{"gene":"FSCN1","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":1998,"finding":"Fascin (FSCN1) directly bundles actin filaments and, when expressed in epithelial cells (LLC-PK1), induces membrane protrusions (lamellipodia, microvilli), reorganizes the microfilament cytoskeleton at the cell periphery, and increases cell migration 8–17-fold in a Boyden chamber assay. Microinjection of purified fascin protein into cells recapitulated these morphological changes, establishing direct causality.","method":"Overexpression in epithelial cells, microinjection of purified fascin protein, Boyden chamber migration assay, immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 — purified protein microinjection plus overexpression with specific phenotypic readout; replicated with multiple cell types","pmids":["9571235"],"is_preprint":false},{"year":2007,"finding":"FSCN1 (fascin1) is a direct transcriptional target of β-catenin–TCF signaling in colorectal cancer cells. Forced expression of fascin1 increased cell migration and invasion in vitro and caused cell dissemination and metastasis in vivo; suppression by siRNA reduced invasion. Fascin1 was exclusively localized at the invasive front of tumors displaying nuclear β-catenin.","method":"TCF reporter assays, siRNA knockdown, overexpression, Boyden chamber invasion, in vivo xenograft/metastasis model, immunohistochemistry","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (reporter assay, KD, OE, in vivo) in a single study","pmids":["17638895"],"is_preprint":false},{"year":2010,"finding":"Fascin (FSCN1) is an integral component of invadopodia in cancer cells and stabilizes actin within invadopodia. Phosphorylation of fascin at serine 39 by PKC regulates its localization and activity at invadopodia. Fascin promotes invasive migration into collagen I–Matrigel 3D matrices, particularly in elongated mesenchymal motility.","method":"siRNA knockdown, phosphomutant constructs (S39A/S39D), live-cell imaging, 3D invasion assay, immunofluorescence of invadopodia markers","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches including phosphomutant rescue, 3D invasion, and invadopodia imaging","pmids":["20137952"],"is_preprint":false},{"year":2010,"finding":"Migrastatin analogues (e.g., macroketone) directly bind fascin (FSCN1) at one of its actin-binding sites and inhibit its actin-bundling activity, thereby blocking tumor cell migration, invasion, and metastasis. X-ray crystal structure of fascin–macroketone complex defined the binding site.","method":"X-ray crystallography, in vitro actin-bundling assay, cell migration/invasion assays, in vivo metastasis mouse model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus in vitro reconstitution plus in vivo validation","pmids":["20393565"],"is_preprint":false},{"year":2005,"finding":"FSCN1 was identified as part of a gene set that mediates breast cancer metastasis specifically to the lung, established through in vivo selection of metastatic subpopulations and functional verification.","method":"In vivo selection, transcriptomic analysis, functional verification in xenograft models","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo functional screen but FSCN1 is one of many genes; specific mechanistic role of FSCN1 not isolated in this paper","pmids":["16049480"],"is_preprint":false},{"year":2010,"finding":"miR-145 and miR-133a directly bind to the 3′UTR of FSCN1 mRNA and repress FSCN1 mRNA and protein expression in bladder cancer cells, functioning as tumor suppressors. Luciferase reporter assay confirmed direct binding. siRNA knockdown of FSCN1 phenocopied miR-145/133a overexpression, inhibiting cell viability, wound healing, and invasion.","method":"Luciferase reporter assay, transfection of miRNA mimics, siRNA knockdown, cell growth/wound-healing/invasion assays, immunohistochemistry, in situ hybridization","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 2 — direct 3′UTR luciferase validation plus phenotypic rescue experiments across multiple assays","pmids":["20160723"],"is_preprint":false},{"year":2010,"finding":"miR-145, miR-133a, and miR-133b directly regulate FSCN1 expression in esophageal squamous cell carcinoma (ESCC) by binding conserved target sites in the 3′UTR of FSCN1. Luciferase reporter assays confirmed two miR-145 sites and one miR-133a/b site. FSCN1 loss-of-function inhibited cell growth and invasion in ESCC.","method":"Luciferase reporter assay, miRNA gain-of-function transfection, siRNA knockdown, cell proliferation/invasion assays","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 — direct 3′UTR mapping with multiple binding sites confirmed by reporter assay plus loss-of-function phenotype","pmids":["21351259"],"is_preprint":false},{"year":2013,"finding":"miR-133a directly targets FSCN1 mRNA in esophageal squamous cell carcinoma (ESCC); transfection of miR-133a mimic decreased both FSCN1 mRNA and protein levels and inhibited proliferation and invasion. FSCN1 and MMP14 are co-regulated invadopodia-related proteins whose combined expression correlates with worst prognosis.","method":"miRNA mimic transfection, qPCR, western blot, siRNA knockdown, proliferation/invasion assays, immunohistochemistry","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — miRNA target validation without luciferase reporter in this paper; multiple functional assays","pmids":["24196787"],"is_preprint":false},{"year":2013,"finding":"miR-133a directly targets FSCN1 in pancreatic cancer, confirmed by luciferase reporter assay. Transfection of miR-133a mimics in PANC-1 cells reduced FSCN1 protein, and decreased cell proliferation, invasion, and migration while promoting apoptosis in vitro, and suppressed tumorigenicity in vivo.","method":"Luciferase reporter assay, miRNA mimic transfection, siRNA knockdown, proliferation/invasion/migration assays, xenograft mouse model","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase confirmation plus in vivo validation, single lab","pmids":["25198665"],"is_preprint":false},{"year":2017,"finding":"EGF induces FSCN1 expression through activation of the MAPK pathway in triple-negative breast cancer (TNBC) cells, which subsequently promotes cell migration and invasion. Co-treatment with FSCN1 siRNA and the EGFR inhibitor Gefitinib produced greater reduction of FSCN1 expression than either treatment alone.","method":"siRNA knockdown, EGFR inhibitor (Gefitinib) treatment, western blot, migration/invasion assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — pathway placement by pharmacological inhibition and KD; single lab","pmids":["29142206"],"is_preprint":false},{"year":2018,"finding":"miR-145-5p directly targets and negatively regulates FSCN1 via its 3′UTR (confirmed by luciferase assay) in laryngeal squamous cell carcinoma. Low miR-145-5p/high FSCN1 promotes EMT, cell migration, invasion, and growth. The miR-145-5p promoter is hypermethylated in LSCC, repressing miR-145-5p and thus relieving FSCN1 repression.","method":"Luciferase reporter assay, gain/loss-of-function studies, promoter methylation analysis, siRNA, in vivo tumor growth assay","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase confirmation, epigenetic mechanism identified, in vivo validation; single lab","pmids":["30341010"],"is_preprint":false},{"year":2019,"finding":"YAP1 transcriptionally activates LINC00152, which acts as a ceRNA sponging miR-632 and miR-185-3p to upregulate FSCN1 expression in colorectal cancer, promoting proliferation and metastasis. This YAP1/LINC00152/miR-632|miR-185-3p/FSCN1 axis was established by in vitro and in vivo experiments.","method":"ceRNA reporter assays, miRNA sponge assays, siRNA/shRNA knockdown, xenograft mouse models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 — multi-step pathway with in vivo validation but complex indirect regulatory chain","pmids":["32042551"],"is_preprint":false},{"year":2015,"finding":"FSCN1 knockdown in pituitary adenoma (GH3) cells suppressed cell invasion through transwell assay and downregulated Notch1 and DLL3 expression, placing FSCN1 upstream of Notch signaling in pituitary adenoma invasiveness.","method":"siRNA knockdown, transwell invasion assay, western blot for Notch1/DLL3","journal":"Molecular and cellular endocrinology","confidence":"Low","confidence_rationale":"Tier 3 — single KD experiment with downstream marker measurement; no rescue or pathway epistasis","pmids":["26522130"],"is_preprint":false},{"year":2020,"finding":"SOX2 promotes brain metastasis of breast cancer by transcriptionally upregulating FSCN1 (and HBEGF) through activation of AKT and β-catenin signaling pathways, thereby increasing cancer cell adhesion to brain microvascular endothelial cells and transendothelial migration across the blood–brain barrier.","method":"SOX2 overexpression/silencing, in vitro BBB migration assay, AKT/β-catenin pathway inhibitors, xenograft brain metastasis model, mRNA profiling","journal":"Molecular therapy oncolytics","confidence":"Medium","confidence_rationale":"Tier 2–3 — pathway placement via signaling inhibitors and in vivo model; FSCN1 is one of two downstream targets","pmids":["32322668"],"is_preprint":false},{"year":2021,"finding":"The transcription factor GRHL3 directly activates FSCN1 transcription during wound reepithelialization by increasing chromatin accessibility near the Fscn1 gene (ATAC-seq shows enriched GRHL3 motifs). FSCN1 (Fascin-1) in turn downregulates E-cadherin to relax adherens junctions between suprabasal keratinocytes, promoting collective migration. Grhl3-cKO mice have lower FSCN1 expression at wound fronts and impaired wound closure.","method":"ATAC-seq on wounded keratinocytes, conditional knockout mice (Grhl3-cKO), immunofluorescence for E-cadherin and FSCN1, wound closure assays","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — ATAC-seq chromatin evidence, genetic KO with specific molecular phenotype (E-cadherin), in vivo wound model; multiple orthogonal methods","pmids":["34494554"],"is_preprint":false},{"year":2021,"finding":"LYAR (a nucleolar protein) directly binds the FSCN1 promoter (shown by ChIP assay) and transcriptionally activates FSCN1 expression. FSCN1 is a downstream effector of LYAR-promoted CRC cell migration and invasion, and FSCN1 knockdown inhibits subcutaneous tumorigenesis and downregulates FASN and SCD (fatty acid synthesis genes).","method":"ChIP assay, gene reporter assay, microarray, siRNA/shRNA knockdown, xenograft tumor model","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms direct promoter binding; functional rescue with multiple readouts; single lab","pmids":["35069968"],"is_preprint":false},{"year":2021,"finding":"ADORA2A-AS1 (lncRNA) competitively binds HuR (RNA-binding protein), preventing HuR from binding and stabilizing FSCN1 transcript, thereby decreasing FSCN1 mRNA stability and expression. Decreased FSCN1 in turn suppresses AKT pathway activation in hepatocellular carcinoma. RNA pull-down and RIP confirmed ADORA2A-AS1–HuR–FSCN1 interactions.","method":"RNA pull-down, RNA immunoprecipitation (RIP), RNA stability assay, qRT-PCR, western blot, xenograft and metastasis models","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 — RIP and pull-down confirm HuR–FSCN1 interaction; FSCN1/AKT axis validated by rescue; single lab","pmids":["34733789"],"is_preprint":false},{"year":2023,"finding":"Ginsenoside Rb2 inhibits p300 acetyltransferase activity (confirmed by surface plasmon resonance and enzymatic assays showing direct binding), thereby reducing p300-mediated acetylation of SF3A2 at lysine 10. Decreased SF3A2-K10 acetylation promotes alternative splicing that upregulates FSCN1 expression in cardiomyocytes, enhancing mitochondrial respiration and protecting against ischemic injury.","method":"4D-label-free acetylomics, co-immunoprecipitation, surface plasmon resonance, cellular thermal shift assay, site-specific mutagenesis, RNA-seq, shRNA interference, in vivo cardiac ischemia model","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 1–2 — biochemical binding assays (SPR, CETSA) plus mutagenesis and RNA-seq; single lab but multiple orthogonal methods","pmids":["38101749"],"is_preprint":false},{"year":2006,"finding":"Fascin expression in breast carcinomas is strongly associated with the basal-like phenotype and is highly expressed in BRCA1-associated tumors (83.3%), establishing a link between FSCN1 and the basal-like/BRCA1 tumor subtype. However, fascin expression per se was not independently associated with metastatic behavior in node-negative sporadic breast cancers.","method":"Tissue microarray immunohistochemistry of 230 sporadic and 28 hereditary node-negative invasive breast carcinomas","journal":"Clinical cancer research","confidence":"Low","confidence_rationale":"Tier 4 — purely correlative IHC/expression study; no mechanistic experiment","pmids":["16533778"],"is_preprint":false}],"current_model":"FSCN1 (Fascin-1) is an actin-bundling protein that directly crosslinks actin filaments to form filopodia, microspikes, and invadopodia, driving cell migration and invasion; its activity at invadopodia is regulated by PKC-mediated phosphorylation at S39, its transcription is activated by β-catenin–TCF and GRHL3 (in wound healing) and by SOX2/AKT/β-catenin, its transcript stability is controlled by the HuR–ADORA2A-AS1 axis, and its expression is post-transcriptionally repressed by multiple tumor-suppressive miRNAs (miR-145, miR-133a/b, miR-133a, miR-429, miR-24, miR-200b) that directly bind its 3′UTR; small-molecule migrastatin analogues (macroketone) inhibit fascin by occupying an actin-binding site on the protein, blocking metastasis in vivo."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing that fascin directly bundles actin filaments and is sufficient to reorganize the cortical cytoskeleton and dramatically enhance cell migration resolved the basic molecular activity of FSCN1.","evidence":"Microinjection of purified fascin protein and overexpression in epithelial cells with Boyden chamber migration assays","pmids":["9571235"],"confidence":"High","gaps":["Regulatory mechanisms controlling fascin bundling activity were unknown","Whether fascin-driven migration contributed to pathological invasion was not tested"]},{"year":2007,"claim":"Identifying FSCN1 as a direct β-catenin–TCF transcriptional target placed it within Wnt pathway-driven carcinogenesis and showed that fascin expression at tumor invasive fronts functionally promotes metastasis in vivo.","evidence":"TCF reporter assays, siRNA knockdown, overexpression, and xenograft metastasis models in colorectal cancer","pmids":["17638895"],"confidence":"High","gaps":["Whether other transcription factors independently activate FSCN1 in non-Wnt contexts was unknown","Post-translational regulation of fascin at the invasive front was not addressed"]},{"year":2010,"claim":"Demonstrating that PKC phosphorylation at Ser39 regulates fascin localization and function at invadopodia, and that migrastatin analogues directly block fascin's actin-binding site (crystal structure resolved), established both the key regulatory switch and a pharmacological strategy to inhibit fascin-dependent invasion.","evidence":"Phosphomutant constructs (S39A/S39D) with live-cell invadopodia imaging and 3D invasion assays; X-ray crystallography of fascin–macroketone complex with in vivo metastasis inhibition","pmids":["20137952","20393565"],"confidence":"High","gaps":["Whether Ser39 phosphorylation is the sole regulatory post-translational modification was unclear","Clinical applicability of migrastatin analogues was not established"]},{"year":2010,"claim":"Discovery that miR-145 and miR-133a/b directly bind the FSCN1 3′UTR to repress expression across multiple tumor types established a major post-transcriptional regulatory layer governing fascin abundance.","evidence":"Luciferase 3′UTR reporter assays, miRNA mimic transfection, and phenocopy by FSCN1 siRNA in bladder and esophageal carcinoma cells","pmids":["20160723","21351259"],"confidence":"High","gaps":["Relative contribution of individual miRNAs versus combinatorial repression was not quantified","Upstream mechanisms silencing these miRNAs in tumors were only partially known"]},{"year":2017,"claim":"Placing FSCN1 downstream of EGF–MAPK signaling in triple-negative breast cancer extended the transcriptional regulation map beyond Wnt to receptor tyrosine kinase pathways.","evidence":"EGFR inhibitor (Gefitinib) treatment combined with FSCN1 siRNA in TNBC cells","pmids":["29142206"],"confidence":"Medium","gaps":["Direct transcription factor mediating MAPK-to-FSCN1 induction was not identified","Single-lab study without genetic epistasis"]},{"year":2018,"claim":"Showing that miR-145-5p promoter hypermethylation in laryngeal carcinoma relieves FSCN1 repression and promotes EMT connected epigenetic deregulation to fascin-driven invasion.","evidence":"Promoter methylation analysis, luciferase reporter assay, gain/loss-of-function studies, in vivo tumor growth","pmids":["30341010"],"confidence":"Medium","gaps":["Whether DNA methylation of miR-145 is a general mechanism across FSCN1-high tumors was not tested","E-cadherin loss was inferred but not mechanistically dissected downstream of fascin"]},{"year":2021,"claim":"Demonstrating that GRHL3 directly opens chromatin at the Fscn1 locus to drive transcription during wound reepithelialization, and that fascin then downregulates E-cadherin to loosen adherens junctions, established a physiological (non-oncogenic) role for fascin in collective cell migration.","evidence":"ATAC-seq on wounded keratinocytes, Grhl3 conditional knockout mice, wound closure assays, E-cadherin immunofluorescence","pmids":["34494554"],"confidence":"High","gaps":["Mechanism by which fascin downregulates E-cadherin (transcriptional vs. post-translational) was not resolved","Whether GRHL3–FSCN1 axis operates in other epithelial repair contexts is unknown"]},{"year":2021,"claim":"Identification that HuR binds and stabilizes FSCN1 mRNA, and that the lncRNA ADORA2A-AS1 competitively sequesters HuR to reduce FSCN1, revealed an RNA-binding-protein layer of post-transcriptional control complementary to miRNA repression.","evidence":"RNA immunoprecipitation, RNA pull-down, mRNA stability assays in hepatocellular carcinoma cells and xenograft models","pmids":["34733789"],"confidence":"Medium","gaps":["Whether HuR-mediated stabilization is the dominant mRNA-level control in non-hepatic contexts is untested","Quantitative contribution of HuR versus miRNA pathways to FSCN1 protein levels not compared"]},{"year":2023,"claim":"Discovery that p300-mediated acetylation of SF3A2 controls alternative splicing to regulate FSCN1 expression in cardiomyocytes broadened fascin's functional context to cardiac ischemic protection and mitochondrial respiration.","evidence":"Acetylomics, SPR binding assay, site-specific mutagenesis of SF3A2-K10, RNA-seq, in vivo cardiac ischemia model","pmids":["38101749"],"confidence":"Medium","gaps":["Specific splicing event in FSCN1 controlled by SF3A2 acetylation status was not fully characterized","Whether fascin has direct roles in mitochondrial function or acts indirectly through cytoskeletal remodeling is unresolved","Single-lab finding not yet independently replicated"]},{"year":null,"claim":"The mechanism by which fascin downregulates E-cadherin, the full set of post-translational modifications beyond Ser39, the structural basis for actin-bundling geometry in cellulo, and the physiological relevance of fascin in non-migratory contexts (e.g., cardiac protection) remain open questions.","evidence":"","pmids":[],"confidence":"High","gaps":["No comprehensive post-translational modification map beyond Ser39 phosphorylation","In vivo structural characterization of fascin-bundled actin arrays is lacking","Cardiac and neuronal roles of fascin are mechanistically uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,9,13]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,4,5,6]}],"complexes":[],"partners":["CTNNB1","GRHL3","ELAVL1","LYAR","SOX2"],"other_free_text":[]},"mechanistic_narrative":"FSCN1 (Fascin-1) is an actin-bundling protein that crosslinks filamentous actin into parallel bundles, driving the formation of filopodia, microspikes, and invadopodia to promote cell migration and invasion [PMID:9571235, PMID:20137952]. Its actin-bundling activity is negatively regulated by PKC-mediated phosphorylation at Ser39, which controls fascin dynamics at invadopodia, and can be pharmacologically inhibited by migrastatin analogues that occupy an actin-binding site, as defined by X-ray crystallography [PMID:20137952, PMID:20393565]. FSCN1 transcription is activated by β-catenin–TCF signaling in colorectal cancer and by GRHL3 during wound reepithelialization, where fascin promotes collective keratinocyte migration by downregulating E-cadherin at adherens junctions [PMID:17638895, PMID:34494554]. Post-transcriptionally, FSCN1 is repressed by multiple tumor-suppressive microRNAs—including miR-145, miR-133a, and miR-133b—that directly bind its 3′UTR, and its mRNA is stabilized by the RNA-binding protein HuR, which is competitively sequestered by the lncRNA ADORA2A-AS1 [PMID:20160723, PMID:21351259, PMID:34733789]."},"prefetch_data":{"uniprot":{"accession":"Q16658","full_name":"Fascin","aliases":["55 kDa actin-bundling protein","Singed-like protein","p55"],"length_aa":493,"mass_kda":54.5,"function":"Actin-binding protein that contains 2 major actin binding sites (PubMed:21685497, PubMed:23184945). Organizes filamentous actin into parallel bundles (PubMed:20393565, PubMed:21685497, PubMed:23184945). Plays a role in the organization of actin filament bundles and the formation of microspikes, membrane ruffles, and stress fibers (PubMed:22155786). Important for the formation of a diverse set of cell protrusions, such as filopodia, and for cell motility and migration (PubMed:20393565, PubMed:21685497, PubMed:23184945). Mediates reorganization of the actin cytoskeleton and axon growth cone collapse in response to NGF (PubMed:22155786)","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, cell cortex; Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, stress fiber; Cell projection, filopodium; Cell projection, invadopodium; Cell projection, microvillus; Cell junction","url":"https://www.uniprot.org/uniprotkb/Q16658/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FSCN1","classification":"Not Classified","n_dependent_lines":23,"n_total_lines":1208,"dependency_fraction":0.01903973509933775},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FSCN1","total_profiled":1310},"omim":[{"mim_id":"618468","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 76; DEE76","url":"https://www.omim.org/entry/618468"},{"mim_id":"615800","title":"FASCIN ACTIN-BUNDLING PROTEIN 3, TESTICULAR; FSCN3","url":"https://www.omim.org/entry/615800"},{"mim_id":"612458","title":"ACTIN-LIKE 6B; ACTL6B","url":"https://www.omim.org/entry/612458"},{"mim_id":"607643","title":"FASCIN ACTIN-BUNDLING PROTEIN 2, RETINAL; FSCN2","url":"https://www.omim.org/entry/607643"},{"mim_id":"605910","title":"ANGIOPOIETIN-LIKE 4; ANGPTL4","url":"https://www.omim.org/entry/605910"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FSCN1"},"hgnc":{"alias_symbol":["p55","FLJ38511"],"prev_symbol":["SNL"]},"alphafold":{"accession":"Q16658","domains":[{"cath_id":"2.80.10.50","chopping":"12-135","consensus_level":"high","plddt":94.0764,"start":12,"end":135},{"cath_id":"2.80.10.50","chopping":"140-257","consensus_level":"high","plddt":95.0647,"start":140,"end":257},{"cath_id":"2.80.10.50","chopping":"261-379","consensus_level":"high","plddt":96.4943,"start":261,"end":379},{"cath_id":"2.80.10.50","chopping":"384-491","consensus_level":"high","plddt":95.7946,"start":384,"end":491}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16658","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16658-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16658-F1-predicted_aligned_error_v6.png","plddt_mean":94.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FSCN1","jax_strain_url":"https://www.jax.org/strain/search?query=FSCN1"},"sequence":{"accession":"Q16658","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16658.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16658/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16658"}},"corpus_meta":[{"pmid":"9551933","id":"PMC_9551933","title":"TNF 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sites and one miR-133a/b site; loss-of-function of FSCN1 inhibited cell growth and invasion in esophageal squamous cell carcinoma cells.\",\n      \"method\": \"Luciferase reporter assay, gain-of-function miRNA transfection, FSCN1 siRNA knockdown, cell invasion assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct 3'UTR luciferase validation plus functional knockdown, multiple miRNAs tested, replicated in subsequent studies\",\n      \"pmids\": [\"21351259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-133a directly targets and suppresses FSCN1 expression in esophageal squamous cell carcinoma, and FSCN1 and MMP14 are co-regulated invadopodia-related proteins; knockdown of either inhibits proliferation and invasion.\",\n      \"method\": \"miRNA mimic transfection, qPCR, luciferase reporter assay, siRNA knockdown, invasion assay\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'UTR targeting confirmed by luciferase assay, functional rescue experiments, replicated across multiple cancer types\",\n      \"pmids\": [\"24196787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YAP1 transcriptionally activates LINC00152, which acts as a competing endogenous RNA sponging miR-632 and miR-185-3p, thereby de-repressing FSCN1 expression and promoting colorectal cancer cell proliferation and metastasis.\",\n      \"method\": \"ChIP, luciferase reporter, miRNA sponge assay, in vitro and in vivo functional experiments\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ceRNA mechanism demonstrated with luciferase and functional rescue; single lab study\",\n      \"pmids\": [\"32042551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-145-5p promoter is hypermethylated in laryngeal squamous cell carcinoma, reducing miR-145-5p expression; miR-145-5p directly suppresses FSCN1 via its 3'UTR, and FSCN1 knockdown or miR-145-5p overexpression inhibits migration, invasion, growth, and EMT while inducing cell-cycle arrest and apoptosis.\",\n      \"method\": \"Luciferase reporter assay, promoter methylation assay, gain/loss-of-function, in vivo xenograft\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'UTR validation, epigenetic mechanism, in vivo confirmation\",\n      \"pmids\": [\"30341010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Epidermal growth factor induces FSCN1 expression through activation of the MAPK pathway in triple-negative breast cancer cells, and FSCN1 overexpression promotes TNBC cell migration and invasion.\",\n      \"method\": \"FSCN1 siRNA, EGFR inhibitor (Gefitinib), migration and invasion assays, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway placement via pharmacological inhibition and siRNA; single lab\",\n      \"pmids\": [\"29142206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GRHL3 transcription factor directly activates FSCN1 transcription during wound healing; FSCN1 acts as a negative regulator of E-cadherin, relaxing cell-cell adhesions between suprabasal keratinocytes in the wound front to promote collective migration and wound closure.\",\n      \"method\": \"ATAC-seq on wounded keratinocytes, conditional knockout mice (Grhl3-cKO), luciferase/motif analysis, E-cadherin immunostaining\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo genetic model, chromatin accessibility (ATAC-seq), epistasis between GRHL3/FSCN1/E-cadherin established\",\n      \"pmids\": [\"34494554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FSCN1 is an actin-bundling protein that induces membrane protrusions, stabilizes filopodia/microspikes, and plays critical roles in cell migration, motility, adhesion, and epithelial-to-mesenchymal transition; it functions downstream of multiple miRNAs via 3'UTR regulation.\",\n      \"method\": \"Review of compiled experimental evidence (in vitro assays, siRNA, overexpression, in vivo xenograft studies across multiple cancer types)\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive synthesis of replicated functional studies across multiple labs\",\n      \"pmids\": [\"35711849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FSCN1 knockdown suppresses invasion of pituitary adenoma GH3 cells and downregulates Notch1 and DLL3, placing FSCN1 upstream of Notch signaling in pituitary adenoma invasion.\",\n      \"method\": \"FSCN1 knockdown, transwell invasion assay, Western blot for Notch1 and DLL3\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss-of-function with pathway marker readout; single lab\",\n      \"pmids\": [\"26522130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SOX2 promotes breast cancer brain metastasis by transcriptionally upregulating FSCN1 (and HBEGF) via activation of AKT and β-catenin signaling pathways; increased FSCN1 increases cancer cell migration and blood-brain barrier permeability.\",\n      \"method\": \"SOX2 overexpression/silencing, AKT/β-catenin pathway inhibition, transendothelial migration assay, in vivo brain metastasis model\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway placement via signaling inhibitors plus in vivo model; single lab\",\n      \"pmids\": [\"32322668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"lncRNA ADORA2A-AS1 binds the RNA-binding protein HuR, competitively blocking HuR binding to FSCN1 mRNA, thereby decreasing FSCN1 transcript stability and expression, and suppressing AKT pathway activation in hepatocellular carcinoma.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation (RIP), RNA stability assay, Western blot, xenograft\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA-protein interaction demonstrated by RIP and pull-down; mRNA stability measured; single lab\",\n      \"pmids\": [\"34733789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Circular RNA circFSCN1 is highly expressed in the cytoplasm of mature dendritic cells; knockdown of circFSCN1 arrests DCs at an immature state, impairs T cell activation, and enhances regulatory T cell generation, prolonging allograft survival in murine heart transplantation.\",\n      \"method\": \"siRNA knockdown of circFSCN1, flow cytometry, mixed lymphocyte reactions, in situ RNA hybridization, in vivo transplant model\",\n      \"journal\": \"The Journal of heart and lung transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular phenotype and in vivo validation; single lab\",\n      \"pmids\": [\"34052126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LYAR (nucleolar protein) directly promotes FSCN1 transcription (demonstrated by ChIP and gene reporter assay); FSCN1 upregulation by LYAR drives CRC cell migration/invasion and downregulates FASN and SCD (fatty acid synthesis enzymes), linking FSCN1 to fatty acid metabolism.\",\n      \"method\": \"ChIP assay, gene reporter assay, microarray analysis of LYAR KD cells, rescue experiments, in vivo xenograft\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + reporter assay + rescue; single lab\",\n      \"pmids\": [\"35069968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ginsenoside Rb2 inhibits p300 acetyltransferase activity, reducing SF3A2 acetylation at lysine 10, which promotes alternative splicing and upregulation of FSCN1 expression, enhancing mitochondrial respiration and protecting against myocardial ischemia/reperfusion injury.\",\n      \"method\": \"4D-label-free acetylomics, co-immunoprecipitation, site-specific mutation, shRNA, cellular thermal shift assay, surface plasmon resonance, RNA-seq\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical interaction demonstrated; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"38101749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"lncRNA CCAT1 acts as a sponge for miR-24-3p; miR-24-3p directly targets FSCN1 3'UTR (confirmed by luciferase and RIP); CCAT1 knockdown reduces FSCN1 expression and sensitizes paclitaxel-resistant prostate cancer cells to paclitaxel.\",\n      \"method\": \"Luciferase reporter assay, RNA immunoprecipitation, RNA pull-down, Western blot, functional rescue\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple direct interaction methods (RIP, pull-down, luciferase); single lab\",\n      \"pmids\": [\"32089062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"XIAP 3'UTR acts as a ceRNA for miR-29a-5p; miR-29a-5p binds both XIAP and FSCN1 3'UTRs; XIAP 3'UTR expression de-represses FSCN1 by sequestering miR-29a-5p, synergistically upregulating FSCN1 to promote breast cancer cell migration, invasion, and EMT.\",\n      \"method\": \"Luciferase reporter, Dicer siRNA, genome-wide transcriptional profiling, co-transfection rescue, in vivo xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ceRNA mechanism supported by luciferase and Dicer dependency; single lab\",\n      \"pmids\": [\"28186968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-429 directly targets FSCN1 3'UTR; overexpression of miR-429 suppresses FSCN1 protein and inhibits gastric cancer cell proliferation, and FSCN1 knockdown phenocopies miR-429 overexpression.\",\n      \"method\": \"Luciferase reporter assay, miRNA overexpression, FSCN1 siRNA, cell proliferation assay\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct 3'UTR validation; FSCN1 loss-of-function rescue; single lab\",\n      \"pmids\": [\"27042104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"lincRNA-ROR acts as a ceRNA of miR-145 in esophageal squamous cell carcinoma, with two validated binding sites for miR-145 on ROR confirmed by dual-luciferase and RIP; FSCN1 is a downstream target of the ROR/miR-145 axis and promotes metastasis.\",\n      \"method\": \"Dual luciferase reporter assay, RNA immunoprecipitation, Western blotting, transwell assay\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct interaction validated by RIP and luciferase; functional transwell assay; single lab\",\n      \"pmids\": [\"29430188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Notch3 binds the promoter region of miR-488 to transcriptionally activate it; miR-488 directly binds the 3'UTR of FSCN1 and suppresses its translation; Notch3/miR-488/FSCN1 axis regulates breast cancer cell proliferation and migration.\",\n      \"method\": \"Luciferase reporter assay, promoter binding assay, CCK8, transwell assay, immunohistochemistry\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct 3'UTR and promoter binding validated; functional rescue; single lab\",\n      \"pmids\": [\"33099573\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FSCN1 encodes an actin-bundling protein that stabilizes filopodia and membrane protrusions to drive cell migration, invasion, and EMT; its expression is post-transcriptionally regulated by multiple miRNAs (including miR-145, miR-133a/b, miR-133b, miR-429, miR-24, miR-200b, miR-488) via direct 3'UTR binding, and transcriptionally activated by GRHL3 (which promotes wound-front keratinocyte migration via FSCN1-mediated E-cadherin downregulation), LYAR, and SOX2 (via AKT/β-catenin); upstream lncRNAs and circRNAs (LINC00152, lincRNA-ROR, CCAT1, PCAT-1, CRNDE, circFSCN1) act as ceRNA sponges to modulate miRNA-mediated repression of FSCN1, placing FSCN1 at a convergence point of multiple oncogenic and developmental signaling pathways controlling cytoskeletal dynamics.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe query gene is FSCN1 (Fascin-1), the actin-bundling protein involved in filopodia, cell migration, and cancer metastasis.\n\n**EXCLUDE papers (alias collisions or off-target):**\n- Papers [1]-[11], [13], [15], [18]-[22], [26]-[32], [34]-[37], [39]-[46], [49]-[51], [55]-[58], [62], [64]-[67], [71], [73]-[76], [78], [80]-[82], [84]-[88], [93]-[98] from main corpus: These describe TNF p55/p75 receptors, erythrocyte p55/MPP1 MAGUK protein, Mycobacterium P55 efflux pump, p55(CDC)/Cdc20, Drosophila p55/CAF1, IL-2R p55, HIV p55(Gag), VacA p-55, SNL (acupuncture/spinal nerve ligation), Arabidopsis SNL, peroxisome SNL tripeptide, inner nuclear membrane p55, etc. — none are FSCN1.\n\n**KEEP papers (about FSCN1):**\n- Main corpus: [2], [12], [17], [19], [23] (miR targets FSCN1), [24], [25], [33], [43], [47], [48], [50], [52], [53], [54], [59], [60], [61], [63], [68], [69], [70], [72], [77], [79], [81], [83], [85], [86], [89], [90], [91], [92], [99], [100]\n- Curated: [1] (FSCN1 in lung metastasis gene set), [18], [19], [23], [24], [26], [28]\n\nNow extracting mechanistic discoveries from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Fascin (FSCN1) directly bundles actin filaments and, when expressed in epithelial cells (LLC-PK1), induces membrane protrusions (lamellipodia, microvilli), reorganizes the microfilament cytoskeleton at the cell periphery, and increases cell migration 8–17-fold in a Boyden chamber assay. Microinjection of purified fascin protein into cells recapitulated these morphological changes, establishing direct causality.\",\n      \"method\": \"Overexpression in epithelial cells, microinjection of purified fascin protein, Boyden chamber migration assay, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — purified protein microinjection plus overexpression with specific phenotypic readout; replicated with multiple cell types\",\n      \"pmids\": [\"9571235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FSCN1 (fascin1) is a direct transcriptional target of β-catenin–TCF signaling in colorectal cancer cells. Forced expression of fascin1 increased cell migration and invasion in vitro and caused cell dissemination and metastasis in vivo; suppression by siRNA reduced invasion. Fascin1 was exclusively localized at the invasive front of tumors displaying nuclear β-catenin.\",\n      \"method\": \"TCF reporter assays, siRNA knockdown, overexpression, Boyden chamber invasion, in vivo xenograft/metastasis model, immunohistochemistry\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter assay, KD, OE, in vivo) in a single study\",\n      \"pmids\": [\"17638895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Fascin (FSCN1) is an integral component of invadopodia in cancer cells and stabilizes actin within invadopodia. Phosphorylation of fascin at serine 39 by PKC regulates its localization and activity at invadopodia. Fascin promotes invasive migration into collagen I–Matrigel 3D matrices, particularly in elongated mesenchymal motility.\",\n      \"method\": \"siRNA knockdown, phosphomutant constructs (S39A/S39D), live-cell imaging, 3D invasion assay, immunofluorescence of invadopodia markers\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches including phosphomutant rescue, 3D invasion, and invadopodia imaging\",\n      \"pmids\": [\"20137952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Migrastatin analogues (e.g., macroketone) directly bind fascin (FSCN1) at one of its actin-binding sites and inhibit its actin-bundling activity, thereby blocking tumor cell migration, invasion, and metastasis. X-ray crystal structure of fascin–macroketone complex defined the binding site.\",\n      \"method\": \"X-ray crystallography, in vitro actin-bundling assay, cell migration/invasion assays, in vivo metastasis mouse model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vitro reconstitution plus in vivo validation\",\n      \"pmids\": [\"20393565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FSCN1 was identified as part of a gene set that mediates breast cancer metastasis specifically to the lung, established through in vivo selection of metastatic subpopulations and functional verification.\",\n      \"method\": \"In vivo selection, transcriptomic analysis, functional verification in xenograft models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo functional screen but FSCN1 is one of many genes; specific mechanistic role of FSCN1 not isolated in this paper\",\n      \"pmids\": [\"16049480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-145 and miR-133a directly bind to the 3′UTR of FSCN1 mRNA and repress FSCN1 mRNA and protein expression in bladder cancer cells, functioning as tumor suppressors. Luciferase reporter assay confirmed direct binding. siRNA knockdown of FSCN1 phenocopied miR-145/133a overexpression, inhibiting cell viability, wound healing, and invasion.\",\n      \"method\": \"Luciferase reporter assay, transfection of miRNA mimics, siRNA knockdown, cell growth/wound-healing/invasion assays, immunohistochemistry, in situ hybridization\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct 3′UTR luciferase validation plus phenotypic rescue experiments across multiple assays\",\n      \"pmids\": [\"20160723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-145, miR-133a, and miR-133b directly regulate FSCN1 expression in esophageal squamous cell carcinoma (ESCC) by binding conserved target sites in the 3′UTR of FSCN1. Luciferase reporter assays confirmed two miR-145 sites and one miR-133a/b site. FSCN1 loss-of-function inhibited cell growth and invasion in ESCC.\",\n      \"method\": \"Luciferase reporter assay, miRNA gain-of-function transfection, siRNA knockdown, cell proliferation/invasion assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct 3′UTR mapping with multiple binding sites confirmed by reporter assay plus loss-of-function phenotype\",\n      \"pmids\": [\"21351259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-133a directly targets FSCN1 mRNA in esophageal squamous cell carcinoma (ESCC); transfection of miR-133a mimic decreased both FSCN1 mRNA and protein levels and inhibited proliferation and invasion. FSCN1 and MMP14 are co-regulated invadopodia-related proteins whose combined expression correlates with worst prognosis.\",\n      \"method\": \"miRNA mimic transfection, qPCR, western blot, siRNA knockdown, proliferation/invasion assays, immunohistochemistry\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — miRNA target validation without luciferase reporter in this paper; multiple functional assays\",\n      \"pmids\": [\"24196787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-133a directly targets FSCN1 in pancreatic cancer, confirmed by luciferase reporter assay. Transfection of miR-133a mimics in PANC-1 cells reduced FSCN1 protein, and decreased cell proliferation, invasion, and migration while promoting apoptosis in vitro, and suppressed tumorigenicity in vivo.\",\n      \"method\": \"Luciferase reporter assay, miRNA mimic transfection, siRNA knockdown, proliferation/invasion/migration assays, xenograft mouse model\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase confirmation plus in vivo validation, single lab\",\n      \"pmids\": [\"25198665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EGF induces FSCN1 expression through activation of the MAPK pathway in triple-negative breast cancer (TNBC) cells, which subsequently promotes cell migration and invasion. Co-treatment with FSCN1 siRNA and the EGFR inhibitor Gefitinib produced greater reduction of FSCN1 expression than either treatment alone.\",\n      \"method\": \"siRNA knockdown, EGFR inhibitor (Gefitinib) treatment, western blot, migration/invasion assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pathway placement by pharmacological inhibition and KD; single lab\",\n      \"pmids\": [\"29142206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-145-5p directly targets and negatively regulates FSCN1 via its 3′UTR (confirmed by luciferase assay) in laryngeal squamous cell carcinoma. Low miR-145-5p/high FSCN1 promotes EMT, cell migration, invasion, and growth. The miR-145-5p promoter is hypermethylated in LSCC, repressing miR-145-5p and thus relieving FSCN1 repression.\",\n      \"method\": \"Luciferase reporter assay, gain/loss-of-function studies, promoter methylation analysis, siRNA, in vivo tumor growth assay\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase confirmation, epigenetic mechanism identified, in vivo validation; single lab\",\n      \"pmids\": [\"30341010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YAP1 transcriptionally activates LINC00152, which acts as a ceRNA sponging miR-632 and miR-185-3p to upregulate FSCN1 expression in colorectal cancer, promoting proliferation and metastasis. This YAP1/LINC00152/miR-632|miR-185-3p/FSCN1 axis was established by in vitro and in vivo experiments.\",\n      \"method\": \"ceRNA reporter assays, miRNA sponge assays, siRNA/shRNA knockdown, xenograft mouse models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multi-step pathway with in vivo validation but complex indirect regulatory chain\",\n      \"pmids\": [\"32042551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FSCN1 knockdown in pituitary adenoma (GH3) cells suppressed cell invasion through transwell assay and downregulated Notch1 and DLL3 expression, placing FSCN1 upstream of Notch signaling in pituitary adenoma invasiveness.\",\n      \"method\": \"siRNA knockdown, transwell invasion assay, western blot for Notch1/DLL3\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single KD experiment with downstream marker measurement; no rescue or pathway epistasis\",\n      \"pmids\": [\"26522130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SOX2 promotes brain metastasis of breast cancer by transcriptionally upregulating FSCN1 (and HBEGF) through activation of AKT and β-catenin signaling pathways, thereby increasing cancer cell adhesion to brain microvascular endothelial cells and transendothelial migration across the blood–brain barrier.\",\n      \"method\": \"SOX2 overexpression/silencing, in vitro BBB migration assay, AKT/β-catenin pathway inhibitors, xenograft brain metastasis model, mRNA profiling\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pathway placement via signaling inhibitors and in vivo model; FSCN1 is one of two downstream targets\",\n      \"pmids\": [\"32322668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The transcription factor GRHL3 directly activates FSCN1 transcription during wound reepithelialization by increasing chromatin accessibility near the Fscn1 gene (ATAC-seq shows enriched GRHL3 motifs). FSCN1 (Fascin-1) in turn downregulates E-cadherin to relax adherens junctions between suprabasal keratinocytes, promoting collective migration. Grhl3-cKO mice have lower FSCN1 expression at wound fronts and impaired wound closure.\",\n      \"method\": \"ATAC-seq on wounded keratinocytes, conditional knockout mice (Grhl3-cKO), immunofluorescence for E-cadherin and FSCN1, wound closure assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ATAC-seq chromatin evidence, genetic KO with specific molecular phenotype (E-cadherin), in vivo wound model; multiple orthogonal methods\",\n      \"pmids\": [\"34494554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LYAR (a nucleolar protein) directly binds the FSCN1 promoter (shown by ChIP assay) and transcriptionally activates FSCN1 expression. FSCN1 is a downstream effector of LYAR-promoted CRC cell migration and invasion, and FSCN1 knockdown inhibits subcutaneous tumorigenesis and downregulates FASN and SCD (fatty acid synthesis genes).\",\n      \"method\": \"ChIP assay, gene reporter assay, microarray, siRNA/shRNA knockdown, xenograft tumor model\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct promoter binding; functional rescue with multiple readouts; single lab\",\n      \"pmids\": [\"35069968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADORA2A-AS1 (lncRNA) competitively binds HuR (RNA-binding protein), preventing HuR from binding and stabilizing FSCN1 transcript, thereby decreasing FSCN1 mRNA stability and expression. Decreased FSCN1 in turn suppresses AKT pathway activation in hepatocellular carcinoma. RNA pull-down and RIP confirmed ADORA2A-AS1–HuR–FSCN1 interactions.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation (RIP), RNA stability assay, qRT-PCR, western blot, xenograft and metastasis models\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP and pull-down confirm HuR–FSCN1 interaction; FSCN1/AKT axis validated by rescue; single lab\",\n      \"pmids\": [\"34733789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ginsenoside Rb2 inhibits p300 acetyltransferase activity (confirmed by surface plasmon resonance and enzymatic assays showing direct binding), thereby reducing p300-mediated acetylation of SF3A2 at lysine 10. Decreased SF3A2-K10 acetylation promotes alternative splicing that upregulates FSCN1 expression in cardiomyocytes, enhancing mitochondrial respiration and protecting against ischemic injury.\",\n      \"method\": \"4D-label-free acetylomics, co-immunoprecipitation, surface plasmon resonance, cellular thermal shift assay, site-specific mutagenesis, RNA-seq, shRNA interference, in vivo cardiac ischemia model\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical binding assays (SPR, CETSA) plus mutagenesis and RNA-seq; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38101749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fascin expression in breast carcinomas is strongly associated with the basal-like phenotype and is highly expressed in BRCA1-associated tumors (83.3%), establishing a link between FSCN1 and the basal-like/BRCA1 tumor subtype. However, fascin expression per se was not independently associated with metastatic behavior in node-negative sporadic breast cancers.\",\n      \"method\": \"Tissue microarray immunohistochemistry of 230 sporadic and 28 hereditary node-negative invasive breast carcinomas\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — purely correlative IHC/expression study; no mechanistic experiment\",\n      \"pmids\": [\"16533778\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FSCN1 (Fascin-1) is an actin-bundling protein that directly crosslinks actin filaments to form filopodia, microspikes, and invadopodia, driving cell migration and invasion; its activity at invadopodia is regulated by PKC-mediated phosphorylation at S39, its transcription is activated by β-catenin–TCF and GRHL3 (in wound healing) and by SOX2/AKT/β-catenin, its transcript stability is controlled by the HuR–ADORA2A-AS1 axis, and its expression is post-transcriptionally repressed by multiple tumor-suppressive miRNAs (miR-145, miR-133a/b, miR-133a, miR-429, miR-24, miR-200b) that directly bind its 3′UTR; small-molecule migrastatin analogues (macroketone) inhibit fascin by occupying an actin-binding site on the protein, blocking metastasis in vivo.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FSCN1 is an actin-bundling protein that stabilizes filopodia and membrane protrusions to drive cell migration, invasion, and epithelial-to-mesenchymal transition across diverse cellular contexts. Its expression is tightly controlled post-transcriptionally by multiple miRNAs (miR-145, miR-133a/b, miR-429, miR-24, miR-488, miR-29a-5p) that directly bind conserved sites in the FSCN1 3′UTR, and by competing endogenous RNA networks in which lncRNAs and circRNAs (LINC00152, lincRNA-ROR, CCAT1) sequester these miRNAs to de-repress FSCN1 [PMID:21351259, PMID:30341010, PMID:32042551, PMID:29430188, PMID:32089062]. Transcriptionally, FSCN1 is directly activated by GRHL3 during wound healing—where it downregulates E-cadherin to relax cell-cell adhesions and promote collective keratinocyte migration—and by LYAR and SOX2 via AKT/β-catenin signaling in cancer contexts [PMID:34494554, PMID:35069968, PMID:32322668]. FSCN1 also feeds forward into Notch signaling and, through a distinct splicing-dependent mechanism involving SF3A2 acetylation, supports mitochondrial respiration during myocardial ischemia/reperfusion [PMID:26522130, PMID:38101749].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing that FSCN1 is a direct post-transcriptional target of miR-145 and miR-133a/b resolved how its overexpression in esophageal squamous cell carcinoma is achieved and linked its 3′UTR to the miRNA regulatory machinery.\",\n      \"evidence\": \"Luciferase reporter assays mapped two miR-145 sites and one miR-133a/b site in the FSCN1 3′UTR; FSCN1 siRNA phenocopied miRNA-mediated invasion suppression in ESCC cells\",\n      \"pmids\": [\"21351259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contribution of individual miRNA sites not quantified\",\n        \"Endogenous miRNA stoichiometry in normal vs. tumor tissue unknown\",\n        \"No structural basis for actin-bundling activity of FSCN1 established\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating co-regulation of FSCN1 and MMP14 by miR-133a placed FSCN1 within an invadopodia-associated program, linking cytoskeletal bundling to extracellular matrix degradation during cancer invasion.\",\n      \"evidence\": \"miR-133a mimic transfection, luciferase reporter, siRNA knockdown of FSCN1 and MMP14 in ESCC cells\",\n      \"pmids\": [\"24196787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether FSCN1 and MMP14 physically interact at invadopodia is untested\",\n        \"Mechanism of coordinate regulation beyond shared miRNA targeting not explored\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placing FSCN1 upstream of Notch1/DLL3 expression in pituitary adenoma cells expanded its role beyond structural actin bundling to signaling pathway modulation during tumor invasion.\",\n      \"evidence\": \"FSCN1 knockdown in GH3 cells followed by Western blot for Notch1 and DLL3, transwell invasion assay\",\n      \"pmids\": [\"26522130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking actin bundling to Notch pathway activation is unknown\",\n        \"No rescue with Notch pathway activation performed\",\n        \"Single cell line tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of miR-429 as an additional direct FSCN1-targeting miRNA demonstrated the breadth of miRNA-mediated convergence on FSCN1, extending regulation to the miR-200 family axis in gastric cancer.\",\n      \"evidence\": \"Luciferase reporter assay confirming miR-429 binding to FSCN1 3′UTR; phenocopy by FSCN1 siRNA in gastric cancer cells\",\n      \"pmids\": [\"27042104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Not independently replicated\",\n        \"Relationship to miR-200 family members (miR-200b) and EMT not examined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing that EGF induces FSCN1 via the MAPK pathway in triple-negative breast cancer connected FSCN1 to receptor tyrosine kinase signaling and identified an upstream growth-factor axis controlling its expression.\",\n      \"evidence\": \"EGFR inhibitor (Gefitinib) and FSCN1 siRNA in TNBC cells; migration/invasion assays, Western blot\",\n      \"pmids\": [\"29142206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MAPK acts directly on the FSCN1 promoter or through intermediate transcription factors is unresolved\",\n        \"Single lab, pharmacological inhibition only\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that the XIAP 3′UTR functions as a ceRNA for miR-29a-5p to de-repress FSCN1 introduced the concept of coding-gene UTRs competing for shared miRNAs to control FSCN1-driven EMT.\",\n      \"evidence\": \"Luciferase reporter, Dicer siRNA dependency, co-transfection rescue, in vivo xenograft in breast cancer\",\n      \"pmids\": [\"28186968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous stoichiometry of XIAP mRNA vs. miR-29a-5p not measured\",\n        \"ceRNA effect size in physiological conditions uncertain\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Epigenetic silencing of miR-145-5p by promoter hypermethylation was shown to relieve FSCN1 repression and drive EMT, establishing a DNA methylation–miRNA–FSCN1 regulatory axis with in vivo validation.\",\n      \"evidence\": \"Promoter methylation assay, luciferase reporter, in vivo xenograft in laryngeal squamous cell carcinoma\",\n      \"pmids\": [\"30341010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the methyltransferase responsible for miR-145-5p silencing not determined\",\n        \"Whether demethylating agents rescue FSCN1-dependent phenotypes in vivo untested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that lincRNA-ROR sponges miR-145 to de-repress FSCN1 in ESCC established lncRNA-mediated ceRNA regulation as a recurrent theme in FSCN1 control.\",\n      \"evidence\": \"Dual luciferase reporter, RNA immunoprecipitation, transwell assay in ESCC cells\",\n      \"pmids\": [\"29430188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Quantitative contribution of ROR sponging vs. other miR-145 sinks not assessed\",\n        \"Single lab, single cancer type\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of the YAP1→LINC00152→miR-632/miR-185-3p→FSCN1 axis in colorectal cancer linked Hippo pathway effector YAP1 to FSCN1 expression through a multi-layered ceRNA circuit.\",\n      \"evidence\": \"ChIP for YAP1 on LINC00152 promoter, luciferase sponge assay, in vitro and in vivo functional experiments\",\n      \"pmids\": [\"32042551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct YAP1 occupancy on LINC00152 not confirmed by independent lab\",\n        \"Whether miR-632 and miR-185-3p have redundant or distinct effects on FSCN1 unclear\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"SOX2 was shown to transcriptionally upregulate FSCN1 through AKT/β-catenin signaling to promote breast cancer brain metastasis, providing a direct transcription-factor–to–cytoskeletal-effector link for transendothelial migration.\",\n      \"evidence\": \"SOX2 overexpression/silencing, pathway inhibitors, transendothelial migration assay, in vivo brain metastasis model\",\n      \"pmids\": [\"32322668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SOX2 binds the FSCN1 promoter directly or acts through β-catenin intermediates is not resolved\",\n        \"Contribution of FSCN1 vs. HBEGF to brain metastasis not separated\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstration that CCAT1 sponges miR-24-3p to de-repress FSCN1 and confer paclitaxel resistance added drug resistance to the functional consequences of ceRNA-mediated FSCN1 upregulation.\",\n      \"evidence\": \"Luciferase, RNA immunoprecipitation, RNA pull-down, functional rescue in paclitaxel-resistant prostate cancer cells\",\n      \"pmids\": [\"32089062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether FSCN1 itself mediates drug resistance or is a bystander of miR-24-3p de-repression not fully resolved\",\n        \"Single lab, single resistant cell line\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Notch3 was found to transcriptionally activate miR-488, which directly suppresses FSCN1, revealing a Notch3→miR-488⊣FSCN1 axis in breast cancer and demonstrating that Notch signaling operates both upstream and downstream of FSCN1.\",\n      \"evidence\": \"Promoter binding assay for Notch3 on miR-488, luciferase reporter for miR-488 on FSCN1 3′UTR, functional assays\",\n      \"pmids\": [\"33099573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Relationship to the FSCN1→Notch1 feedforward observation (PMID:26522130) not tested\",\n        \"Whether Notch3 and Notch1 have opposing roles on FSCN1 expression is unclear\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"In vivo genetic evidence using Grhl3 conditional knockout mice established that GRHL3 directly activates FSCN1 transcription in wound-front keratinocytes, and that FSCN1 downregulates E-cadherin to enable collective cell migration during wound healing—the first physiological (non-cancer) function attributed to this regulatory axis.\",\n      \"evidence\": \"ATAC-seq on wounded keratinocytes, Grhl3-cKO mice, E-cadherin immunostaining, luciferase/motif analysis\",\n      \"pmids\": [\"34494554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which FSCN1 suppresses E-cadherin (transcriptional vs. post-translational) is unknown\",\n        \"Whether this axis operates in other epithelial repair contexts untested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that lncRNA ADORA2A-AS1 competes with HuR for FSCN1 mRNA binding revealed an mRNA-stability control mechanism distinct from the miRNA/ceRNA paradigm, adding RNA-binding protein competition as a regulatory layer.\",\n      \"evidence\": \"RNA pull-down, RIP, mRNA stability assay, xenograft in hepatocellular carcinoma\",\n      \"pmids\": [\"34741789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"HuR binding site on FSCN1 mRNA not mapped at nucleotide resolution\",\n        \"Whether other RBPs also stabilize FSCN1 mRNA is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that circFSCN1 (a circular RNA from the FSCN1 locus) is required for dendritic cell maturation and T cell activation extended FSCN1-locus biology into immune regulation, independent of the linear mRNA product.\",\n      \"evidence\": \"circFSCN1 siRNA in DCs, flow cytometry, mixed lymphocyte reactions, murine heart transplant model\",\n      \"pmids\": [\"34052126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular targets/mechanism of circFSCN1 action in DCs not identified\",\n        \"Whether circFSCN1 regulates FSCN1 protein expression in DCs is untested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ChIP and reporter assays showed LYAR directly activates FSCN1 transcription, and FSCN1 in turn downregulates fatty acid synthesis enzymes FASN and SCD, unexpectedly linking FSCN1 to lipid metabolism in colorectal cancer.\",\n      \"evidence\": \"ChIP, gene reporter, microarray, rescue experiments, xenograft\",\n      \"pmids\": [\"35069968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which an actin-bundling protein regulates fatty acid metabolism enzymes is completely unknown\",\n        \"Single lab; lipid metabolic phenotype not independently validated\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Ginsenoside Rb2 was shown to upregulate FSCN1 via reduced p300-mediated SF3A2 acetylation, altering splicing to favor FSCN1 expression and enhancing mitochondrial respiration in cardiomyocytes—revealing a splicing-dependent, cardioprotective role for FSCN1.\",\n      \"evidence\": \"4D-label-free acetylomics, co-IP, site-directed mutagenesis, SPR, RNA-seq in myocardial ischemia/reperfusion model\",\n      \"pmids\": [\"38101749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which FSCN1 splice variant is upregulated and how it enhances mitochondrial respiration are undefined\",\n        \"Cardioprotective role not tested with genetic FSCN1 overexpression/knockout in vivo\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the structural basis of FSCN1's actin-bundling selectivity, the mechanism by which FSCN1 suppresses E-cadherin and regulates Notch signaling, and whether the metabolic and cardioprotective functions represent direct biochemical activities or indirect consequences of cytoskeletal remodeling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of FSCN1 bound to actin filaments in a cellular context\",\n        \"Mechanism linking actin bundling to transcriptional/metabolic outputs unknown\",\n        \"Relative physiological importance of miRNA vs. transcription-factor regulation of FSCN1 not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 8, 17]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"GRHL3\",\n      \"LYAR\",\n      \"SOX2\",\n      \"HuR\",\n      \"MMP14\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"FSCN1 (Fascin-1) is an actin-bundling protein that crosslinks filamentous actin into parallel bundles, driving the formation of filopodia, microspikes, and invadopodia to promote cell migration and invasion [PMID:9571235, PMID:20137952]. Its actin-bundling activity is negatively regulated by PKC-mediated phosphorylation at Ser39, which controls fascin dynamics at invadopodia, and can be pharmacologically inhibited by migrastatin analogues that occupy an actin-binding site, as defined by X-ray crystallography [PMID:20137952, PMID:20393565]. FSCN1 transcription is activated by β-catenin–TCF signaling in colorectal cancer and by GRHL3 during wound reepithelialization, where fascin promotes collective keratinocyte migration by downregulating E-cadherin at adherens junctions [PMID:17638895, PMID:34494554]. Post-transcriptionally, FSCN1 is repressed by multiple tumor-suppressive microRNAs—including miR-145, miR-133a, and miR-133b—that directly bind its 3′UTR, and its mRNA is stabilized by the RNA-binding protein HuR, which is competitively sequestered by the lncRNA ADORA2A-AS1 [PMID:20160723, PMID:21351259, PMID:34733789].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that fascin directly bundles actin filaments and is sufficient to reorganize the cortical cytoskeleton and dramatically enhance cell migration resolved the basic molecular activity of FSCN1.\",\n      \"evidence\": \"Microinjection of purified fascin protein and overexpression in epithelial cells with Boyden chamber migration assays\",\n      \"pmids\": [\"9571235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Regulatory mechanisms controlling fascin bundling activity were unknown\",\n        \"Whether fascin-driven migration contributed to pathological invasion was not tested\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying FSCN1 as a direct β-catenin–TCF transcriptional target placed it within Wnt pathway-driven carcinogenesis and showed that fascin expression at tumor invasive fronts functionally promotes metastasis in vivo.\",\n      \"evidence\": \"TCF reporter assays, siRNA knockdown, overexpression, and xenograft metastasis models in colorectal cancer\",\n      \"pmids\": [\"17638895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether other transcription factors independently activate FSCN1 in non-Wnt contexts was unknown\",\n        \"Post-translational regulation of fascin at the invasive front was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that PKC phosphorylation at Ser39 regulates fascin localization and function at invadopodia, and that migrastatin analogues directly block fascin's actin-binding site (crystal structure resolved), established both the key regulatory switch and a pharmacological strategy to inhibit fascin-dependent invasion.\",\n      \"evidence\": \"Phosphomutant constructs (S39A/S39D) with live-cell invadopodia imaging and 3D invasion assays; X-ray crystallography of fascin–macroketone complex with in vivo metastasis inhibition\",\n      \"pmids\": [\"20137952\", \"20393565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Ser39 phosphorylation is the sole regulatory post-translational modification was unclear\",\n        \"Clinical applicability of migrastatin analogues was not established\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that miR-145 and miR-133a/b directly bind the FSCN1 3′UTR to repress expression across multiple tumor types established a major post-transcriptional regulatory layer governing fascin abundance.\",\n      \"evidence\": \"Luciferase 3′UTR reporter assays, miRNA mimic transfection, and phenocopy by FSCN1 siRNA in bladder and esophageal carcinoma cells\",\n      \"pmids\": [\"20160723\", \"21351259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contribution of individual miRNAs versus combinatorial repression was not quantified\",\n        \"Upstream mechanisms silencing these miRNAs in tumors were only partially known\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placing FSCN1 downstream of EGF–MAPK signaling in triple-negative breast cancer extended the transcriptional regulation map beyond Wnt to receptor tyrosine kinase pathways.\",\n      \"evidence\": \"EGFR inhibitor (Gefitinib) treatment combined with FSCN1 siRNA in TNBC cells\",\n      \"pmids\": [\"29142206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct transcription factor mediating MAPK-to-FSCN1 induction was not identified\",\n        \"Single-lab study without genetic epistasis\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that miR-145-5p promoter hypermethylation in laryngeal carcinoma relieves FSCN1 repression and promotes EMT connected epigenetic deregulation to fascin-driven invasion.\",\n      \"evidence\": \"Promoter methylation analysis, luciferase reporter assay, gain/loss-of-function studies, in vivo tumor growth\",\n      \"pmids\": [\"30341010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether DNA methylation of miR-145 is a general mechanism across FSCN1-high tumors was not tested\",\n        \"E-cadherin loss was inferred but not mechanistically dissected downstream of fascin\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that GRHL3 directly opens chromatin at the Fscn1 locus to drive transcription during wound reepithelialization, and that fascin then downregulates E-cadherin to loosen adherens junctions, established a physiological (non-oncogenic) role for fascin in collective cell migration.\",\n      \"evidence\": \"ATAC-seq on wounded keratinocytes, Grhl3 conditional knockout mice, wound closure assays, E-cadherin immunofluorescence\",\n      \"pmids\": [\"34494554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which fascin downregulates E-cadherin (transcriptional vs. post-translational) was not resolved\",\n        \"Whether GRHL3–FSCN1 axis operates in other epithelial repair contexts is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification that HuR binds and stabilizes FSCN1 mRNA, and that the lncRNA ADORA2A-AS1 competitively sequesters HuR to reduce FSCN1, revealed an RNA-binding-protein layer of post-transcriptional control complementary to miRNA repression.\",\n      \"evidence\": \"RNA immunoprecipitation, RNA pull-down, mRNA stability assays in hepatocellular carcinoma cells and xenograft models\",\n      \"pmids\": [\"34733789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether HuR-mediated stabilization is the dominant mRNA-level control in non-hepatic contexts is untested\",\n        \"Quantitative contribution of HuR versus miRNA pathways to FSCN1 protein levels not compared\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that p300-mediated acetylation of SF3A2 controls alternative splicing to regulate FSCN1 expression in cardiomyocytes broadened fascin's functional context to cardiac ischemic protection and mitochondrial respiration.\",\n      \"evidence\": \"Acetylomics, SPR binding assay, site-specific mutagenesis of SF3A2-K10, RNA-seq, in vivo cardiac ischemia model\",\n      \"pmids\": [\"38101749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific splicing event in FSCN1 controlled by SF3A2 acetylation status was not fully characterized\",\n        \"Whether fascin has direct roles in mitochondrial function or acts indirectly through cytoskeletal remodeling is unresolved\",\n        \"Single-lab finding not yet independently replicated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which fascin downregulates E-cadherin, the full set of post-translational modifications beyond Ser39, the structural basis for actin-bundling geometry in cellulo, and the physiological relevance of fascin in non-migratory contexts (e.g., cardiac protection) remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No comprehensive post-translational modification map beyond Ser39 phosphorylation\",\n        \"In vivo structural characterization of fascin-bundled actin arrays is lacking\",\n        \"Cardiac and neuronal roles of fascin are mechanistically uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 9, 13]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 4, 5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CTNNB1\",\n      \"GRHL3\",\n      \"ELAVL1\",\n      \"LYAR\",\n      \"SOX2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}