{"gene":"SFN","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2012,"finding":"SFN (14-3-3σ/stratifin) physically interacts with SPARC to form a protein complex in keratinocyte-conditioned media, and this complex controls type I collagen synthesis and expression in dermal fibroblasts. SFN was identified as keratinocyte-derived anti-fibrogenic factor (KDAF) with collagenase-inducing (MMP-1) activity in fibroblasts.","method":"Co-immunoprecipitation, 3D protein modeling, systematic protein purification with mass spectrometry, conditioned media experiments","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus MS identification, single lab, two orthogonal methods","pmids":["22422640"],"is_preprint":false},{"year":2023,"finding":"SFN (stratifin) regulates cervical cancer cell proliferation, apoptosis, cytoskeletal remodeling, and metastasis through the LIMK2/Cofilin signaling pathway. SFN overexpression upregulated LIMK2, p-LIMK2, Cofilin, and p-Cofilin levels, while SFN silencing had opposite effects.","method":"SFN overexpression and silencing cellular models, transwell and scratch assays, Western blotting, immunofluorescence, Actin-Tracker staining, YO-PRO-1/PI and EdU staining","journal":"Molecular biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined cellular phenotype and pathway placement, single lab, multiple orthogonal methods","pmids":["37946061"],"is_preprint":false},{"year":2024,"finding":"SFN (stratifin) promotes renal fibrosis in chronic kidney disease by directly binding to MYH9 (non-muscle myosin heavy chain 9) in the cytoplasm of renal tubular epithelial cells. SFN knockdown reduced Col-1 and α-SMA expression, and silencing SFN decreased MYH9 expression, alleviating TGF-β1-induced fibrosis in vitro and UUO-induced renal fibrosis in vivo.","method":"LC-MS/MS, co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, mouse UUO model","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus MS identification of binding partner, validated in vivo, single lab, multiple orthogonal methods","pmids":["38986830"],"is_preprint":false},{"year":2024,"finding":"SFN knockdown in Barrett's esophagus cells resulted in significant alterations in mitochondrial membrane potential and altered cellular metabolism in esophageal adenocarcinoma cells, placing SFN in a functional role in mitochondrial function regulation.","method":"siRNA-induced knockdown, measurement of reactive oxygen species, mitochondrial mass, mitochondrial membrane potential, and cellular metabolism assays","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method category (KD with phenotype but limited pathway placement for SFN specifically)","pmids":["30404157"],"is_preprint":false},{"year":2019,"finding":"In NPC cells, miR-675-5p directly targets the 3'-UTR of SFN mRNA to suppress 14-3-3σ protein expression; overexpression of miR-675-5p inhibits SFN protein levels and promotes invasion and metastasis of NPC cells, while miR-675-5p inhibitor increases SFN expression and reduces invasiveness.","method":"Dual-luciferase reporter assay (3'-UTR binding), Western blot, miRNA mimic/inhibitor transfection, transwell and scratch assays","journal":"Current molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase 3'-UTR reporter plus functional gain/loss-of-function, single lab, two orthogonal methods","pmids":["31677258"],"is_preprint":false},{"year":2019,"finding":"SFN knockdown in cervical cancer cells inhibited cell proliferation, migration, and invasion while promoting apoptosis, demonstrating a functional role for SFN in promoting cervical cancer cell survival and metastatic behavior.","method":"siRNA-mediated SFN silencing, colony formation assay, EdU staining, CCK-8 assay, flow cytometry, apoptosis protein analysis, transwell and wound-healing assays","journal":"BMC cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD with phenotype but limited mechanistic/pathway placement beyond ceRNA axis","pmids":["31779593"],"is_preprint":false},{"year":2019,"finding":"SFN (stratifin) transgenic overexpression in mouse lung (Tg-SPC-SFN mice) acts as a potent oncogene driving lung adenocarcinoma development; NNK-induced tumors in these mice recapitulate human lung adenocarcinoma histology and show activation of PI3K/AKT signaling and apoptosis signaling pathways.","method":"SFN-transgenic mouse model, carcinogen (NNK) treatment, whole-exome sequencing, histopathology, pathway analysis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic gain-of-function with defined oncogenic phenotype and pathway activation, single lab","pmids":["31144406"],"is_preprint":false}],"current_model":"SFN (stratifin/14-3-3σ) is a multifunctional scaffold protein that promotes cancer cell proliferation and metastasis by activating the LIMK2/Cofilin signaling axis to drive cytoskeletal remodeling, acts as an oncogene in lung adenocarcinoma, promotes renal fibrosis by binding MYH9 in renal tubular epithelial cells, forms a complex with SPARC in keratinocytes to regulate MMP-1 and suppress type I collagen synthesis in fibroblasts, and is post-transcriptionally regulated by microRNAs (e.g., miR-675-5p) targeting its 3'-UTR; its expression is also epigenetically silenced by promoter methylation in multiple tumor types."},"narrative":{"mechanistic_narrative":"SFN (stratifin/14-3-3σ) is a scaffold protein that regulates cytoskeletal dynamics, cell survival, and extracellular matrix remodeling, and behaves as a context-dependent driver of proliferation and fibrosis [PMID:37946061, PMID:31144406]. In cancer cells it promotes proliferation, migration, invasion, and metastasis while suppressing apoptosis by activating the LIMK2/Cofilin axis to drive actin cytoskeletal remodeling, with SFN overexpression raising LIMK2, p-LIMK2, Cofilin, and p-Cofilin levels and silencing reversing these effects [PMID:37946061]. Transgenic SFN overexpression in mouse lung acts as a potent oncogene that drives lung adenocarcinoma and activates PI3K/AKT signaling [PMID:31144406]. SFN exerts its effects through direct physical partners: it binds non-muscle myosin heavy chain 9 (MYH9) in the cytoplasm of renal tubular epithelial cells to promote TGF-β1- and UUO-induced renal fibrosis, increasing Col-1 and α-SMA, while SFN knockdown reduces MYH9 and alleviates fibrosis [PMID:38986830], and it forms a complex with SPARC in keratinocyte-conditioned media that induces MMP-1 (collagenase) activity and suppresses type I collagen synthesis in dermal fibroblasts, identifying SFN as a keratinocyte-derived anti-fibrogenic factor [PMID:22422640]. SFN protein levels are constrained post-transcriptionally by miR-675-5p, which directly targets its 3'-UTR to repress expression and thereby modulate tumor cell invasiveness [PMID:31677258].","teleology":[{"year":2012,"claim":"Established that SFN acts as a secreted intercellular signal by physically partnering with SPARC to control matrix homeostasis, answering how keratinocyte-derived SFN influences fibroblast collagen turnover.","evidence":"Reciprocal Co-IP, mass spectrometry, and conditioned-media experiments with 3D protein modeling in keratinocyte/fibroblast systems","pmids":["22422640"],"confidence":"Medium","gaps":["Binding interface and stoichiometry of the SFN–SPARC complex not structurally resolved","Mechanism linking the complex to MMP-1 induction and collagen suppression not defined","Single-lab finding without independent replication"]},{"year":2019,"claim":"Identified miR-675-5p as a direct upstream repressor of SFN, showing SFN protein levels are set post-transcriptionally and influence tumor cell invasion.","evidence":"Dual-luciferase 3'-UTR reporter assay with miRNA mimic/inhibitor transfection and transwell/scratch assays in NPC cells","pmids":["31677258"],"confidence":"Medium","gaps":["Downstream effectors linking SFN levels to invasion not mapped","Whether other miRNAs converge on the SFN 3'-UTR unknown"]},{"year":2019,"claim":"Defined SFN as a pro-survival, pro-metastatic factor in cervical cancer cells through loss-of-function phenotyping.","evidence":"siRNA silencing with proliferation, apoptosis, migration, and invasion assays in cervical cancer cells","pmids":["31779593"],"confidence":"Low","gaps":["Phenotype not yet anchored to a defined molecular pathway in this study","No rescue experiment to confirm specificity"]},{"year":2019,"claim":"Demonstrated in vivo that SFN is sufficient to drive tumorigenesis, establishing it as an oncogene rather than a correlative marker.","evidence":"SFN-transgenic (Tg-SPC-SFN) mouse model with NNK carcinogen treatment, whole-exome sequencing, histopathology, and pathway analysis","pmids":["31144406"],"confidence":"Medium","gaps":["Direct molecular link between SFN and PI3K/AKT activation not mechanistically dissected","Single-lab transgenic model"]},{"year":2023,"claim":"Placed SFN's cancer-promoting activity onto a defined signaling axis, showing it drives cytoskeletal remodeling and metastasis via LIMK2/Cofilin.","evidence":"Gain- and loss-of-function cellular models with transwell/scratch assays, Western blot, and actin imaging in cervical cancer cells","pmids":["37946061"],"confidence":"Medium","gaps":["Whether SFN binds LIMK2 directly or acts upstream indirectly not resolved","In vivo validation of the LIMK2/Cofilin axis absent"]},{"year":2024,"claim":"Identified MYH9 as a direct cytoplasmic binding partner that mediates SFN-driven renal fibrosis, providing a physical mechanism for SFN's pro-fibrotic role.","evidence":"LC-MS/MS, reciprocal Co-IP, immunofluorescence co-localization, siRNA knockdown, and mouse UUO model","pmids":["38986830"],"confidence":"Medium","gaps":["How SFN binding stabilizes or regulates MYH9 expression not defined","Connection between SFN–MYH9 and TGF-β1 signaling upstream/downstream unclear"]},{"year":2024,"claim":"Linked SFN to mitochondrial and metabolic regulation in esophageal adenocarcinoma, broadening its functional scope beyond cytoskeletal and matrix roles.","evidence":"siRNA knockdown with ROS, mitochondrial mass, membrane potential, and metabolic assays in Barrett's esophagus/EAC cells","pmids":["30404157"],"confidence":"Low","gaps":["No molecular partner or pathway identified for the mitochondrial phenotype","Single method category without mechanistic placement","Not independently confirmed"]},{"year":null,"claim":"It remains unresolved how SFN's distinct partner interactions (SPARC, MYH9) and signaling outputs (LIMK2/Cofilin, PI3K/AKT) are integrated, and whether a unifying 14-3-3 scaffolding mechanism underlies its tissue-specific roles.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of SFN bound to its partners","Tissue-specificity determinants of SFN function unknown","Direct versus indirect basis of pathway activation unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,6]}],"complexes":[],"partners":["SPARC","MYH9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P31947","full_name":"14-3-3 protein sigma","aliases":["Epithelial cell marker protein 1","Stratifin"],"length_aa":248,"mass_kda":27.8,"function":"Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways (PubMed:15731107, PubMed:22634725, PubMed:28202711, PubMed:37797010). Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif (PubMed:15731107, PubMed:22634725, PubMed:28202711, PubMed:37797010). Binding generally results in the modulation of the activity of the binding partner (PubMed:15731107, PubMed:22634725, PubMed:28202711, PubMed:37797010). Promotes cytosolic retention of GBP1 GTPase by binding to phosphorylated GBP1, thereby inhibiting the innate immune response (PubMed:37797010). Also acts as a TP53/p53-regulated inhibitor of G2/M progression (PubMed:9659898). When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). Acts to maintain desmosome cell junction adhesion in epithelial cells via interacting with and sequestering PKP3 to the cytoplasm, thereby restricting its translocation to existing desmosome structures and therefore maintaining desmosome protein homeostasis (PubMed:24124604). Also acts to facilitate PKP3 exchange at desmosome plaques, thereby maintaining keratinocyte intercellular adhesion (PubMed:29678907). May also regulate MDM2 autoubiquitination and degradation and thereby activate p53/TP53 (PubMed:18382127)","subcellular_location":"Cytoplasm; Nucleus; Secreted","url":"https://www.uniprot.org/uniprotkb/P31947/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SFN","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COL4A3BP","stoichiometry":0.2},{"gene":"PMVK","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SFN","total_profiled":1310},"omim":[{"mim_id":"616769","title":"NITRILASE FAMILY MEMBER 2; NIT2","url":"https://www.omim.org/entry/616769"},{"mim_id":"616758","title":"KERATINOCYTE DIFFERENTIATION FACTOR 1; KDF1","url":"https://www.omim.org/entry/616758"},{"mim_id":"614729","title":"COP9 SIGNALOSOME, SUBUNIT 6; COPS6","url":"https://www.omim.org/entry/614729"},{"mim_id":"614259","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 57; CFAP57","url":"https://www.omim.org/entry/614259"},{"mim_id":"608067","title":"RING FINGER AND WD REPEAT DOMAINS-CONTAINING PROTEIN 2; RFWD2","url":"https://www.omim.org/entry/608067"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli rim","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":2404.7},{"tissue":"skin 1","ntpm":1183.0},{"tissue":"vagina","ntpm":678.0}],"url":"https://www.proteinatlas.org/search/SFN"},"hgnc":{"alias_symbol":["YWHAS"],"prev_symbol":[]},"alphafold":{"accession":"P31947","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31947","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31947-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31947-F1-predicted_aligned_error_v6.png","plddt_mean":92.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SFN","jax_strain_url":"https://www.jax.org/strain/search?query=SFN"},"sequence":{"accession":"P31947","fasta_url":"https://rest.uniprot.org/uniprotkb/P31947.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31947/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31947"}},"corpus_meta":[{"pmid":"26453055","id":"PMC_26453055","title":"Simultaneous Targeting of Bladder Tumor Growth, Survival, and Epithelial-to-Mesenchymal Transition with a Novel Therapeutic 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Nasalpharyngeal Cancer Cells.","date":"2019","source":"Current molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31677258","citation_count":19,"is_preprint":false},{"pmid":"32243901","id":"PMC_32243901","title":"The promyelocytic leukemia protein isoform PML1 is an oncoprotein and a direct target of the antioxidant sulforaphane (SFN).","date":"2020","source":"Biochimica et biophysica acta. 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SFN was identified as keratinocyte-derived anti-fibrogenic factor (KDAF) with collagenase-inducing (MMP-1) activity in fibroblasts.\",\n      \"method\": \"Co-immunoprecipitation, 3D protein modeling, systematic protein purification with mass spectrometry, conditioned media experiments\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus MS identification, single lab, two orthogonal methods\",\n      \"pmids\": [\"22422640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SFN (stratifin) regulates cervical cancer cell proliferation, apoptosis, cytoskeletal remodeling, and metastasis through the LIMK2/Cofilin signaling pathway. SFN overexpression upregulated LIMK2, p-LIMK2, Cofilin, and p-Cofilin levels, while SFN silencing had opposite effects.\",\n      \"method\": \"SFN overexpression and silencing cellular models, transwell and scratch assays, Western blotting, immunofluorescence, Actin-Tracker staining, YO-PRO-1/PI and EdU staining\",\n      \"journal\": \"Molecular biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined cellular phenotype and pathway placement, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37946061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SFN (stratifin) promotes renal fibrosis in chronic kidney disease by directly binding to MYH9 (non-muscle myosin heavy chain 9) in the cytoplasm of renal tubular epithelial cells. SFN knockdown reduced Col-1 and α-SMA expression, and silencing SFN decreased MYH9 expression, alleviating TGF-β1-induced fibrosis in vitro and UUO-induced renal fibrosis in vivo.\",\n      \"method\": \"LC-MS/MS, co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, mouse UUO model\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus MS identification of binding partner, validated in vivo, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38986830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SFN knockdown in Barrett's esophagus cells resulted in significant alterations in mitochondrial membrane potential and altered cellular metabolism in esophageal adenocarcinoma cells, placing SFN in a functional role in mitochondrial function regulation.\",\n      \"method\": \"siRNA-induced knockdown, measurement of reactive oxygen species, mitochondrial mass, mitochondrial membrane potential, and cellular metabolism assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method category (KD with phenotype but limited pathway placement for SFN specifically)\",\n      \"pmids\": [\"30404157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In NPC cells, miR-675-5p directly targets the 3'-UTR of SFN mRNA to suppress 14-3-3σ protein expression; overexpression of miR-675-5p inhibits SFN protein levels and promotes invasion and metastasis of NPC cells, while miR-675-5p inhibitor increases SFN expression and reduces invasiveness.\",\n      \"method\": \"Dual-luciferase reporter assay (3'-UTR binding), Western blot, miRNA mimic/inhibitor transfection, transwell and scratch assays\",\n      \"journal\": \"Current molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase 3'-UTR reporter plus functional gain/loss-of-function, single lab, two orthogonal methods\",\n      \"pmids\": [\"31677258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SFN knockdown in cervical cancer cells inhibited cell proliferation, migration, and invasion while promoting apoptosis, demonstrating a functional role for SFN in promoting cervical cancer cell survival and metastatic behavior.\",\n      \"method\": \"siRNA-mediated SFN silencing, colony formation assay, EdU staining, CCK-8 assay, flow cytometry, apoptosis protein analysis, transwell and wound-healing assays\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD with phenotype but limited mechanistic/pathway placement beyond ceRNA axis\",\n      \"pmids\": [\"31779593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SFN (stratifin) transgenic overexpression in mouse lung (Tg-SPC-SFN mice) acts as a potent oncogene driving lung adenocarcinoma development; NNK-induced tumors in these mice recapitulate human lung adenocarcinoma histology and show activation of PI3K/AKT signaling and apoptosis signaling pathways.\",\n      \"method\": \"SFN-transgenic mouse model, carcinogen (NNK) treatment, whole-exome sequencing, histopathology, pathway analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic gain-of-function with defined oncogenic phenotype and pathway activation, single lab\",\n      \"pmids\": [\"31144406\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SFN (stratifin/14-3-3σ) is a multifunctional scaffold protein that promotes cancer cell proliferation and metastasis by activating the LIMK2/Cofilin signaling axis to drive cytoskeletal remodeling, acts as an oncogene in lung adenocarcinoma, promotes renal fibrosis by binding MYH9 in renal tubular epithelial cells, forms a complex with SPARC in keratinocytes to regulate MMP-1 and suppress type I collagen synthesis in fibroblasts, and is post-transcriptionally regulated by microRNAs (e.g., miR-675-5p) targeting its 3'-UTR; its expression is also epigenetically silenced by promoter methylation in multiple tumor types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SFN (stratifin/14-3-3σ) is a scaffold protein that regulates cytoskeletal dynamics, cell survival, and extracellular matrix remodeling, and behaves as a context-dependent driver of proliferation and fibrosis [#1, #6]. In cancer cells it promotes proliferation, migration, invasion, and metastasis while suppressing apoptosis by activating the LIMK2/Cofilin axis to drive actin cytoskeletal remodeling, with SFN overexpression raising LIMK2, p-LIMK2, Cofilin, and p-Cofilin levels and silencing reversing these effects [#1]. Transgenic SFN overexpression in mouse lung acts as a potent oncogene that drives lung adenocarcinoma and activates PI3K/AKT signaling [#6]. SFN exerts its effects through direct physical partners: it binds non-muscle myosin heavy chain 9 (MYH9) in the cytoplasm of renal tubular epithelial cells to promote TGF-β1- and UUO-induced renal fibrosis, increasing Col-1 and α-SMA, while SFN knockdown reduces MYH9 and alleviates fibrosis [#2], and it forms a complex with SPARC in keratinocyte-conditioned media that induces MMP-1 (collagenase) activity and suppresses type I collagen synthesis in dermal fibroblasts, identifying SFN as a keratinocyte-derived anti-fibrogenic factor [#0]. SFN protein levels are constrained post-transcriptionally by miR-675-5p, which directly targets its 3'-UTR to repress expression and thereby modulate tumor cell invasiveness [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that SFN acts as a secreted intercellular signal by physically partnering with SPARC to control matrix homeostasis, answering how keratinocyte-derived SFN influences fibroblast collagen turnover.\",\n      \"evidence\": \"Reciprocal Co-IP, mass spectrometry, and conditioned-media experiments with 3D protein modeling in keratinocyte/fibroblast systems\",\n      \"pmids\": [\"22422640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface and stoichiometry of the SFN–SPARC complex not structurally resolved\", \"Mechanism linking the complex to MMP-1 induction and collagen suppression not defined\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified miR-675-5p as a direct upstream repressor of SFN, showing SFN protein levels are set post-transcriptionally and influence tumor cell invasion.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR reporter assay with miRNA mimic/inhibitor transfection and transwell/scratch assays in NPC cells\",\n      \"pmids\": [\"31677258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors linking SFN levels to invasion not mapped\", \"Whether other miRNAs converge on the SFN 3'-UTR unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined SFN as a pro-survival, pro-metastatic factor in cervical cancer cells through loss-of-function phenotyping.\",\n      \"evidence\": \"siRNA silencing with proliferation, apoptosis, migration, and invasion assays in cervical cancer cells\",\n      \"pmids\": [\"31779593\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Phenotype not yet anchored to a defined molecular pathway in this study\", \"No rescue experiment to confirm specificity\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated in vivo that SFN is sufficient to drive tumorigenesis, establishing it as an oncogene rather than a correlative marker.\",\n      \"evidence\": \"SFN-transgenic (Tg-SPC-SFN) mouse model with NNK carcinogen treatment, whole-exome sequencing, histopathology, and pathway analysis\",\n      \"pmids\": [\"31144406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between SFN and PI3K/AKT activation not mechanistically dissected\", \"Single-lab transgenic model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed SFN's cancer-promoting activity onto a defined signaling axis, showing it drives cytoskeletal remodeling and metastasis via LIMK2/Cofilin.\",\n      \"evidence\": \"Gain- and loss-of-function cellular models with transwell/scratch assays, Western blot, and actin imaging in cervical cancer cells\",\n      \"pmids\": [\"37946061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SFN binds LIMK2 directly or acts upstream indirectly not resolved\", \"In vivo validation of the LIMK2/Cofilin axis absent\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified MYH9 as a direct cytoplasmic binding partner that mediates SFN-driven renal fibrosis, providing a physical mechanism for SFN's pro-fibrotic role.\",\n      \"evidence\": \"LC-MS/MS, reciprocal Co-IP, immunofluorescence co-localization, siRNA knockdown, and mouse UUO model\",\n      \"pmids\": [\"38986830\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SFN binding stabilizes or regulates MYH9 expression not defined\", \"Connection between SFN–MYH9 and TGF-β1 signaling upstream/downstream unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked SFN to mitochondrial and metabolic regulation in esophageal adenocarcinoma, broadening its functional scope beyond cytoskeletal and matrix roles.\",\n      \"evidence\": \"siRNA knockdown with ROS, mitochondrial mass, membrane potential, and metabolic assays in Barrett's esophagus/EAC cells\",\n      \"pmids\": [\"30404157\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular partner or pathway identified for the mitochondrial phenotype\", \"Single method category without mechanistic placement\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how SFN's distinct partner interactions (SPARC, MYH9) and signaling outputs (LIMK2/Cofilin, PI3K/AKT) are integrated, and whether a unifying 14-3-3 scaffolding mechanism underlies its tissue-specific roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of SFN bound to its partners\", \"Tissue-specificity determinants of SFN function unknown\", \"Direct versus indirect basis of pathway activation unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SPARC\", \"MYH9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}