{"gene":"KRT80","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2022,"finding":"OTUB2, a deubiquitinating enzyme, stabilizes KRT80 protein by deubiquitinating it at Lys-48 and Lys-63 linkages, shielding it from proteasome-mediated degradation; OTUB2 and KRT80 together activate the Akt signaling pathway to promote gastric cancer cell proliferation.","method":"Co-immunoprecipitation, western blotting, in vitro and in vivo proliferation assays, KRT80 rescue experiments upon OTUB2 knockdown","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal functional rescue plus ubiquitination site identification, single lab","pmids":["35110531"],"is_preprint":false},{"year":2020,"finding":"CircPIP5K1A acts as a competing endogenous RNA (ceRNA) by sponging miR-671-5p, thereby de-repressing KRT80 expression; elevated KRT80 in turn activates the PI3K/AKT pathway to promote gastric cancer cell proliferation, invasion, migration, and EMT.","method":"Luciferase reporter assay, Ago2-RIP assay, siRNA knockdown, miR-671-5p inhibitor rescue, western blot for PI3K/AKT pathway components, in vivo xenograft","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (luciferase, RIP, rescue experiments), single lab","pmids":["32169757"],"is_preprint":false},{"year":2024,"finding":"KRT80 physically interacts with valosin-containing protein (VCP); VCP knockdown reduces KRT80 protein stability, and KRT80 overexpression partially rescues the growth-inhibitory effect of VCP knockdown, establishing VCP as a regulator of KRT80 stability in lung adenocarcinoma.","method":"Immunoprecipitation and mass spectrometry, VCP knockdown with KRT80 overexpression rescue, cell viability and migration assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — IP-MS identification of interaction plus functional rescue, single lab","pmids":["38495507"],"is_preprint":false},{"year":2025,"finding":"RNF8, an E3 ubiquitin ligase, interacts with KRT80 and promotes its ubiquitination-mediated degradation; KRT80 in turn activates glycolytic pathway components (GLUT1, HK2, LDHA) to drive glioblastoma cell proliferation and progression.","method":"Immunofluorescence co-localization, co-immunoprecipitation, overexpression/knockout cell lines, in vivo tumor formation, flow cytometry (apoptosis), real-time PCR, non-targeted metabolomics","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus multiple orthogonal functional assays in single lab","pmids":["40146410"],"is_preprint":false},{"year":2024,"finding":"KRT80 knockdown in esophageal cancer cells suppresses anti-apoptosis, migration, invasion, chemoresistance, and lipogenesis; overexpression of lipogenic enzymes ACC1 and ACLY reverses the inhibitory effects of KRT80 knockdown on lipogenesis and chemoresistance, placing KRT80 upstream of ACC1/ACLY-mediated lipid droplet assembly.","method":"siRNA knockdown, ACC1/ACLY overexpression rescue, functional assays (migration, invasion, apoptosis, lipogenesis)","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — epistatic rescue experiment linking KRT80 to lipogenic pathway, single lab","pmids":["38241178"],"is_preprint":false},{"year":2022,"finding":"The lncRNA HNSCAT1 positively regulates KRT80 expression in head and neck squamous cell carcinoma; miR-1245 simultaneously interacts with both KRT80 3'-UTR and HNSCAT1, bridging HNSCAT1's regulatory function to KRT80 expression modulation.","method":"RNA-seq, RACE assay, RNA-FISH, luciferase/miRNA interaction assays, in vivo and in vitro overexpression studies","journal":"Oxidative medicine and cellular longevity","confidence":"Low","confidence_rationale":"Tier 3 — mechanistic link inferred from correlation and bioinformatics with partial functional follow-up, single lab","pmids":["35965679"],"is_preprint":false},{"year":2023,"finding":"LINC01485 sponges miR-383-5p to de-repress KRT80 expression in colorectal cancer; elevated KRT80 promotes cell proliferation and inhibits apoptosis (reduced Bax, elevated Bcl-2), as validated in xenograft models.","method":"RIP assay, dual-luciferase assay, qRT-PCR, western blotting, CCK-8, colony formation, xenograft","journal":"Environmental toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — dual-luciferase and RIP confirm binding, functional in vivo validation, single lab","pmids":["37782686"],"is_preprint":false},{"year":2025,"finding":"miR-195-5p directly targets the KRT80 3'-UTR to suppress KRT80 expression, causing G1-phase cell cycle arrest in colorectal cancer cells; this phenotype mimics direct KRT80 siRNA silencing and was validated in a mouse colitis-associated CRC model.","method":"Bioinformatic prediction of miR-195-5p binding sites, transfection of miR-195-5p mimics, siRNA knockdown comparison, flow cytometry cell cycle analysis, in vivo mouse model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — direct target validation with functional cell cycle readout plus in vivo confirmation, single lab","pmids":["40647481"],"is_preprint":false},{"year":2026,"finding":"KRT80 modulates STAT3 phosphorylation in colon adenocarcinoma cells; KRT80 knockdown reduces and overexpression promotes STAT3 pathway activation, proliferation, migration, and invasion.","method":"Western blot for phospho-STAT3, stable knockdown/overexpression, CCK-8, Transwell, wound healing assays","journal":"Translational cancer research","confidence":"Low","confidence_rationale":"Tier 3 — single method for pathway link (western blot), no mechanistic detail of how KRT80 contacts STAT3, single lab","pmids":["41969516"],"is_preprint":false},{"year":2024,"finding":"KRT80 promotes hepatocellular carcinoma cell proliferation, migration, invasion, and angiogenesis by activating the PI3K/AKT signaling pathway and inducing epithelial-mesenchymal transition (EMT); these effects are abrogated by KRT80 silencing in vivo and in vitro.","method":"Gain-of-function and loss-of-function experiments, western blot for PI3K/AKT and EMT markers, in vitro and in vivo assays","journal":"IUBMB life","confidence":"Low","confidence_rationale":"Tier 3 — pathway activation inferred from western blot without direct mechanistic link, single lab","pmids":["39569942"],"is_preprint":false},{"year":2020,"finding":"siRNA-mediated knockdown of KRT80 in colorectal cancer cell lines decreases cell viability and proliferation, and co-expressed protein network analysis places KRT80 within cell cycle and DNA replication pathways.","method":"siRNA knockdown, cell viability assay, co-expression network/pathway analysis","journal":"Experimental and therapeutic medicine","confidence":"Low","confidence_rationale":"Tier 3 — functional KD with phenotype, pathway placement is computational, single lab","pmids":["33101466"],"is_preprint":false}],"current_model":"KRT80 is a type II intermediate filament keratin that promotes cancer cell proliferation, migration, invasion, and chemoresistance by activating the PI3K/AKT and STAT3 signaling pathways and driving EMT; its protein stability is regulated post-translationally by deubiquitination via OTUB2 (at K48/K63 linkages) and by ubiquitin-mediated degradation via the E3 ligase RNF8, while its expression is controlled upstream by competing endogenous RNA axes (e.g., circPIP5K1A/miR-671-5p, LINC01485/miR-383-5p) and by miR-195-5p-mediated translational repression; additionally, KRT80 interacts with VCP to maintain its stability, and acts upstream of ACC1/ACLY-mediated lipogenesis."},"narrative":{"teleology":[{"year":2020,"claim":"Establishing KRT80 as a functionally relevant oncogenic factor: prior to 2020 the cellular consequences of KRT80 perturbation were unknown; siRNA knockdown in colorectal cancer cells demonstrated that KRT80 is required for cell viability, and circPIP5K1A/miR-671-5p was identified as an upstream ceRNA axis that de-represses KRT80 to activate PI3K/AKT signaling and EMT in gastric cancer.","evidence":"siRNA knockdown viability assays in CRC cells; luciferase reporter, Ago2-RIP, miR inhibitor rescue, xenograft in gastric cancer cells","pmids":["33101466","32169757"],"confidence":"Medium","gaps":["No direct biochemical mechanism linking KRT80 to PI3K/AKT activation was identified","ceRNA axis validated in single labs only","Whether KRT80 intermediate filament assembly is required for signaling was not tested"]},{"year":2022,"claim":"Identifying how KRT80 protein stability is maintained: OTUB2 was shown to directly deubiquitinate KRT80 at K48 and K63 linkages, protecting it from proteasomal degradation and enabling AKT pathway activation in gastric cancer, providing the first post-translational regulatory mechanism for KRT80.","evidence":"Co-immunoprecipitation, ubiquitination assays, OTUB2 knockdown with KRT80 rescue, proliferation assays","pmids":["35110531"],"confidence":"Medium","gaps":["The E3 ligase responsible for basal KRT80 ubiquitination was not identified in this study","Structural basis of OTUB2–KRT80 interaction is unknown","Specific ubiquitinated lysine residues on KRT80 were not mapped"]},{"year":2023,"claim":"Expanding the ceRNA regulatory network: LINC01485/miR-383-5p was identified as a second independent ceRNA axis controlling KRT80 expression, this time in colorectal cancer, where KRT80 promotes proliferation and anti-apoptotic Bcl-2/Bax signaling.","evidence":"RIP assay, dual-luciferase reporter, qRT-PCR, xenograft validation","pmids":["37782686"],"confidence":"Medium","gaps":["Whether LINC01485 and circPIP5K1A axes are tissue-specific or convergent is untested","Direct KRT80–Bcl-2 regulatory mechanism is not defined"]},{"year":2024,"claim":"Defining downstream metabolic effectors: KRT80 was placed upstream of ACC1/ACLY-mediated lipogenesis and lipid droplet assembly in esophageal cancer, and VCP was identified as a physical interactor that maintains KRT80 stability in lung adenocarcinoma, broadening the functional landscape beyond AKT signaling.","evidence":"IP-MS for VCP interaction with rescue; siRNA knockdown of KRT80 with ACC1/ACLY overexpression epistasis rescue; viability, migration, lipogenesis assays","pmids":["38241178","38495507"],"confidence":"Medium","gaps":["How KRT80 signals to ACC1/ACLY is mechanistically undefined","Whether VCP acts through its segregase activity or a scaffolding role is unknown","The connection between lipogenesis and PI3K/AKT signaling downstream of KRT80 has not been tested"]},{"year":2025,"claim":"Identifying the opposing E3 ligase and additional microRNA regulation: RNF8 was shown to ubiquitinate KRT80 for degradation in glioblastoma, completing the deubiquitinase–E3 ligase regulatory axis, while miR-195-5p was validated as a direct repressor of KRT80 that induces G1 arrest in colorectal cancer.","evidence":"Co-IP and co-localization for RNF8–KRT80; metabolomics linking KRT80 to glycolysis; miR-195-5p mimic transfection with cell cycle flow cytometry and in vivo CRC model","pmids":["40146410","40647481"],"confidence":"Medium","gaps":["RNF8–KRT80 interaction validated in single lab; independent confirmation needed","Whether RNF8 and OTUB2 compete on the same KRT80 pool is untested","Mechanism linking KRT80 to glycolytic enzyme expression (GLUT1/HK2/LDHA) is correlative"]},{"year":null,"claim":"The direct biochemical mechanism by which a cytoskeletal intermediate filament protein activates PI3K/AKT, STAT3, and metabolic reprogramming remains unresolved; whether KRT80 functions through filament-dependent scaffolding, direct kinase interaction, or an unconventional signaling role is unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biophysical characterization of KRT80 signaling complexes exists","Whether KRT80 intermediate filament polymerization is required for its oncogenic functions has not been tested","The physiological role of KRT80 in normal (non-cancer) epithelial biology is essentially uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,9]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,9]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,3]}],"complexes":[],"partners":["OTUB2","VCP","RNF8","ACC1","ACLY"],"other_free_text":[]},"mechanistic_narrative":"KRT80 is a type II intermediate filament keratin that functions as a pro-proliferative and pro-invasive factor across multiple cancer types by activating the PI3K/AKT signaling pathway and promoting epithelial-mesenchymal transition [PMID:32169757, PMID:39569942]. KRT80 protein stability is regulated by opposing ubiquitin-editing enzymes: the deubiquitinase OTUB2 stabilizes KRT80 by removing K48- and K63-linked ubiquitin chains, while the E3 ligase RNF8 promotes its proteasomal degradation, and the AAA-ATPase VCP additionally maintains KRT80 protein levels [PMID:35110531, PMID:40146410, PMID:38495507]. KRT80 expression is controlled post-transcriptionally by competing endogenous RNA axes in which long noncoding RNAs or circular RNAs (circPIP5K1A, LINC01485) sponge inhibitory microRNAs (miR-671-5p, miR-383-5p, miR-195-5p) to de-repress KRT80 translation [PMID:32169757, PMID:37782686, PMID:40647481]. Downstream, KRT80 drives chemoresistance and lipogenesis through ACC1/ACLY-dependent lipid droplet assembly and enhances glycolysis via GLUT1/HK2/LDHA activation [PMID:38241178, PMID:40146410]."},"prefetch_data":{"uniprot":{"accession":"Q6KB66","full_name":"Keratin, type II cytoskeletal 80","aliases":["Cytokeratin-80","CK-80","Keratin-80","K80","Type-II keratin Kb20"],"length_aa":452,"mass_kda":50.5,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q6KB66/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRT80","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KRT80","total_profiled":1310},"omim":[{"mim_id":"615241","title":"TERMINAL DIFFERENTIATION-INDUCED NONCODING RNA; TINCR","url":"https://www.omim.org/entry/615241"},{"mim_id":"611161","title":"KERATIN 80, TYPE II; KRT80","url":"https://www.omim.org/entry/611161"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Intermediate filaments","reliability":"Enhanced"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":211.1}],"url":"https://www.proteinatlas.org/search/KRT80"},"hgnc":{"alias_symbol":["KB20"],"prev_symbol":[]},"alphafold":{"accession":"Q6KB66","domains":[{"cath_id":"-","chopping":"165-233_249-393","consensus_level":"medium","plddt":93.5298,"start":165,"end":393}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6KB66","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6KB66-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6KB66-F1-predicted_aligned_error_v6.png","plddt_mean":75.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRT80","jax_strain_url":"https://www.jax.org/strain/search?query=KRT80"},"sequence":{"accession":"Q6KB66","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6KB66.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6KB66/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6KB66"}},"corpus_meta":[{"pmid":"32169757","id":"PMC_32169757","title":"CircPIP5K1A activates KRT80 and PI3K/AKT pathway to promote gastric cancer development through sponging miR-671-5p.","date":"2020","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/32169757","citation_count":64,"is_preprint":false},{"pmid":"35110531","id":"PMC_35110531","title":"OTUB2 regulates KRT80 stability via deubiquitination and promotes tumour proliferation in gastric cancer.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35110531","citation_count":24,"is_preprint":false},{"pmid":"32830257","id":"PMC_32830257","title":"A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil.","date":"2021","source":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","url":"https://pubmed.ncbi.nlm.nih.gov/32830257","citation_count":19,"is_preprint":false},{"pmid":"37211956","id":"PMC_37211956","title":"Characters of KRT80 and its roles in neoplasms diseases.","date":"2023","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37211956","citation_count":16,"is_preprint":false},{"pmid":"33101466","id":"PMC_33101466","title":"Small interfering RNA-mediated knockdown of KRT80 suppresses colorectal cancer proliferation.","date":"2020","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33101466","citation_count":14,"is_preprint":false},{"pmid":"38241178","id":"PMC_38241178","title":"The facilitating effects of KRT80 on chemoresistance, lipogenesis, and invasion of esophageal cancer.","date":"2024","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38241178","citation_count":8,"is_preprint":false},{"pmid":"35965679","id":"PMC_35965679","title":"The Long Noncoding Transcript HNSCAT1 Activates KRT80 and Triggers Therapeutic Efficacy in Head and Neck Squamous Cell Carcinoma.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/35965679","citation_count":7,"is_preprint":false},{"pmid":"38495507","id":"PMC_38495507","title":"KRT80 Promotes Lung Adenocarcinoma Progression and Serves as a Substrate for VCP.","date":"2024","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38495507","citation_count":6,"is_preprint":false},{"pmid":"37782686","id":"PMC_37782686","title":"LINC01485 contributes to colorectal cancer progression by targeting miR-383-5p/KRT80 axis.","date":"2023","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/37782686","citation_count":6,"is_preprint":false},{"pmid":"37129345","id":"PMC_37129345","title":"KRT80 expression works as a biomarker and a target for differentiation in gastric cancer.","date":"2023","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/37129345","citation_count":4,"is_preprint":false},{"pmid":"39569942","id":"PMC_39569942","title":"KRT80 in hepatocellular carcinoma plays oncogenic role via epithelial-mesenchymal transition and PI3K/AKT pathway.","date":"2024","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/39569942","citation_count":2,"is_preprint":false},{"pmid":"40146410","id":"PMC_40146410","title":"KRT80, Regulated by RNF8-Mediated Ubiquitination, Contributes to Glucose Metabolic Reprogramming and Progression of Glioblastoma.","date":"2025","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/40146410","citation_count":1,"is_preprint":false},{"pmid":"40647481","id":"PMC_40647481","title":"miR-195-5p Suppresses KRT80 Expression Inducing Cell Cycle Arrest in Colon Cancer.","date":"2025","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/40647481","citation_count":0,"is_preprint":false},{"pmid":"41969516","id":"PMC_41969516","title":"KRT80 promotes colon adenocarcinoma progression via stat3 pathway activation and immune microenvironment remodeling.","date":"2026","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41969516","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9157,"output_tokens":2566,"usd":0.032981},"stage2":{"model":"claude-opus-4-6","input_tokens":5890,"output_tokens":2104,"usd":0.123075},"total_usd":0.156056,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"OTUB2, a deubiquitinating enzyme, stabilizes KRT80 protein by deubiquitinating it at Lys-48 and Lys-63 linkages, shielding it from proteasome-mediated degradation; OTUB2 and KRT80 together activate the Akt signaling pathway to promote gastric cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, in vitro and in vivo proliferation assays, KRT80 rescue experiments upon OTUB2 knockdown\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional rescue plus ubiquitination site identification, single lab\",\n      \"pmids\": [\"35110531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CircPIP5K1A acts as a competing endogenous RNA (ceRNA) by sponging miR-671-5p, thereby de-repressing KRT80 expression; elevated KRT80 in turn activates the PI3K/AKT pathway to promote gastric cancer cell proliferation, invasion, migration, and EMT.\",\n      \"method\": \"Luciferase reporter assay, Ago2-RIP assay, siRNA knockdown, miR-671-5p inhibitor rescue, western blot for PI3K/AKT pathway components, in vivo xenograft\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (luciferase, RIP, rescue experiments), single lab\",\n      \"pmids\": [\"32169757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KRT80 physically interacts with valosin-containing protein (VCP); VCP knockdown reduces KRT80 protein stability, and KRT80 overexpression partially rescues the growth-inhibitory effect of VCP knockdown, establishing VCP as a regulator of KRT80 stability in lung adenocarcinoma.\",\n      \"method\": \"Immunoprecipitation and mass spectrometry, VCP knockdown with KRT80 overexpression rescue, cell viability and migration assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IP-MS identification of interaction plus functional rescue, single lab\",\n      \"pmids\": [\"38495507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF8, an E3 ubiquitin ligase, interacts with KRT80 and promotes its ubiquitination-mediated degradation; KRT80 in turn activates glycolytic pathway components (GLUT1, HK2, LDHA) to drive glioblastoma cell proliferation and progression.\",\n      \"method\": \"Immunofluorescence co-localization, co-immunoprecipitation, overexpression/knockout cell lines, in vivo tumor formation, flow cytometry (apoptosis), real-time PCR, non-targeted metabolomics\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus multiple orthogonal functional assays in single lab\",\n      \"pmids\": [\"40146410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KRT80 knockdown in esophageal cancer cells suppresses anti-apoptosis, migration, invasion, chemoresistance, and lipogenesis; overexpression of lipogenic enzymes ACC1 and ACLY reverses the inhibitory effects of KRT80 knockdown on lipogenesis and chemoresistance, placing KRT80 upstream of ACC1/ACLY-mediated lipid droplet assembly.\",\n      \"method\": \"siRNA knockdown, ACC1/ACLY overexpression rescue, functional assays (migration, invasion, apoptosis, lipogenesis)\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistatic rescue experiment linking KRT80 to lipogenic pathway, single lab\",\n      \"pmids\": [\"38241178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The lncRNA HNSCAT1 positively regulates KRT80 expression in head and neck squamous cell carcinoma; miR-1245 simultaneously interacts with both KRT80 3'-UTR and HNSCAT1, bridging HNSCAT1's regulatory function to KRT80 expression modulation.\",\n      \"method\": \"RNA-seq, RACE assay, RNA-FISH, luciferase/miRNA interaction assays, in vivo and in vitro overexpression studies\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic link inferred from correlation and bioinformatics with partial functional follow-up, single lab\",\n      \"pmids\": [\"35965679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LINC01485 sponges miR-383-5p to de-repress KRT80 expression in colorectal cancer; elevated KRT80 promotes cell proliferation and inhibits apoptosis (reduced Bax, elevated Bcl-2), as validated in xenograft models.\",\n      \"method\": \"RIP assay, dual-luciferase assay, qRT-PCR, western blotting, CCK-8, colony formation, xenograft\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual-luciferase and RIP confirm binding, functional in vivo validation, single lab\",\n      \"pmids\": [\"37782686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"miR-195-5p directly targets the KRT80 3'-UTR to suppress KRT80 expression, causing G1-phase cell cycle arrest in colorectal cancer cells; this phenotype mimics direct KRT80 siRNA silencing and was validated in a mouse colitis-associated CRC model.\",\n      \"method\": \"Bioinformatic prediction of miR-195-5p binding sites, transfection of miR-195-5p mimics, siRNA knockdown comparison, flow cytometry cell cycle analysis, in vivo mouse model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct target validation with functional cell cycle readout plus in vivo confirmation, single lab\",\n      \"pmids\": [\"40647481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KRT80 modulates STAT3 phosphorylation in colon adenocarcinoma cells; KRT80 knockdown reduces and overexpression promotes STAT3 pathway activation, proliferation, migration, and invasion.\",\n      \"method\": \"Western blot for phospho-STAT3, stable knockdown/overexpression, CCK-8, Transwell, wound healing assays\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method for pathway link (western blot), no mechanistic detail of how KRT80 contacts STAT3, single lab\",\n      \"pmids\": [\"41969516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KRT80 promotes hepatocellular carcinoma cell proliferation, migration, invasion, and angiogenesis by activating the PI3K/AKT signaling pathway and inducing epithelial-mesenchymal transition (EMT); these effects are abrogated by KRT80 silencing in vivo and in vitro.\",\n      \"method\": \"Gain-of-function and loss-of-function experiments, western blot for PI3K/AKT and EMT markers, in vitro and in vivo assays\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pathway activation inferred from western blot without direct mechanistic link, single lab\",\n      \"pmids\": [\"39569942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"siRNA-mediated knockdown of KRT80 in colorectal cancer cell lines decreases cell viability and proliferation, and co-expressed protein network analysis places KRT80 within cell cycle and DNA replication pathways.\",\n      \"method\": \"siRNA knockdown, cell viability assay, co-expression network/pathway analysis\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional KD with phenotype, pathway placement is computational, single lab\",\n      \"pmids\": [\"33101466\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT80 is a type II intermediate filament keratin that promotes cancer cell proliferation, migration, invasion, and chemoresistance by activating the PI3K/AKT and STAT3 signaling pathways and driving EMT; its protein stability is regulated post-translationally by deubiquitination via OTUB2 (at K48/K63 linkages) and by ubiquitin-mediated degradation via the E3 ligase RNF8, while its expression is controlled upstream by competing endogenous RNA axes (e.g., circPIP5K1A/miR-671-5p, LINC01485/miR-383-5p) and by miR-195-5p-mediated translational repression; additionally, KRT80 interacts with VCP to maintain its stability, and acts upstream of ACC1/ACLY-mediated lipogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KRT80 is a type II intermediate filament keratin that functions as a pro-proliferative and pro-invasive factor across multiple cancer types by activating the PI3K/AKT signaling pathway and promoting epithelial-mesenchymal transition [PMID:32169757, PMID:39569942]. KRT80 protein stability is regulated by opposing ubiquitin-editing enzymes: the deubiquitinase OTUB2 stabilizes KRT80 by removing K48- and K63-linked ubiquitin chains, while the E3 ligase RNF8 promotes its proteasomal degradation, and the AAA-ATPase VCP additionally maintains KRT80 protein levels [PMID:35110531, PMID:40146410, PMID:38495507]. KRT80 expression is controlled post-transcriptionally by competing endogenous RNA axes in which long noncoding RNAs or circular RNAs (circPIP5K1A, LINC01485) sponge inhibitory microRNAs (miR-671-5p, miR-383-5p, miR-195-5p) to de-repress KRT80 translation [PMID:32169757, PMID:37782686, PMID:40647481]. Downstream, KRT80 drives chemoresistance and lipogenesis through ACC1/ACLY-dependent lipid droplet assembly and enhances glycolysis via GLUT1/HK2/LDHA activation [PMID:38241178, PMID:40146410].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing KRT80 as a functionally relevant oncogenic factor: prior to 2020 the cellular consequences of KRT80 perturbation were unknown; siRNA knockdown in colorectal cancer cells demonstrated that KRT80 is required for cell viability, and circPIP5K1A/miR-671-5p was identified as an upstream ceRNA axis that de-represses KRT80 to activate PI3K/AKT signaling and EMT in gastric cancer.\",\n      \"evidence\": \"siRNA knockdown viability assays in CRC cells; luciferase reporter, Ago2-RIP, miR inhibitor rescue, xenograft in gastric cancer cells\",\n      \"pmids\": [\"33101466\", \"32169757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct biochemical mechanism linking KRT80 to PI3K/AKT activation was identified\",\n        \"ceRNA axis validated in single labs only\",\n        \"Whether KRT80 intermediate filament assembly is required for signaling was not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying how KRT80 protein stability is maintained: OTUB2 was shown to directly deubiquitinate KRT80 at K48 and K63 linkages, protecting it from proteasomal degradation and enabling AKT pathway activation in gastric cancer, providing the first post-translational regulatory mechanism for KRT80.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, OTUB2 knockdown with KRT80 rescue, proliferation assays\",\n      \"pmids\": [\"35110531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The E3 ligase responsible for basal KRT80 ubiquitination was not identified in this study\",\n        \"Structural basis of OTUB2–KRT80 interaction is unknown\",\n        \"Specific ubiquitinated lysine residues on KRT80 were not mapped\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanding the ceRNA regulatory network: LINC01485/miR-383-5p was identified as a second independent ceRNA axis controlling KRT80 expression, this time in colorectal cancer, where KRT80 promotes proliferation and anti-apoptotic Bcl-2/Bax signaling.\",\n      \"evidence\": \"RIP assay, dual-luciferase reporter, qRT-PCR, xenograft validation\",\n      \"pmids\": [\"37782686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether LINC01485 and circPIP5K1A axes are tissue-specific or convergent is untested\",\n        \"Direct KRT80–Bcl-2 regulatory mechanism is not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining downstream metabolic effectors: KRT80 was placed upstream of ACC1/ACLY-mediated lipogenesis and lipid droplet assembly in esophageal cancer, and VCP was identified as a physical interactor that maintains KRT80 stability in lung adenocarcinoma, broadening the functional landscape beyond AKT signaling.\",\n      \"evidence\": \"IP-MS for VCP interaction with rescue; siRNA knockdown of KRT80 with ACC1/ACLY overexpression epistasis rescue; viability, migration, lipogenesis assays\",\n      \"pmids\": [\"38241178\", \"38495507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How KRT80 signals to ACC1/ACLY is mechanistically undefined\",\n        \"Whether VCP acts through its segregase activity or a scaffolding role is unknown\",\n        \"The connection between lipogenesis and PI3K/AKT signaling downstream of KRT80 has not been tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying the opposing E3 ligase and additional microRNA regulation: RNF8 was shown to ubiquitinate KRT80 for degradation in glioblastoma, completing the deubiquitinase–E3 ligase regulatory axis, while miR-195-5p was validated as a direct repressor of KRT80 that induces G1 arrest in colorectal cancer.\",\n      \"evidence\": \"Co-IP and co-localization for RNF8–KRT80; metabolomics linking KRT80 to glycolysis; miR-195-5p mimic transfection with cell cycle flow cytometry and in vivo CRC model\",\n      \"pmids\": [\"40146410\", \"40647481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"RNF8–KRT80 interaction validated in single lab; independent confirmation needed\",\n        \"Whether RNF8 and OTUB2 compete on the same KRT80 pool is untested\",\n        \"Mechanism linking KRT80 to glycolytic enzyme expression (GLUT1/HK2/LDHA) is correlative\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct biochemical mechanism by which a cytoskeletal intermediate filament protein activates PI3K/AKT, STAT3, and metabolic reprogramming remains unresolved; whether KRT80 functions through filament-dependent scaffolding, direct kinase interaction, or an unconventional signaling role is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biophysical characterization of KRT80 signaling complexes exists\",\n        \"Whether KRT80 intermediate filament polymerization is required for its oncogenic functions has not been tested\",\n        \"The physiological role of KRT80 in normal (non-cancer) epithelial biology is essentially uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"OTUB2\",\n      \"VCP\",\n      \"RNF8\",\n      \"ACC1\",\n      \"ACLY\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}