus cis element to regulate KRT7 expression, where KRT7 loss selectively blocks migration without affecting proliferation [#5]. KRT7 expression is further controlled by a KRT7-AS antisense lncRNA that forms an RNA-RNA hybrid with KRT7 mRNA to raise keratin 7 protein levels and promote proliferation and migration [#0]; this duplex is stabilized by METTL3-deposited m6A at A877 via IGF2BP1/HuR, while YTHDF1/eEF-1 mediates FTO-regulated translational elongation of KRT7 mRNA methylated at A950, together driving metastasis [#1]. In pancreatic ductal adenocarcinoma, KRT7 overexpression promotes liver metastasis by stimulating FGF2 secretion, which suppresses cancer-associated fibroblast proliferation and ECM gene transcription through Wnt/\\u03b2-catenin signaling to establish a prometastatic, ECM-depleted niche [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that KRT7 expression is set post-transcriptionally by an antisense lncRNA, revealing a non-canonical layer of control over a structural keratin.\",\n      \"evidence\": \"RNA-seq, RNA-RNA hybrid assay, and domain-mapped overexpression of KRT7-AS in gastric cancer cells with proliferation/migration readouts\",\n      \"pmids\": [\"26876208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define how the KRT7-AS/KRT7 duplex mechanistically stabilizes the mRNA\", \"Limited to gastric cancer context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed KRT7 downstream of FOXA1 in a transcriptional program, framing the keratin as an effector of a forkhead factor in epithelial cancer invasion.\",\n      \"evidence\": \"FOXA1 siRNA knockdown with RT-PCR readout of KRT7 mRNA and invasion/migration assays in esophageal squamous cell carcinoma\",\n      \"pmids\": [\"20043065\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct KRT7-driven mechanism not tested\\u2014only mRNA correlation with FOXA1\", \"Functional phenotypes attributed to FOXA1, not isolated KRT7\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed FOXA1 directly transactivates KRT7 and that KRT7 mediates FOXA1's oncogenic and chemoresistance functions, converting correlation into a causal transcriptional axis.\",\n      \"evidence\": \"Dual luciferase reporter assay plus gain/loss-of-function epistasis and 5-FU sensitivity assays in gastric cancer cells\",\n      \"pmids\": [\"31317696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FOXA1 binding site on the KRT7 promoter not mapped\", \"Mechanism by which KRT7 protein alters chemosensitivity unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the downstream signaling through which KRT7 drives EMT and adhesion, linking the keratin to TGF-\\u03b2/Smad2/3 and integrin-\\u03b21/FAK pathways.\",\n      \"evidence\": \"KRT7 siRNA knockdown with pathway Western blots, migration/proliferation assays, and xenograft model in ovarian cancer\",\n      \"pmids\": [\"33416175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KRT7 acts upstream of or in parallel to TGF-\\u03b2 signaling not resolved\", \"Direct molecular partners connecting KRT7 to integrin-\\u03b21/FAK not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a second forkhead activator (FoxM1) acting through an AP-2 cis element and showed KRT7 loss selectively blocks migration, separating its migratory from proliferative roles.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, qPCR, and KRT7 siRNA knockdown phenotyping in ovarian cancer cells\",\n      \"pmids\": [\"32659254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between FoxM1 and FOXA1 regulation of KRT7 not reconciled\", \"Mechanistic basis of migration-specific dependence unexplained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected an external stimulus to KRT7 induction, showing bacterial infection upregulates KRT7-AS/KRT7 via NF-\\u03baB to promote metastasis.\",\n      \"evidence\": \"RNA-seq, NF-\\u03baB pathway analysis, KRT7-AS siRNA depletion, and in vivo lung metastasis model in colorectal cancer with Fusobacterium nucleatum\",\n      \"pmids\": [\"31910722\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"KRT7 protein function not directly tested\\u2014effects attributed to KRT7-AS\", \"Direct NF-\\u03baB target locus not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the m6A logic governing KRT7, mapping methylation sites and reader complexes that stabilize the KRT7-AS/KRT7 duplex and tune KRT7 translation.\",\n      \"evidence\": \"Epi-transcriptome analysis, site-specific mutagenesis (A877, A950), RIP/pulldown for IGF2BP1/HuR and YTHDF1/eEF-1, and in vivo lung metastasis in breast cancer\",\n      \"pmids\": [\"33795252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of duplex stabilization versus translational elongation to phenotype not dissected\", \"Single lab; reader-complex assignments not orthogonally confirmed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended upstream regulation to a miR-216a/WT1 cascade feeding into KRT7 in pancreatic cancer linked to PI3K/AKT activity.\",\n      \"evidence\": \"miRNA microarray, transcription reporter for WT1\\u2192KRT7, knockdown/overexpression cascade, and in vivo pancreatic tumor model\",\n      \"pmids\": [\"33759343\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"KRT7's mechanistic contribution is indirect within the axis\", \"WT1 binding to the KRT7 promoter not directly mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed KRT7 is required for cell-in-cell and cell cluster formation in pancreatic cancer, implicating it in collective cellular organization beyond single-cell migration.\",\n      \"evidence\": \"KRT7 siRNA knockdown with CIC, cluster, proliferation, migration, and invasion assays in PDAC cell lines\",\n      \"pmids\": [\"35974300\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No downstream molecular mechanism for CIC formation defined\", \"In vivo relevance of cluster formation not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a non-cell-autonomous mechanism whereby KRT7 reshapes the metastatic microenvironment through FGF2-driven CAF and ECM remodeling.\",\n      \"evidence\": \"KRT7 overexpression in PDAC, orthotopic model, scRNA-seq of CAFs, FGF2 secretion measurement, Wnt/\\u03b2-catenin analysis, and in vivo FGF2 targeting\",\n      \"pmids\": [\"40011455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking intracellular KRT7 to FGF2 secretion not defined\", \"Whether this niche remodeling generalizes beyond PDAC liver metastasis unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KRT7's structural filament role mechanistically connects to its diverse signaling outputs (TGF-\\u03b2/Smad, integrin/FAK, FGF2/Wnt) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biophysical link between keratin filament assembly and signaling activation established\", \"No direct protein interactors of KRT7 mapped in the corpus\", \"Whether signaling effects require filament integrity vs. soluble KRT7 untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0008953854\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KRT7-AS\", \"METTL3\", \"IGF2BP1\", \"HuR\", \"YTHDF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}