Affinage

TFF3

Trefoil factor 3 · UniProt Q07654

Length
80 aa
Mass
8.6 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TFF3 is a secreted trefoil-domain peptide that maintains mucosal integrity and drives epithelial wound healing, and which exerts context-dependent oncogenic and tumor-suppressive effects in malignant cells (PMID:31562318, PMID:19303021, PMID:15665295). In the intestinal mucus layer it is stored predominantly as a high-molecular-weight heteromer disulfide-linked to FCGBP (and to MUC2 C-terminal domains), with the active monomer/dimer releasable by hydrogen sulfide; this complex assembly is conserved across colonic and salivary secretions (PMID:20423149, PMID:21629776, PMID:31658587). TFF3 signals through distinct cell-surface receptors: it binds LINGO2 to disrupt inhibitory EGFR–LINGO2 complexes and de-repress EGFR signaling, and binds CD147 to enhance CD147–CD44s interaction, driving STAT3 activation and COX-2/PGE2 production (PMID:31562318, PMID:34262017). Downstream it engages overlapping ERK, PI3K/AKT, and JAK/STAT3 cascades to drive collective cell migration, with CXCR4/CXCR7 required for the motogenic response (PMID:27616044, PMID:22389405, PMID:26780310). These pathways converge on barrier and migration effectors—TFF3 remodels tight junctions by raising claudin-1 and lowering claudin-2, downregulates E-cadherin transcriptionally and post-translationally, and phosphorylates the planar-cell-polarity effector Vangl1 to promote restitution (PMID:17018241, PMID:15177884, PMID:16410243). TFF3 inhibits intrinsic mitochondrial apoptosis by maintaining BCL2 over BAX and blocking cytochrome C/Smac release (PMID:30139961). Its transcription is induced by TLR2 in goblet cells, by HIF-1 under hypoxia, by IL-6/STAT3, and by the transcription factors CDX2 and SPDEF, and is repressed by TNF-α via NF-κB (PMID:19303021, PMID:19076725, PMID:20229017, PMID:17182120, PMID:29555969, PMID:12912861). Beyond the epithelium, TFF3 suppresses hepatic gluconeogenesis downstream of GALE to improve glucose tolerance, and induces NF-κB/COX2-dependent PMN-MDSC activity in immune modulation (PMID:24086476, PMID:28877911, PMID:33547649).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 High

    Establishing the genomic location placed TFF3 within a tightly linked trefoil-peptide gene cluster, framing it as one member of a coordinately organized family.

    Evidence Somatic cell hybrid PCR, FISH, and pulsed-field gel mapping to 21q22.3

    PMID:8641134 PMID:8833157

    Open questions at the time
    • Does not address protein function or regulation
    • No link between physical clustering and coordinate expression
  2. 2001 Medium

    Resolving how TFF3 is released showed its secretion is under enteric nervous and immune control and that luminal TFF3 already exists as a disulfide-linked complex.

    Evidence Isolated vascularly perfused rat colon with pharmacological secretagogues, radioimmunoassay, gel chromatography

    PMID:11495677

    Open questions at the time
    • Identity of the disulfide partner not yet defined
    • Mechanism coupling neural/immune signals to secretion unknown
  3. 2003 Medium

    Demonstrating saturable basolateral binding of dimeric TFF3 to specific cells provided early evidence for a receptor-mediated mode of action distinct for the dimer.

    Evidence Intravenous 125I-TFF3 in rats with autoradiography and cold-ligand displacement

    PMID:12972324

    Open questions at the time
    • Molecular identity of the binding site not determined
    • Functional consequence of binding not tested
  4. 2005 High

    Identifying STAT3 and ERK/NF-κB as effectors connected TFF3 to invasion and inflammatory gene control, establishing it as an upstream activator of these cascades.

    Evidence Phospho-STAT3 western blot, siRNA, pharmacological inhibition, Matrigel invasion, xenograft; NF-κB reporter assays and Twist silencing

    PMID:15665295 PMID:16014704

    Open questions at the time
    • Receptor coupling TFF3 to STAT3/ERK not identified in these studies
    • Crosstalk between the two pathways not yet dissected
  5. 2006 High

    Linking TFF3 to Vangl1 phosphorylation and to claudin remodeling defined concrete effectors for its migratory and barrier-tightening functions.

    Evidence Phosphoproteomics with siRNA/overexpression and wound assays; stable TFF3 expression with claudin westerns and transepithelial resistance

    PMID:16410243 PMID:17018241

    Open questions at the time
    • Kinase phosphorylating Vangl1 not identified
    • Mechanism linking claudin switch to resistance change unresolved
  6. 2009 High

    Showing TLR2 selectively induces goblet-cell TFF3 and that recombinant TFF3 rescues TLR2-deficient mice established TFF3 as the effector of innate-immune-driven mucosal protection.

    Evidence TFF3-/- and TLR2-/- mice, DSS colitis, oral TFF3 rescue, TLR2-R753Q variant wounding assay

    PMID:19303021

    Open questions at the time
    • Signaling between TLR2 and the TFF3 promoter not mapped
    • Receptor mediating the protective TFF3 response not identified here
  7. 2010 High

    Biochemical purification identified FCGBP as the disulfide partner of intestinal TFF3 and showed H2S can liberate active peptide, explaining the storage-and-release logic of mucosal TFF3.

    Evidence Colonic TFF3 purification, LC-ESI-MS/MS, in vitro H2S reduction; parallel rat work showing TFF3-FCGBP-MUC2 heteropolymers disrupted by DTT

    PMID:20423149 PMID:21629776

    Open questions at the time
    • Physiological source/regulation of H2S release unresolved
    • Whether complexed TFF3 is inactive in vivo not established
  8. 2013 Medium

    Defining DMBT1 binding specificity for dimeric TFF3 and revealing a hepatic glucose-lowering function expanded TFF3 partners and physiological scope beyond mucosa.

    Evidence Calcium-dependent ELISA binding with recombinant TFF3 forms; adenoviral Tff3 overexpression in hepatocytes and diabetic/obese mice with GTT/ITT

    PMID:23691218 PMID:24086476

    Open questions at the time
    • DMBT1-TFF3 functional consequence not tested
    • Receptor mediating hepatic glucose effect unidentified
  9. 2016 Medium

    Dissecting receptor and pathway requirements showed CXCR4/CXCR7 are needed for motogenesis while ERK and JAK/STAT3 act in parallel with crosstalk to drive migration and E-cadherin loss.

    Evidence Receptor blocking and migration assays in conjunctival cells; U0126/AG490 inhibition with migration, MMP, and E-cadherin readouts in intestinal cells

    PMID:26780310 PMID:27616044

    Open questions at the time
    • Whether CXCR4/CXCR7 bind TFF3 directly not shown
    • Hierarchy among the multiple converging pathways unresolved
  10. 2021 High

    Identifying LINGO2 and CD147 as receptors gave TFF3 defined surface partners coupling it to EGFR de-repression and to STAT3/COX-2/PGE2 output.

    Evidence Reciprocal co-IP, Lingo2 knockout mice, apoptosis/colitis models (LINGO2); co-IP, NMR mapping, mutagenesis, xenograft (CD147)

    PMID:31562318 PMID:34262017

    Open questions at the time
    • Relative contribution of LINGO2 vs CD147 across tissues not defined
    • Structural basis of receptor selectivity for dimer vs monomer not resolved
  11. 2021 Medium

    Demonstrating TFF3-driven NF-κB/COX2 activation of PMN-MDSCs in a T-cell-dependent manner extended TFF3 function into adaptive-immune-coupled tissue protection.

    Evidence In vitro MDSC induction, NF-κB/COX2 analysis, Rag1 KO adoptive transfer with CD4+ T cell rescue in necrotizing enterocolitis

    PMID:33547649

    Open questions at the time
    • Receptor on MDSCs mediating TFF3 effect unknown
    • Whether this operates in human disease untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single secreted peptide selects among LINGO2, CD147, and CXCR4/CXCR7 to produce opposing oncogenic versus tumor-suppressive outcomes across tissues.
  • No unified model of receptor selection
  • Determinants of pro- vs anti-apoptotic outcome unknown
  • Role of monomer/dimer/complex state in receptor choice not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 4 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2
Partners
CD147CXCR4CXCR7DMBT1EGFRFCGBPLINGO2MUC2
Complex memberships
TFF3-FCGBP heterodimerTFF3-FCGBP-MUC2 heteropolymer

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 TFF3 physically interacts with LINGO2 on the cell membrane of intestinal epithelial cells (co-immunoprecipitation and co-localization), and TFF3-LINGO2 interactions disrupt inhibitory EGFR-LINGO2 complexes, resulting in enhanced EGFR signaling that mediates TFF3's anti-apoptotic and wound healing functions. Co-immunoprecipitation, co-localization, Lingo2 knockout mice, apoptosis assays, colitis and helminth infection models Nature communications High 31562318
2021 CD147 (a membrane protein) was identified as a binding partner for TFF3; TFF3 binding to CD147 enhances CD147-CD44s interaction, leading to STAT3 activation and PTGS2 (COX-2) expression, which drives migration, proliferation, invasion and generates PGE2 that acts via PTGER4. Solution NMR identified key TFF3 residues critical for CD147 binding. Co-immunoprecipitation, competitive inhibitory antibodies, siRNA knockdown, xenograft mouse model, solution NMR Signal transduction and targeted therapy High 34262017
2010 Human intestinal TFF3 exists predominantly as a high-molecular-weight heteromer disulfide-linked to FCGBP (IgG Fc binding protein) in colonic extracts; this complex can be dissociated in vitro by hydrogen sulfide (H2S), releasing biologically active TFF3 monomer/dimer forms. Purification of colonic TFF3, LC-ESI-MS/MS identification of FCGBP as partner, in vitro H2S reduction assay Journal of proteome research High 20423149
2011 Rat TFF3, IgGFcγBP and Muc2 C-terminal domains are bound together by covalent (disulfide) interactions in the soluble fraction of intestinal mucus, forming heteropolymers in both the loose and firm mucus layers; co-immunoprecipitation confirmed these interactions, which are disrupted by DTT. Western blotting under reducing/non-reducing conditions, co-immunoprecipitation, immunostaining PloS one Medium 21629776
2013 DMBT1(gp340) binds specifically to dimeric TFF3 (but not monomeric TFF3, monomeric TFF2 or glycosylated TFF2) in a calcium-dependent manner, as shown by ELISA binding assay. ELISA binding assay with recombinant TFF3 forms, monoclonal antibody characterization PloS one Medium 23691218
2006 Van Gogh-like protein 1 (Vangl1) is Ser/Thr phosphorylated in response to ITF/TFF3 stimulation; Vangl1 overexpression enhances ITF-stimulated wound closure in intestinal epithelial cells, and siRNA knockdown of Vangl1 inhibits the migratory response to ITF, identifying Vangl1 as a downstream effector of TFF3 signaling in mucosal repair. Immunoprecipitation of phosphoproteins + mass spectrometry identification, siRNA knockdown, overexpression, wound closure assays, confocal microscopy The Journal of biological chemistry High 16410243
2005 TFF3 activates STAT3 signaling via Tyr705 phosphorylation of both STAT3α and STAT3β isoforms in colorectal cancer cells; blockade of STAT3 signaling abrogates TFF3-induced cellular invasion, establishing TFF3 as an activator of STAT3-dependent invasion. Western blot for phospho-STAT3, siRNA depletion of STAT3, pharmacological STAT3 inhibition, Matrigel invasion assay, tumor xenograft model Cancer research High 15665295
2005 TFF3 triggers transient NF-κB activation and prolonged upregulation of Twist protein via an ERK kinase-mediated pathway in intestinal epithelial cells, in contrast to TNF-α which causes persistent NF-κB activation and Twist degradation via the proteasome; TFF3-induced Twist prevents IL-8 production downstream of NF-κB. NF-κB reporter assays, western blotting, siRNA silencing of Twist, IL-8 ELISA, pharmacological MEK inhibition American journal of physiology. Cell physiology Medium 16014704
2016 TFF3-induced cell migration in conjunctival epithelial cells requires CXCR4 and CXCR7 (chemokine receptors); blocking CXCR4 and/or CXCR7 completely suppressed TFF3-stimulated migration, while ERK1/2 pathway activation by TFF3 was independent of CXCR4/CXCR7 signaling. X-ray structure-based molecular modeling, flow cytometry, receptor blocking assays, migration assays, western blot for ERK activation Investigative ophthalmology & visual science Medium 26780310
2004 TFF3 reduces E-cadherin levels in intestinal epithelial cells through two distinct mechanisms: transcriptional downregulation of E-cadherin (shown by RT-PCR) and increased E-cadherin degradation (shown by pulse-chase experiments), with concomitant reduction of α- and β-catenin levels. FLAG-hTFF3 stable transfection, multiplex RT-PCR, methylation-specific PCR, pulse-chase experiments Peptides Medium 15177884
2006 TFF3 expression in stably transfected HT29/B6 and MDCK cells increases claudin-1 levels, decreases claudin-2 levels, and increases transepithelial resistance in confluent monolayers, indicating TFF3 regulates intestinal barrier function by altering tight junction claudin composition. Stable transfection of FLAG-hTFF3, western blotting for claudins and tight junction proteins, transepithelial resistance measurement Peptides Medium 17018241
2001 TFF3 secretion from the isolated vascularly perfused rat colon is induced by bethanechol, VIP, bombesin, IL-1β, and degranulator compound bromolasalocid, but not by somatostatin, neurotensin, or PYY, indicating TFF3 release is regulated by the enteric nervous system and resident immune cells; colonic TFF3 is present in a disulfide-linked complex in luminal effluent. Isolated vascularly perfused rat colon preparation, radioimmunoassay, gel chromatography Regulatory peptides Medium 11495677
2003 TNF-α reduces TFF3 expression up to 10-fold in colonic tumor cells via NF-κB activation; NF-κB directly represses TFF3 transcription as shown by reporter gene assays, and this repression is reversible by IκB overexpression; in vivo, increased NF-κB expression in colitis coincides with reduced TFF3. Quantitative real-time PCR, reporter gene assays with NF-κB subunit overexpression and IκB co-expression, immunohistochemistry in rat colitis model Gut Medium 12912861
2008 Hypoxia-inducible factor-1 (HIF-1) mediates induction of TFF3 (and TFF1, TFF2) gene expression by hypoxia in gastric epithelial cells; siRNA knockdown of HIF-1α reduced TFF induction by hypoxia, and overexpression of HIF-1α in non-hypoxic cells induced TFF gene expression and transactivated a TFF1 reporter construct. HIF-1α siRNA transfection, HIF-1α overexpression, TFF1 reporter assay, qRT-PCR, in vivo aspirin-treated rat gastric damage model with hypoxyprobe immunostaining British journal of pharmacology Medium 19076725
2010 IL-6 induces TFF3 expression in human biliary epithelial cells via STAT3 phosphorylation; STAT3 siRNA knockdown abrogates IL-6-induced TFF3 expression and cell migration, and exogenous TFF3 rescues migration defects caused by STAT3 silencing, placing TFF3 downstream of IL-6/STAT3 in a wound healing pathway. siRNA knockdown of STAT3, western blot for phospho-STAT3, RT-PCR, in vitro wound healing assay, rescue with exogenous TFF3 Molecular biology reports Medium 20229017
2006 CDX2 transcriptionally activates TFF3; CDX2 overexpression significantly upregulates TFF3 reporter gene transcription, EMSA identified at least two CDX-binding sites in the TFF3 promoter (with the proximal site at -63 being most important), and CDX2 stable transfection increased endogenous TFF3 mRNA. Transient transfection reporter assays, EMSA, deletion analysis, stable transfection with qRT-PCR for endogenous TFF3 Regulatory peptides Medium 17182120
2016 TFF3 (ITF) simultaneously activates ERK and JAK/STAT3 signaling pathways in intestinal epithelial cells, with crosstalk between the two pathways; MEK inhibitor U0126 and JAK inhibitor AG490 each abolished TFF3-induced cell migration, MMP2/MMP9 upregulation, and E-cadherin degradation. Western blot for phospho-ERK and phospho-STAT3, pharmacological inhibition (U0126, AG490), Transwell migration assay, qRT-PCR for MMPs, immunofluorescence for E-cadherin Scientific reports Medium 27616044
2009 TFF3 signals through MAPK (JNK, p38, ERK1/2) and PI3K/PKB pathways in oral keratinocytes, as detected by phosphoprotein array; TFF3 stimulation induces changes in genes related to cell survival, growth/proliferation, and migration including transient upregulation of FOS and MYCBP2. Phosphoprotein array, mRNA microarray, RT-PCR validation European journal of oral sciences Low 19758246
2005 PI3-K/Akt pathway promotes TFF3 expression and MUC2 expression during intestinal goblet cell differentiation; pharmacological PI3-K inhibition (LY294002) profoundly reduced TFF3 and MUC2 expression and mucin granule content, while MEK inhibition did not affect differentiation. PI3-K activity assay, LY294002 and PD98059 pharmacological inhibition, RT-PCR, Northern blot, RIA, dominant negative STAT6 transfection Differentiation; research in biological diversity Medium 15733066
2013 Overexpression of Tff3 in primary mouse hepatocytes inhibited gluconeogenic gene expression (G6pc, PEPCK, PGC-1α) and decreased glucose output; adenovirus-mediated Tff3 overexpression in diabetic/obese mice improved glucose tolerance and insulin sensitivity. Adenovirus-mediated overexpression in primary hepatocytes and in vivo, glucose tolerance test (GTT), insulin tolerance test (ITT), gene expression analysis PloS one Medium 24086476
2017 Hepatic GALE overexpression impairs glucose tolerance via downregulation of Tff3; restoration of Tff3 expression in GALE-overexpressing mice corrected glucose intolerance, placing Tff3 downstream of GALE in a hepatic glucose homeostasis pathway. Inducible tissue-specific mouse model, transcriptional profiling, Tff3 restoration rescue experiment, glucose tolerance tests Diabetes Medium 28877911
2003 Injected radiolabeled TFF3 dimer (but not monomer to the same extent in the stomach) binds specifically to TFF2-immunoreactive cells in the gastrointestinal tract at basolateral sites with receptor-like activity; binding is saturable (displaced by excess unlabeled TFF3) and distinct from TFF1/TFF3-immunoreactive cells. Intravenous injection of 125I-TFF3 in rats, gamma counting, autoradiography, displacement with excess unlabeled peptide, TCA precipitation Regulatory peptides Medium 12972324
2007 TFF3 and EGF induce different cell migration patterns in intestinal epithelial cells: TFF3 promotes collective sheet migration with continuous coverage, while EGF induces network-like migration with gaps; both treatments trigger E-cadherin internalization/recycling. Scratch wound assay, time-lapse video microscopy, morphometry, immunocytochemistry/confocal microscopy Cellular physiology and biochemistry Medium 17762162
2019 TFF3 exerts oncogenic function in lung adenocarcinoma through upregulation of ARAF and enhanced downstream activation of MEK1/2 and ERK1/2; pharmacological inhibition of TFF3 dimerization (AMPC) combined with MEK1/2 inhibitors showed synergistic growth inhibition. Forced expression and siRNA depletion, western blot for ARAF/MEK/ERK, xenograft mouse model, small-molecule inhibitor (AMPC) Oncogenesis Medium 31685806
2018 TFF3 silencing in prostate cancer cells decreased BCL2, increased BAX, induced BAX translocation to mitochondria, elevated cytochrome C and Smac/DIABLO release, and activated caspase-3, -9 and PARP cleavage, demonstrating TFF3 blocks mitochondria-mediated (intrinsic) apoptosis. siRNA silencing of TFF3, western blot for BCL2/BAX/cytochrome C/Smac/caspases, mitochondrial fractionation, flow cytometry for apoptosis Experimental & molecular medicine Medium 30139961
2017 TFF3 mediates resistance to TNF-α/IFN-γ-induced apoptosis in colorectal adenocarcinoma cells via PI3K/AKT-dependent downregulation of miR-491-5p, which results in accumulation of lncRNA PRINS; PRINS co-localizes with and immunoprecipitates with PMAIP1 (NOXA), inhibiting apoptosis. siRNA gain/loss-of-function, pharmacological PI3K/AKT inhibition, immunoprecipitation of lncRNA-protein complex, miRNA and lncRNA profiling Cell death discovery Medium 28149533
2019 TFF3 overexpression in retinoblastoma cells activates p53, induces miR-34a, and reduces EMP1 expression; caspase-3-dependent apoptosis is triggered by TFF3, and EMP1 knockdown phenocopies TFF3-mediated growth suppression, placing TFF3 upstream of p53/miR-34a/EMP1 in a tumor suppressive pathway in retinoblastoma. pG13-luciferase reporter assay for p53, western blot, WST-1/BrdU/DAPI assays, caspase inhibition, CAM assay International journal of molecular sciences Medium 31450568
2012 TFF3 activates Akt by phosphorylation of EGFR in colonic epithelial cells infected with Shigella dysenteriae; TFF3-activated Akt phosphorylates/inactivates GSK-3β, preventing β-catenin ubiquitylation and promoting its nuclear translocation, which induces MUC5AC and cyclin D1 expression; TFF3 also downregulates E-cadherin. Western blot for EGFR phosphorylation and downstream signaling, β-catenin localization, mRNA/protein expression in HT29MTX cells Journal of cell science Medium 22389405
2021 TFF3 activates NF-κB/COX2 signaling to induce PMN-MDSC activation; prostaglandin E2 is a major TFF3-mediated MDSC target; TFF3-derived PMN-MDSCs attenuate necrotizing enterocolitis in a T-cell-dependent manner (NEC severity was not reduced in Rag1 KO mice given TFF3-MDSCs, but was rescued by co-injection with CD4+ T cells). In vitro MDSC induction assays, NF-κB/COX2 pathway analysis, Rag1 KO mouse adoptive transfer, CD4+ T cell co-injection rescue European journal of immunology Medium 33547649
2018 TFF3 contributes to EMT in papillary thyroid carcinoma cells by activating the MAPK/ERK signaling pathway, affecting Snail and Slug transcription factor expression and altering E-cadherin/N-cadherin levels; TFF3 knockdown inhibited proliferation, adhesion, colony formation, migration and invasion of TPC-1 cells. shRNA knockdown, western blot, qRT-PCR, wound-healing, Transwell invasion assays, IHC in clinical specimens Journal of Cancer Low 30519349
2017 TFF3 negatively regulates HER2 signaling in HER2+/ER+ breast cancer cells; HER2 activation decreases TFF3 expression, trastuzumab treatment increases TFF3 expression partially in an ERα-independent manner, and forced TFF3 expression activates all HER family receptors (HER1-4), suggesting a feedback loop. Western blot, siRNA depletion, small molecule TFF3 inhibitor, trastuzumab treatment, HER receptor phosphorylation analysis Oncotarget Medium 29088778
2019 Human salivary TFF3 exists in high-molecular-mass form as a heterodimer with FCGBP and in low-molecular-mass forms as homodimeric TFF3 and a C-terminally truncated form, as characterized by FPLC and proteomics. Fast protein liquid chromatography (FPLC), proteomics/mass spectrometry International journal of molecular sciences Medium 31658587
2009 TLR2 activation selectively induces TFF3 synthesis in goblet cells; the colitis-associated TLR2-R753Q variant is functionally deficient in inducing TFF3 synthesis, leading to impaired wound healing; recombinant TFF3 rescues TLR2-deficient mice from increased morbidity/mortality during colonic injury, demonstrating TFF3 as the effector of TLR2-mediated mucosal protection. Quantitative RT-PCR, western blotting, confocal microscopy, TFF3-/- and TLR2-/- mice, DSS colitis model, oral TFF3 rescue treatment, TLR2-R753Q overexpression and wounding assay in Caco-2 cells Gastroenterology High 19303021
2015 TFF3 forced expression in mammary carcinoma cells promotes HUVEC proliferation, survival, invasion and tubule formation (angiogenesis) both directly and indirectly via STAT3-mediated IL-8 transcription; antibody inhibition of IL-8 or inhibition of its receptor CXCR2 partially abrogated TFF3-stimulated HUVEC angiogenesis; STAT3 depletion partially diminished TFF3's angiogenic capability. Forced TFF3 expression, siRNA depletion, HUVEC co-culture angiogenesis assays, IL-8 antibody neutralization, CXCR2 inhibition, STAT3 siRNA, in vivo tumor microvessel density PloS one Medium 26559818
1996 The TFF3 gene (hITF) maps to chromosome 21q22.3, tightly linked to TFF1 (pS2/BCEI) and TFF2 (hSP/SML1) genes, as determined by somatic cell hybrid panel mapping and fluorescence in situ hybridization with pulsed-field gel electrophoresis. Somatic cell hybrid panel PCR, FISH, pulsed-field gel electrophoresis Genomics High 8641134 8833157
2018 SPDEF transcription factor directly binds the TFF3 promoter and regulates TFF3 expression; nucleotide treatment of intestinal epithelial cells induces SPDEF expression and downstream TFF3, which activates PI3K/Akt, ERK1/2, p38, and JAK/STAT pathways to improve intestinal barrier function. Chromatin immunoprecipitation (ChIP) for SPDEF-TFF3 promoter binding, siRNA, western blot, TER measurement Scientific reports Medium 29555969

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency. Gastroenterology 187 19303021
2002 ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with beta-catenin defects and promotes neoplastic transformation. Cancer cell 129 12086873
2019 Exosomes Derived from miR-143-Overexpressing MSCs Inhibit Cell Migration and Invasion in Human Prostate Cancer by Downregulating TFF3. Molecular therapy. Nucleic acids 110 31563120
1999 Localization of TFF3, a new mucus-associated peptide of the human respiratory tract. American journal of respiratory and critical care medicine 100 10194185
2002 Expression of trefoil peptides (TFF1, TFF2, and TFF3) in gastric carcinomas, intestinal metaplasia, and non-neoplastic gastric tissues. The Journal of pathology 99 12210076
2010 Human intestinal TFF3 forms disulfide-linked heteromers with the mucus-associated FCGBP protein and is released by hydrogen sulfide. Journal of proteome research 86 20423149
2005 Implication of STAT3 signaling in human colonic cancer cells during intestinal trefoil factor 3 (TFF3) -- and vascular endothelial growth factor-mediated cellular invasion and tumor growth. Cancer research 84 15665295
2001 Id-1, ITF-2, and Id-2 comprise a network of helix-loop-helix proteins that regulate mammary epithelial cell proliferation, differentiation, and apoptosis. The Journal of biological chemistry 84 11498533
1999 The trefoil peptides TFF2 and TFF3 are expressed in rat lymphoid tissues and participate in the immune response. FEBS letters 82 10452549
2001 Augmented intestinal trefoil factor (TFF3) and loss of pS2 (TFF1) expression precedes metaplastic differentiation of gastric epithelium. Laboratory investigation; a journal of technical methods and pathology 81 11310832
2019 TFF3 interacts with LINGO2 to regulate EGFR activation for protection against colitis and gastrointestinal helminths. Nature communications 76 31562318
2012 TFF3 is a normal breast epithelial protein and is associated with differentiated phenotype in early breast cancer but predisposes to invasion and metastasis in advanced disease. The American journal of pathology 72 22341453
2013 Gut-associated biomarkers L-FABP, I-FABP, and TFF3 and LIT score for diagnosis of surgical necrotizing enterocolitis in preterm infants. Annals of surgery 71 23470582
1998 Primary mucinous carcinomas of the skin express TFF1, TFF3, estrogen receptor, and progesterone receptors. The American journal of surgical pathology 64 9737246
2003 Tumour necrosis factor alpha and nuclear factor kappaB inhibit transcription of human TFF3 encoding a gastrointestinal healing peptide. Gut 63 12912861
2008 Induction of trefoil factor (TFF)1, TFF2 and TFF3 by hypoxia is mediated by hypoxia inducible factor-1: implications for gastric mucosal healing. British journal of pharmacology 62 19076725
1996 A splice variant of the ITF-2 transcript encodes a transcription factor that inhibits MyoD activity. The Journal of biological chemistry 59 8631961
2021 CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression. Signal transduction and targeted therapy 57 34262017
1999 Secretory peptides TFF1 and TFF3 synthesized in human conjunctival goblet cells. Investigative ophthalmology & visual science 57 10476786
2008 Intestinal trefoil factor/TFF3 promotes re-epithelialization of corneal wounds. The Journal of biological chemistry 55 18326859
2002 Expression of TFF1, TFF2 and TFF3 in gastric cancer. International journal of oncology 53 12168114
2013 Circulating serum trefoil factor 3 (TFF3) is dramatically increased in chronic kidney disease. PloS one 52 24282531
2004 A gradient of TFF3 (trefoil factor family 3) peptide synthesis within the normal human gastric mucosa. Cell and tissue research 52 14968359
2010 IL-6/STAT3/TFF3 signaling regulates human biliary epithelial cell migration and wound healing in vitro. Molecular biology reports 50 20229017
1999 Temporal changes in TFF3 expression and jejunal morphology during methotrexate-induced damage and repair. The American journal of physiology 49 10516144
2005 Frequent trefoil factor 3 (TFF3) overexpression and promoter hypomethylation in mouse and human hepatocellular carcinomas. International journal of oncology 48 15645121
2004 TIMP1 and SERPIN-A overexpression and TFF3 and CRABP1 underexpression as biomarkers for papillary thyroid carcinoma. Head & neck 48 15515157
2015 TFF3 is a valuable predictive biomarker of endocrine response in metastatic breast cancer. Endocrine-related cancer 47 25900183
2017 Serum TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer. Scientific reports 46 28687783
2006 TFF3-peptide increases transepithelial resistance in epithelial cells by modulating claudin-1 and -2 expression. Peptides 46 17018241
2013 A variant form of the human deleted in malignant brain tumor 1 (DMBT1) gene shows increased expression in inflammatory bowel diseases and interacts with dimeric trefoil factor 3 (TFF3). PloS one 45 23691218
2007 TFF3 and EGF induce different migration patterns of intestinal epithelial cells in vitro and trigger increased internalization of E-cadherin. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 44 17762162
2020 LINC00160 mediated paclitaxel-And doxorubicin-resistance in breast cancer cells by regulating TFF3 via transcription factor C/EBPβ. Journal of cellular and molecular medicine 43 32652877
2020 Urinary I-FABP, L-FABP, TFF-3, and SAA Can Diagnose and Predict the Disease Course in Necrotizing Enterocolitis at the Early Stage of Disease. Journal of immunology research 39 32190704
2016 CXCR4 and CXCR7 Mediate TFF3-Induced Cell Migration Independently From the ERK1/2 Signaling Pathway. Investigative ophthalmology & visual science 39 26780310
2006 Vangl1 protein acts as a downstream effector of intestinal trefoil factor (ITF)/TFF3 signaling and regulates wound healing of intestinal epithelium. The Journal of biological chemistry 39 16410243
2001 ITF expression in mouse brain during acquisition of alcohol self-administration. Brain research 39 11164784
2008 Quantitative analysis of the effect of Helicobacter pylori on the expressions of SOX2, CDX2, MUC2, MUC5AC, MUC6, TFF1, TFF2, and TFF3 mRNAs in human gastric carcinoma cells. Scandinavian journal of gastroenterology 38 18938748
2012 Differential expression of gastric MUC5AC in colonic epithelial cells: TFF3-wired IL1 β/Akt crosstalk-induced mucosal immune response against Shigella dysenteriae infection. Journal of cell science 36 22389405
2018 TFF3 Contributes to Epithelial-Mesenchymal Transition (EMT) in Papillary Thyroid Carcinoma Cells via the MAPK/ERK Signaling Pathway. Journal of Cancer 35 30519349
2015 Trefoil factor 3 (TFF3) enhances the oncogenic characteristics of prostate carcinoma cells and reduces sensitivity to ionising radiation. Cancer letters 35 25748388
2013 Tff3, as a novel peptide, regulates hepatic glucose metabolism. PloS one 34 24086476
2005 TFF3 modulates NF-{kappa}B and a novel negative regulatory molecule of NF-{kappa}B in intestinal epithelial cells via a mechanism distinct from TNF-{alpha}. American journal of physiology. Cell physiology 34 16014704
1996 The gene encoding human intestinal trefoil factor (TFF3) is located on chromosome 21q22.3 clustered with other members of the trefoil peptide family. Genomics 34 8833157
2015 Trefoil Factor 3 (TFF3) Is Regulated by Food Intake, Improves Glucose Tolerance and Induces Mucinous Metaplasia. PloS one 33 26083576
2015 Trefoil Factor-3 (TFF3) Stimulates De Novo Angiogenesis in Mammary Carcinoma both Directly and Indirectly via IL-8/CXCR2. PloS one 33 26559818
2017 Overexpression of trefoil factor 3 (TFF3) contributes to the malignant progression in cervical cancer cells. Cancer cell international 32 28070169
2017 Hepatic GALE Regulates Whole-Body Glucose Homeostasis by Modulating Tff3 Expression. Diabetes 32 28877911
2015 Clinical value of ERG, TFF3, and SPINK1 for molecular subtyping of prostate cancer. Cancer 32 25639219
2013 ER+ /PR+ /TFF3+ /IMP3- immunoprofile distinguishes endometrioid from serous and clear cell carcinomas of the endometrium: a study of 401 cases. Histopathology 32 23570281
2004 Molecular mechanisms involved in TFF3 peptide-mediated modulation of the E-cadherin/catenin cell adhesion complex. Peptides 32 15177884
2018 Glycolytic inhibitor 2-Deoxy-d-Glucose activates migration and invasion in glioblastoma cells through modulation of the miR-7-5p/TFF3 signaling pathway. Biochemical and biophysical research communications 28 29621542
2016 ITF promotes migration of intestinal epithelial cells through crosstalk between the ERK and JAK/STAT3 pathways. Scientific reports 28 27616044
2014 Trefoil factor family peptide 3 (TFF3) is upregulated under experimental conditions similar to dry eye disease and supports corneal wound healing effects in vitro. Investigative ophthalmology & visual science 28 24713479
2011 The rat IgGFcγBP and Muc2 C-terminal domains and TFF3 in two intestinal mucus layers bind together by covalent interaction. PloS one 28 21629776
2007 Localization of TFF3 peptide in human esophageal submucosal glands and gastric cardia: differentiation of two types of gastric pit cells along the rostro-caudal axis. Cell and tissue research 28 17216196
2003 Injected TFF1 and TFF3 bind to TFF2-immunoreactive cells in the gastrointestinal tract in rats. Regulatory peptides 28 12972324
2013 Trefoil factor family 3 (TFF3) expression and its interaction with estrogen receptor (ER) in endometrial adenocarcinoma. Gynecologic oncology 27 23578537
2012 TFF3 and survivin expressions associate with a lower survival rate in gastric cancer. Clinical and experimental medicine 27 22996285
2010 Butyrate enemas do not affect human colonic MUC2 and TFF3 expression. European journal of gastroenterology & hepatology 27 20461009
2019 Different Forms of TFF3 in the Human Saliva: Heterodimerization with IgG Fc Binding Protein (FCGBP). International journal of molecular sciences 26 31658587
2006 Effects of Trichinella spiralis infection on intestinal pathology in mice lacking interleukin-4 (IL-4) or intestinal trefoil factor (ITF/TFF3). Parasitology international 26 16814598
2018 Overexpression of TFF3 is involved in prostate carcinogenesis via blocking mitochondria-mediated apoptosis. Experimental & molecular medicine 25 30139961
2008 TFF3-based candidate gene discrimination of benign and malignant thyroid tumors in a region with borderline iodine deficiency. The Journal of clinical endocrinology and metabolism 25 18198227
2019 Inhibition of TFF3 Enhances Sensitivity-and Overcomes Acquired Resistance-to Doxorubicin in Estrogen Receptor-Positive Mammary Carcinoma. Cancers 24 31658702
1996 A third P-domain peptide gene (TFF3), human intestinal trefoil factor, maps to 21q22.3. Cytogenetics and cell genetics 24 8641134
2019 A novel small-molecule inhibitor of trefoil factor 3 (TFF3) potentiates MEK1/2 inhibition in lung adenocarcinoma. Oncogenesis 23 31685806
2019 Role of TFF3 as an adjunct in the diagnosis of Barrett's esophagus using a minimally invasive esophageal sampling device-The CytospongeTM. Diagnostic cytopathology 23 31814330
2007 Cellular localization, binding sites, and pharmacologic effects of TFF3 in experimental colitis in mice. Digestive diseases and sciences 23 17342398
2005 Expression of intestinal trefoil factor (TFF-3) in hepatocellular carcinoma. International journal of gastrointestinal cancer 23 16110118
2019 Pharmacological Inhibition of TFF3 Enhances Sensitivity of CMS4 Colorectal Carcinoma to 5-Fluorouracil through Inhibition of p44/42 MAPK. International journal of molecular sciences 22 31835445
2006 Regulation of TFF3 expression by homeodomain protein CDX2. Regulatory peptides 22 17182120
2001 Secretion of the trefoil factor TFF3 from the isolated vascularly perfused rat colon. Regulatory peptides 22 11495677
2022 iDRNA-ITF: identifying DNA- and RNA-binding residues in proteins based on induction and transfer framework. Briefings in bioinformatics 21 35709747
2021 TFF3 mediates the NF-κB/COX2 pathway to regulate PMN-MDSCs activation and protect against necrotizing enterocolitis. European journal of immunology 21 33547649
2017 TFF3-dependent resistance of human colorectal adenocarcinoma cells HT-29/B6 to apoptosis is mediated by miR-491-5p regulation of lncRNA PRINS. Cell death discovery 21 28149533
2016 DcR3, TFF3, and Midkine Are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors. Neuroendocrinology 21 27829249
2014 TFF3 and HER2 expression and their correlation with survival in gastric cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 21 25514872
2013 Significance of TFF3 protein and Her-2/neu status in patients with gastric adenocarcinoma. Pathology, research and practice 21 23822993
2011 TFF3 mediated induction of VEGF via hypoxia in human gastric cancer SGC-7901 cells. Molecular biology reports 21 21769478
2017 MicroRNA‑7‑5p regulates the expression of TFF3 in inflammatory bowel disease. Molecular medicine reports 20 28627600
2014 Serum TFF3 may be a pharamcodynamic marker of responses to chemotherapy in gastrointestinal cancers. BMC clinical pathology 20 25031551
2007 Expression of TFF3 during multistep colon carcinogenesis. Histology and histopathology 20 17455148
2017 Release of HER2 repression of trefoil factor 3 (TFF3) expression mediates trastuzumab resistance in HER2+/ER+ mammary carcinoma. Oncotarget 19 29088778
2015 Differential regional and cellular distribution of TFF3 peptide in the human brain. Amino acids 19 25691144
2009 Signal transduction and gene transcription induced by TFF3 in oral keratinocytes. European journal of oral sciences 19 19758246
2008 Trefoil factor 3 (TFF3): a promising indicator for diagnosing thyroid follicular carcinoma. Endocrine journal 19 18506086
2014 Tff3 is expressed in neurons and microglial cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 18 25504043
2009 ITF-2 is disrupted via allelic loss of chromosome 18q21, and ITF-2B expression is lost at the adenoma-carcinoma transition. Gastroenterology 18 19394332
2005 Expression of human TFF3 in relation to growth of HT-29 cell subpopulations: involvement of PI3-K but not STAT6. Differentiation; research in biological diversity 18 15733066
2002 Coordinate late expression of trefoil peptide genes (pS2/TFF1 and ITF/TFF3) in human breast, colon, and gastric tumor cells exposed to X-rays. Molecular cancer therapeutics 18 12477053
2000 Analysis of the inhibition of MyoD activity by ITF-2B and full-length E12/E47. The Journal of biological chemistry 17 10833525
2019 p53, miR-34a and EMP1-Newly Identified Targets of TFF3 Signaling in Y79 Retinoblastoma Cells. International journal of molecular sciences 16 31450568
2000 ITF mapping after drugs of abuse: pharmacological versus perceptional effects. Acta neurobiologiae experimentalis 16 11200183
1999 Cyclic pentapeptides of chiral sequence DLDDL as scaffold for antagonism of G-protein coupled receptors: synthesis, activity and conformational analysis by NMR and molecular dynamics of ITF 1565 a substance P inhibitor. Biopolymers 16 10380345
1993 Chemical and biological characterization of iron-protein succinylate (ITF 282). International journal of clinical pharmacology, therapy, and toxicology 16 8444516
2023 Small molecule inhibition of TFF3 overcomes tamoxifen resistance and enhances taxane efficacy in ER+ mammary carcinoma. Cancer letters 15 37858772
2003 Ontogeny and prenatal expression of trefoil factor 3/ITF in the human intestine. Early human development 15 12663147
2018 Nucleotide-mediated SPDEF modulates TFF3-mediated wound healing and intestinal barrier function during the weaning process. Scientific reports 14 29555969
2016 Forced Trefoil Factor Family Peptide 3 (TFF3) Expression Reduces Growth, Viability, and Tumorigenicity of Human Retinoblastoma Cell Lines. PloS one 14 27626280

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