{"gene":"LGALS7","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2021,"finding":"Galectin-7 (Gal-7) physically interacts with HMGCS1 (3-hydroxy-3-methylglutaryl coenzyme A synthase 1); the interaction was mapped to phenylalanine 26 of HMGCS1 and confirmed by yeast two-hybrid, in vitro beta-galactosidase assay, Biacore, and co-immunoprecipitation. Exogenous Gal-7 upregulates HMGCS1 expression in keratinocytes, and LGALS7 siRNA knockdown reduces HMGCS1 levels. Overexpression of HMGCS1 in turn induces Gal-7 expression, indicating a positive feedback loop. Gal-7 treatment increases cellular cholesterol levels in a manner dependent on the Gal-7/HMGCS1 interaction, as a phenylalanine 26-mutated HMGCS1 peptide failed to inhibit this effect.","method":"Yeast two-hybrid, in vitro beta-galactosidase assay, Biacore surface plasmon resonance, co-immunoprecipitation, siRNA knockdown, cholesterol quantification, site-directed mutagenesis (F26 of HMGCS1)","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro binding assays (yeast two-hybrid, Biacore, co-IP), mutagenesis of interaction site, functional rescue/knockdown in cells, single lab but highly rigorous","pmids":["34454908"],"is_preprint":false},{"year":2017,"finding":"Extracellular galectin-7 controls intracellular gal-7 levels in cancer cells via two mechanisms: (1) autocrine transcriptional upregulation of the LGALS7 gene (dose- and time-dependent, confirmed by luciferase reporter assay with the lgals7 promoter in MDA-MB-231 cells), and (2) endocytosis of extracellular gal-7 allowing re-entry into cytosolic and mitochondrial compartments. This constitutes a positive self-amplification pathway.","method":"Luciferase reporter assay (lgals7 promoter), RT-PCR for mRNA quantification, exogenous recombinant gal-7 treatment, subcellular fractionation (cytosolic/mitochondrial), cell line panel (ovarian and breast cancer)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, fractionation, mRNA quantification) in a single lab; functional mechanistic claim well-supported within the study","pmids":["29117220"],"is_preprint":false},{"year":2023,"finding":"Galectin-7 (Gal-7) promotes non-melanoma skin carcinogenesis by recruiting immunosuppressive CD11b+Gr1+ myeloid cells: Tg46 mice overexpressing Gal-7 in keratinocytes developed more papillomas and showed heightened c-Met activation and CXCL-1 expression. Gal-7 bound to the surface of CD11b+Ly6ChiLy6Glo monocytic myeloid cells and enhanced their immunosuppressive activity (increased IL-10 and TGF-β1 secretion and T-cell inhibitory activity). Adoptive transfer of Gal-7-conditioned monocytic myeloid cells to Lgals7-/- mice restored tumor development, and depletion of these cells in Tg46 mice reduced papilloma number.","method":"Transgenic (Tg46) overexpression mouse model, Lgals7-/- knockout mouse model, DMBA/TPA skin carcinogenesis protocol, RNAseq, flow cytometry, adoptive transfer experiments, myeloid cell depletion, IL-10/TGF-β1 ELISA, T-cell suppression assay, surface binding assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic gain- and loss-of-function in vivo models with multiple mechanistic readouts, adoptive transfer epistasis, replicated across transgenic and knockout contexts","pmids":["36693903"],"is_preprint":false},{"year":2020,"finding":"Galectin-7 mediates Er:YAG laser-induced proliferation, migration, and invasion in human periodontal ligament (PDL) fibroblasts: Er:YAG laser irradiation upregulated galectin-7 mRNA and protein, and siRNA-mediated knockdown of galectin-7 abrogated the laser-induced increases in cell proliferation, migration, and invasion.","method":"Er:YAG laser irradiation of PDL fibroblasts, MTT proliferation assay, transwell migration/invasion assay, scratch wound healing assay, qRT-PCR, Western blot, siRNA knockdown","journal":"Journal of the Formosan Medical Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function knockdown with specific phenotypic rescue, multiple cellular readouts, single lab","pmids":["32540310"],"is_preprint":false},{"year":2024,"finding":"In gastric cancer AGS cells, ANGPTL4 overexpression upregulates LGALS7, and LGALS7 mediates an anticancer phenotype; LGALS7 in turn regulates the Hedgehog signaling pathway to promote GC progression (proliferation, migration, apoptosis evasion, angiogenesis, lymphangiogenesis) in other cell contexts. ANGPTL4 and LGALS7 interaction was detected by co-immunoprecipitation.","method":"RNA-seq, qPCR, Western blot, co-immunoprecipitation, EdU assay, MTT assay, flow cytometry, wound healing assay, transwell assay, tube formation, chorioallantoic membrane model, nude mouse xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for interaction, multiple functional assays, in vivo xenograft, single lab","pmids":["39369030"],"is_preprint":false},{"year":2025,"finding":"LGALS7 expression in colorectal cancer is transcriptionally repressed by a nuclear ncRNA/RBP/histone complex: the ncRNA PANC754 (whose expression is regulated by m6A modification via METTL3) binds to RBP PSPC1, which interacts with chromatin-accessible histone mark H3K4me1 at the LGALS7 locus to suppress its transcription, thereby reducing immune evasion mediated by LGALS7.","method":"Loss- and gain-of-function experiments (PANC754 overexpression/knockdown), molecular docking, bioinformatic analysis, co-culture immune assay with anti-NKG2A checkpoint inhibitor, m6A modification analysis (METTL3), in vitro and in vivo experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic experiments (m6A, RBP interaction, chromatin accessibility, functional immune assays) in a single lab; pathway placement via genetic epistasis","pmids":["40634299"],"is_preprint":false}],"current_model":"Galectin-7 (LGALS7) is a β-galactoside-binding lectin that functions through multiple mechanisms: it interacts with HMGCS1 at phenylalanine 26 to promote cholesterol biosynthesis and accumulation in keratinocytes; it amplifies its own intracellular levels via autocrine transcriptional upregulation and endocytic re-entry; it promotes skin carcinogenesis by binding CD11b+Ly6Chi monocytic myeloid cells and enhancing their immunosuppressive activity (IL-10, TGF-β1 secretion) downstream of c-Met/CXCL-1 signaling; in periodontal fibroblasts it mediates laser-induced proliferation and migration; it is regulated at the transcriptional level by a METTL3/m6A-dependent ncRNA-PSPC1-H3K4me1 repression complex; and it interfaces with the Hedgehog pathway in gastric cancer downstream of ANGPTL4."},"narrative":{"mechanistic_narrative":"Galectin-7 (LGALS7) is a β-galactoside-binding lectin that operates both intracellularly and extracellularly to control lipid metabolism, cell proliferation, and tumor-associated immune modulation [PMID:34454908, PMID:36693903]. In keratinocytes it physically binds HMGCS1 through phenylalanine 26 of HMGCS1 and upregulates HMGCS1 expression, raising cellular cholesterol levels in an interaction-dependent manner, with HMGCS1 in turn inducing Gal-7 to form a positive feedback loop [PMID:34454908]. Gal-7 also amplifies its own abundance in cancer cells: extracellular Gal-7 drives autocrine transcriptional upregulation of the LGALS7 promoter and is taken up by endocytosis to re-enter cytosolic and mitochondrial compartments [PMID:29117220]. In the tumor microenvironment, keratinocyte-overexpressed Gal-7 promotes non-melanoma skin carcinogenesis by binding CD11b+Ly6Chi monocytic myeloid cells and enhancing their immunosuppressive activity (IL-10 and TGF-β1 secretion, T-cell inhibition) downstream of c-Met activation and CXCL-1, an effect transferable by adoptive transfer of Gal-7-conditioned myeloid cells [PMID:36693903]. Gal-7 additionally mediates Er:YAG laser-induced proliferation, migration, and invasion of periodontal ligament fibroblasts [PMID:32540310], and in gastric cancer it acts downstream of ANGPTL4 to engage Hedgehog signaling [PMID:39369030]. Its expression is transcriptionally repressed in colorectal cancer by a METTL3/m6A-regulated ncRNA (PANC754)–PSPC1–H3K4me1 complex at the LGALS7 locus, limiting Gal-7-mediated immune evasion [PMID:40634299].","teleology":[{"year":2017,"claim":"Established that Gal-7 sustains its own levels, resolving how extracellular lectin influences intracellular pools by defining a self-amplification loop.","evidence":"Luciferase promoter reporter, mRNA quantification, and subcellular fractionation after recombinant Gal-7 treatment in breast and ovarian cancer lines","pmids":["29117220"],"confidence":"Medium","gaps":["Endocytic receptor mediating Gal-7 re-entry not identified","Functional consequence of mitochondrial Gal-7 not defined","Single-lab cell-line evidence"]},{"year":2020,"claim":"Showed Gal-7 is a required effector of laser-induced fibroblast responses, linking it to proliferation, migration, and invasion in periodontal tissue.","evidence":"Er:YAG laser irradiation of PDL fibroblasts with siRNA knockdown and proliferation/migration/invasion assays","pmids":["32540310"],"confidence":"Medium","gaps":["Molecular partners downstream of Gal-7 in fibroblasts unknown","Mechanism coupling laser to LGALS7 transcription undefined","Single-lab knockdown only"]},{"year":2021,"claim":"Identified a direct molecular partner and metabolic function, answering how Gal-7 promotes cholesterol accumulation in keratinocytes.","evidence":"Yeast two-hybrid, Biacore, co-IP, F26 site-directed mutagenesis, siRNA knockdown, and cholesterol quantification","pmids":["34454908"],"confidence":"High","gaps":["Whether the HMGCS1 interaction depends on lectin carbohydrate-binding activity not resolved","Structural basis of F26 recognition not determined","Physiological/disease consequence of the cholesterol increase not tested"]},{"year":2023,"claim":"Defined an in vivo immunomodulatory mechanism, establishing that Gal-7 drives skin carcinogenesis by reprogramming monocytic myeloid cells into immunosuppressors.","evidence":"Tg46 overexpression and Lgals7-/- mice in DMBA/TPA carcinogenesis with surface binding, myeloid depletion, and adoptive transfer epistasis","pmids":["36693903"],"confidence":"High","gaps":["Myeloid surface receptor for Gal-7 not identified","Relationship between c-Met/CXCL-1 and direct Gal-7 binding not mechanistically dissected","Human relevance not tested"]},{"year":2024,"claim":"Placed Gal-7 in a gastric cancer signaling axis, linking upstream ANGPTL4 to downstream Hedgehog pathway activity.","evidence":"RNA-seq, co-IP for ANGPTL4 interaction, functional assays, and nude mouse xenograft in AGS cells","pmids":["39369030"],"confidence":"Medium","gaps":["Direct vs indirect ANGPTL4–LGALS7 interaction not distinguished","Mechanism by which LGALS7 engages Hedgehog signaling undefined","Apparent context-dependent anticancer vs pro-progression roles unreconciled"]},{"year":2025,"claim":"Resolved how LGALS7 is silenced, defining an m6A/ncRNA/chromatin repression circuit that limits its immune-evasion function in colorectal cancer.","evidence":"PANC754 gain/loss-of-function, m6A/METTL3 analysis, PSPC1 binding, H3K4me1 chromatin assessment, and co-culture immune assays in vitro and in vivo","pmids":["40634299"],"confidence":"Medium","gaps":["Direct PSPC1 occupancy at the LGALS7 locus vs docking prediction not fully validated","Mechanism of LGALS7-driven immune evasion not molecularly detailed","Single-lab model"]},{"year":null,"claim":"The molecular receptors and binding partners through which extracellular Gal-7 engages target cells (myeloid cells, fibroblasts) and unifies its metabolic, proliferative, and immunosuppressive roles remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No surface receptor identified for Gal-7 on myeloid or fibroblast targets","No structural model of Gal-7 partner complexes","Context-dependent pro- vs anti-tumor activity not reconciled across tissues"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"complexes":[],"partners":["HMGCS1","ANGPTL4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P47929","full_name":"Galectin-7","aliases":["HKL-14","PI7","p53-induced gene 1 protein"],"length_aa":136,"mass_kda":15.1,"function":"Could be involved in cell-cell and/or cell-matrix interactions necessary for normal growth control. Pro-apoptotic protein that functions intracellularly upstream of JNK activation and cytochrome c release","subcellular_location":"Cytoplasm; Nucleus; Secreted","url":"https://www.uniprot.org/uniprotkb/P47929/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LGALS7","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1046,"dependency_fraction":0.0028680688336520078},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LGALS7","total_profiled":1310},"omim":[{"mim_id":"617139","title":"LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 7B; LGALS7B","url":"https://www.omim.org/entry/617139"},{"mim_id":"600615","title":"LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 7; LGALS7","url":"https://www.omim.org/entry/600615"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"cervix","ntpm":331.6},{"tissue":"esophagus","ntpm":613.2},{"tissue":"skin 1","ntpm":1404.3}],"url":"https://www.proteinatlas.org/search/LGALS7"},"hgnc":{"alias_symbol":["GAL7","PIG1","TP53I1","LGALS7A"],"prev_symbol":[]},"alphafold":{"accession":"P47929","domains":[{"cath_id":"2.60.120.200","chopping":"5-134","consensus_level":"high","plddt":97.3655,"start":5,"end":134}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P47929","model_url":"https://alphafold.ebi.ac.uk/files/AF-P47929-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P47929-F1-predicted_aligned_error_v6.png","plddt_mean":96.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LGALS7","jax_strain_url":"https://www.jax.org/strain/search?query=LGALS7"},"sequence":{"accession":"P47929","fasta_url":"https://rest.uniprot.org/uniprotkb/P47929.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P47929/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P47929"}},"corpus_meta":[{"pmid":"30774578","id":"PMC_30774578","title":"Quantitative proteomic characterization of lung tissue in idiopathic pulmonary fibrosis.","date":"2019","source":"Clinical proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/30774578","citation_count":60,"is_preprint":false},{"pmid":"20177751","id":"PMC_20177751","title":"Gene signature of the metastatic potential of cutaneous melanoma: too much for too little?","date":"2010","source":"Clinical & experimental metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/20177751","citation_count":56,"is_preprint":false},{"pmid":"31889940","id":"PMC_31889940","title":"The plasma peptides of breast versus ovarian cancer.","date":"2019","source":"Clinical proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/31889940","citation_count":27,"is_preprint":false},{"pmid":"15919778","id":"PMC_15919778","title":"Transcriptome analysis in blastocyst hatching by cDNA microarray.","date":"2005","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15919778","citation_count":26,"is_preprint":false},{"pmid":"37131961","id":"PMC_37131961","title":"Genome-wide Association Studies of Retinal Vessel Tortuosity Identify Numerous Novel Loci Revealing Genes and Pathways Associated With Ocular and Cardiometabolic Diseases.","date":"2023","source":"Ophthalmology science","url":"https://pubmed.ncbi.nlm.nih.gov/37131961","citation_count":25,"is_preprint":false},{"pmid":"32540310","id":"PMC_32540310","title":"Er:YAG laser promotes proliferation and wound healing capacity of human periodontal ligament fibroblasts through Galectin-7 induction.","date":"2020","source":"Journal of the Formosan Medical Association = Taiwan yi zhi","url":"https://pubmed.ncbi.nlm.nih.gov/32540310","citation_count":22,"is_preprint":false},{"pmid":"37774922","id":"PMC_37774922","title":"A novel multi-ancestry proteome-wide Mendelian randomization study implicates extracellular proteins, tubular cells, and fibroblasts in estimated glomerular filtration rate regulation.","date":"2023","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/37774922","citation_count":21,"is_preprint":false},{"pmid":"29117220","id":"PMC_29117220","title":"Intracellular galectin-7 expression in cancer cells results from an autocrine transcriptional mechanism and endocytosis of extracellular galectin-7.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29117220","citation_count":17,"is_preprint":false},{"pmid":"36693903","id":"PMC_36693903","title":"Galectin-7 reprograms skin carcinogenesis by fostering innate immune evasive programs.","date":"2023","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/36693903","citation_count":13,"is_preprint":false},{"pmid":"31602302","id":"PMC_31602302","title":"Natural and synthetic pathogen associated molecular patterns modulate galectin expression in cow blood.","date":"2019","source":"Journal of animal science and technology","url":"https://pubmed.ncbi.nlm.nih.gov/31602302","citation_count":11,"is_preprint":false},{"pmid":"34647699","id":"PMC_34647699","title":"Quantitative proteomics identifies biomarkers to distinguish pulmonary from head and neck squamous cell carcinomas by immunohistochemistry.","date":"2021","source":"The journal of pathology. Clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/34647699","citation_count":6,"is_preprint":false},{"pmid":"34454908","id":"PMC_34454908","title":"Interaction of Gal-7 with HMGCS1 In Vitro May Facilitate Cholesterol Deposition in Cultured Keratinocytes.","date":"2021","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/34454908","citation_count":5,"is_preprint":false},{"pmid":"23554673","id":"PMC_23554673","title":"Development and optimization of an antibody array method for potential cancer biomarker detection.","date":"2011","source":"Journal of biomedical research","url":"https://pubmed.ncbi.nlm.nih.gov/23554673","citation_count":5,"is_preprint":false},{"pmid":"39369030","id":"PMC_39369030","title":"ANGPTL4 plays a paradoxical role in gastric cancer through the LGALS7 and Hedgehog pathways.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39369030","citation_count":3,"is_preprint":false},{"pmid":"40718829","id":"PMC_40718829","title":"Analysis of cancer-associated glycosyltransferases reveals novel targets of non-small cell lung cancer pathogenesis.","date":"2025","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40718829","citation_count":3,"is_preprint":false},{"pmid":"40322912","id":"PMC_40322912","title":"Melanoma Proteomics Unveiled: Harmonizing Diverse Data Sets for Biomarker Discovery and Clinical Insights via MEL-PLOT.","date":"2025","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/40322912","citation_count":3,"is_preprint":false},{"pmid":"41514380","id":"PMC_41514380","title":"Machine learning-driven proteomics classifier deciphers tumor origins of primary and metastatic squamous cell carcinomas.","date":"2026","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/41514380","citation_count":1,"is_preprint":false},{"pmid":"35401111","id":"PMC_35401111","title":"Human Galectin-7 Gene LGALS7 Promoter Sequence Polymorphisms and Risk of Spontaneous Intracerebral Hemorrhage: A Prospective Study.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35401111","citation_count":0,"is_preprint":false},{"pmid":"40634299","id":"PMC_40634299","title":"M6A-METTL3-dependent nuclear PANC754/PSPC1/H3K4me1 repression complex regulate immune evasive LGALS7 signal to enhance immunotherapy against colorectal cancer.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40634299","citation_count":0,"is_preprint":false},{"pmid":"41306978","id":"PMC_41306978","title":"Mitogen-activated protein kinase pathway and four genes involved in the development of benign prostatic hyperplasia: in vivo and vitro validation.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41306978","citation_count":0,"is_preprint":false},{"pmid":"41898372","id":"PMC_41898372","title":"Spatial Distribution of K13-Positive Airway Epithelial Cells in Idiopathic Pulmonary Fibrosis.","date":"2026","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/41898372","citation_count":0,"is_preprint":false},{"pmid":"18956639","id":"PMC_18956639","title":"[Different expression of liver-specific insulin-like growth factor I gene in breast cancer; expression with mice].","date":"2008","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/18956639","citation_count":0,"is_preprint":false},{"pmid":"41907605","id":"PMC_41907605","title":"Disorder of the immune and inflammatory response involving galectin-1, -3 and -7 in women with invasive breast cancer - potential importance in diagnosis and monitoring the course of the disease.","date":"2026","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41907605","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16701,"output_tokens":2273,"usd":0.042099,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9297,"output_tokens":2642,"usd":0.056267,"stage2_stop_reason":"end_turn"},"total_usd":0.098366,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"Galectin-7 (Gal-7) physically interacts with HMGCS1 (3-hydroxy-3-methylglutaryl coenzyme A synthase 1); the interaction was mapped to phenylalanine 26 of HMGCS1 and confirmed by yeast two-hybrid, in vitro beta-galactosidase assay, Biacore, and co-immunoprecipitation. Exogenous Gal-7 upregulates HMGCS1 expression in keratinocytes, and LGALS7 siRNA knockdown reduces HMGCS1 levels. Overexpression of HMGCS1 in turn induces Gal-7 expression, indicating a positive feedback loop. Gal-7 treatment increases cellular cholesterol levels in a manner dependent on the Gal-7/HMGCS1 interaction, as a phenylalanine 26-mutated HMGCS1 peptide failed to inhibit this effect.\",\n      \"method\": \"Yeast two-hybrid, in vitro beta-galactosidase assay, Biacore surface plasmon resonance, co-immunoprecipitation, siRNA knockdown, cholesterol quantification, site-directed mutagenesis (F26 of HMGCS1)\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro binding assays (yeast two-hybrid, Biacore, co-IP), mutagenesis of interaction site, functional rescue/knockdown in cells, single lab but highly rigorous\",\n      \"pmids\": [\"34454908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Extracellular galectin-7 controls intracellular gal-7 levels in cancer cells via two mechanisms: (1) autocrine transcriptional upregulation of the LGALS7 gene (dose- and time-dependent, confirmed by luciferase reporter assay with the lgals7 promoter in MDA-MB-231 cells), and (2) endocytosis of extracellular gal-7 allowing re-entry into cytosolic and mitochondrial compartments. This constitutes a positive self-amplification pathway.\",\n      \"method\": \"Luciferase reporter assay (lgals7 promoter), RT-PCR for mRNA quantification, exogenous recombinant gal-7 treatment, subcellular fractionation (cytosolic/mitochondrial), cell line panel (ovarian and breast cancer)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, fractionation, mRNA quantification) in a single lab; functional mechanistic claim well-supported within the study\",\n      \"pmids\": [\"29117220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Galectin-7 (Gal-7) promotes non-melanoma skin carcinogenesis by recruiting immunosuppressive CD11b+Gr1+ myeloid cells: Tg46 mice overexpressing Gal-7 in keratinocytes developed more papillomas and showed heightened c-Met activation and CXCL-1 expression. Gal-7 bound to the surface of CD11b+Ly6ChiLy6Glo monocytic myeloid cells and enhanced their immunosuppressive activity (increased IL-10 and TGF-β1 secretion and T-cell inhibitory activity). Adoptive transfer of Gal-7-conditioned monocytic myeloid cells to Lgals7-/- mice restored tumor development, and depletion of these cells in Tg46 mice reduced papilloma number.\",\n      \"method\": \"Transgenic (Tg46) overexpression mouse model, Lgals7-/- knockout mouse model, DMBA/TPA skin carcinogenesis protocol, RNAseq, flow cytometry, adoptive transfer experiments, myeloid cell depletion, IL-10/TGF-β1 ELISA, T-cell suppression assay, surface binding assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic gain- and loss-of-function in vivo models with multiple mechanistic readouts, adoptive transfer epistasis, replicated across transgenic and knockout contexts\",\n      \"pmids\": [\"36693903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Galectin-7 mediates Er:YAG laser-induced proliferation, migration, and invasion in human periodontal ligament (PDL) fibroblasts: Er:YAG laser irradiation upregulated galectin-7 mRNA and protein, and siRNA-mediated knockdown of galectin-7 abrogated the laser-induced increases in cell proliferation, migration, and invasion.\",\n      \"method\": \"Er:YAG laser irradiation of PDL fibroblasts, MTT proliferation assay, transwell migration/invasion assay, scratch wound healing assay, qRT-PCR, Western blot, siRNA knockdown\",\n      \"journal\": \"Journal of the Formosan Medical Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function knockdown with specific phenotypic rescue, multiple cellular readouts, single lab\",\n      \"pmids\": [\"32540310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In gastric cancer AGS cells, ANGPTL4 overexpression upregulates LGALS7, and LGALS7 mediates an anticancer phenotype; LGALS7 in turn regulates the Hedgehog signaling pathway to promote GC progression (proliferation, migration, apoptosis evasion, angiogenesis, lymphangiogenesis) in other cell contexts. ANGPTL4 and LGALS7 interaction was detected by co-immunoprecipitation.\",\n      \"method\": \"RNA-seq, qPCR, Western blot, co-immunoprecipitation, EdU assay, MTT assay, flow cytometry, wound healing assay, transwell assay, tube formation, chorioallantoic membrane model, nude mouse xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for interaction, multiple functional assays, in vivo xenograft, single lab\",\n      \"pmids\": [\"39369030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LGALS7 expression in colorectal cancer is transcriptionally repressed by a nuclear ncRNA/RBP/histone complex: the ncRNA PANC754 (whose expression is regulated by m6A modification via METTL3) binds to RBP PSPC1, which interacts with chromatin-accessible histone mark H3K4me1 at the LGALS7 locus to suppress its transcription, thereby reducing immune evasion mediated by LGALS7.\",\n      \"method\": \"Loss- and gain-of-function experiments (PANC754 overexpression/knockdown), molecular docking, bioinformatic analysis, co-culture immune assay with anti-NKG2A checkpoint inhibitor, m6A modification analysis (METTL3), in vitro and in vivo experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic experiments (m6A, RBP interaction, chromatin accessibility, functional immune assays) in a single lab; pathway placement via genetic epistasis\",\n      \"pmids\": [\"40634299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Galectin-7 (LGALS7) is a β-galactoside-binding lectin that functions through multiple mechanisms: it interacts with HMGCS1 at phenylalanine 26 to promote cholesterol biosynthesis and accumulation in keratinocytes; it amplifies its own intracellular levels via autocrine transcriptional upregulation and endocytic re-entry; it promotes skin carcinogenesis by binding CD11b+Ly6Chi monocytic myeloid cells and enhancing their immunosuppressive activity (IL-10, TGF-β1 secretion) downstream of c-Met/CXCL-1 signaling; in periodontal fibroblasts it mediates laser-induced proliferation and migration; it is regulated at the transcriptional level by a METTL3/m6A-dependent ncRNA-PSPC1-H3K4me1 repression complex; and it interfaces with the Hedgehog pathway in gastric cancer downstream of ANGPTL4.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Galectin-7 (LGALS7) is a β-galactoside-binding lectin that operates both intracellularly and extracellularly to control lipid metabolism, cell proliferation, and tumor-associated immune modulation [#0, #2]. In keratinocytes it physically binds HMGCS1 through phenylalanine 26 of HMGCS1 and upregulates HMGCS1 expression, raising cellular cholesterol levels in an interaction-dependent manner, with HMGCS1 in turn inducing Gal-7 to form a positive feedback loop [#0]. Gal-7 also amplifies its own abundance in cancer cells: extracellular Gal-7 drives autocrine transcriptional upregulation of the LGALS7 promoter and is taken up by endocytosis to re-enter cytosolic and mitochondrial compartments [#1]. In the tumor microenvironment, keratinocyte-overexpressed Gal-7 promotes non-melanoma skin carcinogenesis by binding CD11b+Ly6Chi monocytic myeloid cells and enhancing their immunosuppressive activity (IL-10 and TGF-β1 secretion, T-cell inhibition) downstream of c-Met activation and CXCL-1, an effect transferable by adoptive transfer of Gal-7-conditioned myeloid cells [#2]. Gal-7 additionally mediates Er:YAG laser-induced proliferation, migration, and invasion of periodontal ligament fibroblasts [#3], and in gastric cancer it acts downstream of ANGPTL4 to engage Hedgehog signaling [#4]. Its expression is transcriptionally repressed in colorectal cancer by a METTL3/m6A-regulated ncRNA (PANC754)–PSPC1–H3K4me1 complex at the LGALS7 locus, limiting Gal-7-mediated immune evasion [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that Gal-7 sustains its own levels, resolving how extracellular lectin influences intracellular pools by defining a self-amplification loop.\",\n      \"evidence\": \"Luciferase promoter reporter, mRNA quantification, and subcellular fractionation after recombinant Gal-7 treatment in breast and ovarian cancer lines\",\n      \"pmids\": [\"29117220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endocytic receptor mediating Gal-7 re-entry not identified\", \"Functional consequence of mitochondrial Gal-7 not defined\", \"Single-lab cell-line evidence\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed Gal-7 is a required effector of laser-induced fibroblast responses, linking it to proliferation, migration, and invasion in periodontal tissue.\",\n      \"evidence\": \"Er:YAG laser irradiation of PDL fibroblasts with siRNA knockdown and proliferation/migration/invasion assays\",\n      \"pmids\": [\"32540310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners downstream of Gal-7 in fibroblasts unknown\", \"Mechanism coupling laser to LGALS7 transcription undefined\", \"Single-lab knockdown only\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a direct molecular partner and metabolic function, answering how Gal-7 promotes cholesterol accumulation in keratinocytes.\",\n      \"evidence\": \"Yeast two-hybrid, Biacore, co-IP, F26 site-directed mutagenesis, siRNA knockdown, and cholesterol quantification\",\n      \"pmids\": [\"34454908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the HMGCS1 interaction depends on lectin carbohydrate-binding activity not resolved\", \"Structural basis of F26 recognition not determined\", \"Physiological/disease consequence of the cholesterol increase not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined an in vivo immunomodulatory mechanism, establishing that Gal-7 drives skin carcinogenesis by reprogramming monocytic myeloid cells into immunosuppressors.\",\n      \"evidence\": \"Tg46 overexpression and Lgals7-/- mice in DMBA/TPA carcinogenesis with surface binding, myeloid depletion, and adoptive transfer epistasis\",\n      \"pmids\": [\"36693903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Myeloid surface receptor for Gal-7 not identified\", \"Relationship between c-Met/CXCL-1 and direct Gal-7 binding not mechanistically dissected\", \"Human relevance not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed Gal-7 in a gastric cancer signaling axis, linking upstream ANGPTL4 to downstream Hedgehog pathway activity.\",\n      \"evidence\": \"RNA-seq, co-IP for ANGPTL4 interaction, functional assays, and nude mouse xenograft in AGS cells\",\n      \"pmids\": [\"39369030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect ANGPTL4–LGALS7 interaction not distinguished\", \"Mechanism by which LGALS7 engages Hedgehog signaling undefined\", \"Apparent context-dependent anticancer vs pro-progression roles unreconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved how LGALS7 is silenced, defining an m6A/ncRNA/chromatin repression circuit that limits its immune-evasion function in colorectal cancer.\",\n      \"evidence\": \"PANC754 gain/loss-of-function, m6A/METTL3 analysis, PSPC1 binding, H3K4me1 chromatin assessment, and co-culture immune assays in vitro and in vivo\",\n      \"pmids\": [\"40634299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PSPC1 occupancy at the LGALS7 locus vs docking prediction not fully validated\", \"Mechanism of LGALS7-driven immune evasion not molecularly detailed\", \"Single-lab model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular receptors and binding partners through which extracellular Gal-7 engages target cells (myeloid cells, fibroblasts) and unifies its metabolic, proliferative, and immunosuppressive roles remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No surface receptor identified for Gal-7 on myeloid or fibroblast targets\", \"No structural model of Gal-7 partner complexes\", \"Context-dependent pro- vs anti-tumor activity not reconciled across tissues\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HMGCS1\", \"ANGPTL4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}