Disease relevance of TFF3

• Taken together, our data suggest that TFF3 and the essential tumor angiogenesis regulator VEGF(165) exert potent proinvasive activity through STAT3 signaling in human colorectal cancer cells [1].
• TFF3 appears also as a component of the mucus, for example from patients with chronic bronchitis [2].
• Cutaneous mucinous carcinoma shows strong similarities to its mammary counterpart, including expression of estrogen receptor, TFF1, and TFF3 mRNA [3].
• TFF3 was down-regulated in 2 out of 12 cases (16.7%) of primary gastric cancer, and was up-regulated in 5 out of 12 cases (41.7%) [4].
• TFF1, TFF2 and TFF3 proteins might be applicable for chemoprevention of gastrointestinal cancer associated with chronic persistent inflammation [5].

Psychiatry related information on TFF3

• CONCLUSIONS: Cell proliferation, as measured by the Ki-67 LI at the ITF, has a positive relationship with clinical staging, tumour thickness, smoking status of the patient and alcohol consumption [6].

High impact information on TFF3

• Induction of ITF and sucrase-isomaltase after MEK inhibition in HT29-N2 cells did not involve loss of MAP kinase responsiveness and was not mediated by receptor tyrosine kinases [7].
• Conversely, mucin glycoproteins isolated from the rat colon or stomach facilitated protection when added with human spasmolysin or human intestinal trefoil factor [8].
• Three distinct members of the family (pS2, intestinal trefoil factor, and spasmolytic polypeptide) are produced in the mammalian gastrointestinal tract by mucus-secreting cells and targeted primarily for luminal secretion [9].
• TFF3 has been shown to promote migration of intestinal epithelial cells in vitro and to enhance mucosal healing and epithelial restitution in vivo [10].
• Intestinal trefoil factor 3 (TFF3) is a member of the trefoil family of peptides, small molecules constitutively expressed in epithelial tissues, including the gastrointestinal tract [10].

Chemical compound and disease context of TFF3

• In contrast to another trefoil protein, pS2, the expression of ITF/hP1.B is not under control of estrogen in the human breast cancer cell line MCF-7 [11].
• Anti-sense trefoil factor family-3 (intestinal trefoil factor) inhibits cell growth and induces chemosensitivity to adriamycin in human gastric cancer cells [12].

Biological context of TFF3

• The gene encoding human intestinal trefoil factor (TFF3) is located on chromosome 21q22.3 clustered with other members of the trefoil peptide family [13].
• Promoter methylation analyses showed that, in tissues where these genes are normally expressed, the proximal promoters of TFF1 and TFF2 are specifically not methylated and that of TFF3 is partially demethylated [14].
• In a rodent-human somatic cell hybrid panel, the hITF (HGMW-approved symbol TFF3) genomic locus segregated with human chromosome 21q [13].
• TFF3 and BCEI, both containing one trefoil motif, are composed of three exons each, suggesting gene duplication and exon-shuffling events during evolution [15].
• Here, we have systematically investigated TFF3 expression in the esophagus and gastric cardia by the use of reverse transcription/polymerase chain reaction (RT-PCR) analysis and immunohistochemistry [16].

Anatomical context of TFF3

• MUC2 and TFF3 were colocalised throughout the large and small bowel mucosa [17].
• Immunohistochemistry revealed significant accumulation of TFF3 to mucous cells in the acini of submucosal glands and varying amounts in goblet cells at the ductular portions and the surface epithelium [2].
• CONCLUSIONS: This finding in oesophageal carcinoma contrasts with the situation found in normal and neoplastic stomach epithelium where TFF1 and TFF2 are found co-expressed and TFF3 remains silent [18].
• 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 [16].
• This indicates the special requirement, particularly of the esophagogastric junction, for TFF3-triggered protection and repair [16].

Associations of TFF3 with chemical compounds

• TFF3 expression was analyzed by RT-PCR, Northern blot, and radioimmunoassay (RIA) in relation to cell growth in subclones of HT-29 cells including the CL.16E and methotrexate (MTX) cell lines, which both exhibit a phenotype of mucus-secreting intestinal cells [19].
• The core of the trefoil domain in hITF consists of a two-stranded antiparallel beta-sheet (Cys 36 to Asp 39 and Trp 47 to Lys 50), which is capped by an irregular loop and forms a central hairpin (loop 3) [20].
• TFF3 might therefore have important physiological functions in the stomach, e.g. as a luminal surveillance peptide maintaining particularly the integrity of the antral and pyloric mucosa [21].
• TFF3 is a member of the trefoil factor family (TFF) peptides, which enhance the surface integrity of mucous epithelia, and is typically secreted by intestinal goblet cells together with the mucin MUC2 [21].
• TFF1 and TFF3 transcriptional response to X-irradiation differed from that to H2O2 or ES in the timing of their induction as well as tissue-type dependence, i.e., their induction pattern after X-irradiation was late and sustained, whereas their induction by H2O2 or ES was early and transient [22].

Physical interactions of TFF3

• Although only one consensus STAT6 binding site is contained in the TFF3 gene, located in the intron 1, it did not operate as an enhancer in the context of an SV40 promoter/luciferase construct [23].

Co-localisations of TFF3

• TFF3 immunoreactivity was colocalized with insulin and glucagon in distinct cell clusters in human fetal pancreas at wk 14 and in the newborn rat pancreas [24].

Regulatory relationships of TFF3

• These results suggest that TFF3 enhances cell migration through modulation of E-cadherin/catenin complex function [25].
• TFF3 was expressed in the ampulla of Vater. mRNA expression of TFF1 was detected in only approximately 25% of the investigated samples [26].
• Stepwise logistic regression analysis, duplex PCR data evaluation with recursive partition machine algorithm and hierarchical cluster analysis identified SFTPB (upregulated) and TFF3 (downregulated) gene combination as most favorable for differential molecular diagnosis of PTC [27].
• Carbachol, an analog of acetylcholine, and the neuroendocrine peptides somatostatin and vasoactive intestinal polypeptide (VIP) stimulated increased expression of hITF mRNA within 5 min [28].
• CONCLUSION: TFF-3 is commonly expressed in HCC and its expression correlates with tumor grade [29].

Other interactions of TFF3

• Both ITF and SP enhanced restitution of primary rabbit corneal epithelial cells in vitro [30].
• Thus, a structural function of TFF3 for the airway mucus is discussed, possibly together with the mucins MUC5B and MUC5AC [2].
• Three human trefoil peptides have been described: the estrogen-inducible pS2 protein, the spasmolytic protein and the intestinal trefoil factor [15].
• Moreover, stable transfection of HT-29 CL.16E cells with a dominant negative form of STAT6 had no effect on TFF3 induction [19].
• Expression of TFF3 was also shown by use of the polymerase chain reaction [2].

Analytical, diagnostic and therapeutic context of TFF3

• RT-PCR analysis revealed a more complex pattern: TFF1 and TFF3 expressed the corresponding mRNA in all samples investigated; the third member, TFF2, was active in 45.5% of the carcinoma biopsies and not in the corresponding native tissue [18].
• Using in situ hybridization, TFF1 and TFF3 mRNA were predominantly localized in epithelial cells and submucosal glandular epithelium [31].
• TFF1 and TFF3 were specifically localised in the mucus layer of HT-29 MTX cells by confocal microscopy [32].
• A precursor for a human secretory polypeptide has been discovered by molecular cloning and deduced to have a single P-domain, termed hP1.B. The pre-pro-peptide has 67% amino acid identity with rat intestinal trefoil factor [33].
• TFF3 had a gender-specific negative survival advantage, with a 91.3% disease-free survival in female patients with TFF3-negative advanced gastric carcinoma [34].

References