Identification of human intestinal trefoil factor. Goblet cell-specific expression of a peptide targeted for apical secretion.

Podolsky, Daniel K.; Lynch-Devaney, Kathryn; Stow, Jennifer L.; Oates, Philip; Murgue, Bernadette; DeBeaumont, Michelle; Sands, Bruce E.; Mahida, Yashwant R.

doi:10.1016/s0021-9258(18)53305-6

Cited by 234 publications

(22 citation statements)

References 29 publications

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“…Increased expression of TFF peptides is observed after injury in the gastrointestinal tract. 1 , 2 Research suggests that TFF3, which is expressed mainly by intestinal goblet cells, plays an important role in protecting the intestinal mucosa from a variety of injuries and is essential for effective mucosal restitution by facilitating cell migration and inhibiting apoptosis and anoikis. 3 Studies have reported that TFF3 expression is increased during the development and progression of human cancer, including CRC.…”

Section: Introductionmentioning

confidence: 99%

CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression

Cui

Wang

Song

et al. 2021

Sig Transduct Target Ther

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Major gaps in understanding the molecular mechanisms of colorectal cancer (CRC) progression and intestinal mucosal repair have hampered therapeutic development for gastrointestinal disorders. Trefoil factor 3 (TFF3) has been reported to be involved in CRC progression and intestinal mucosal repair; however, how TFF3 drives tumors to become more aggressive or metastatic and how TFF3 promotes intestinal mucosal repair are still poorly understood. Here, we found that the upregulated TFF3 in CRC predicted a worse overall survival rate. TFF3 deficiency impaired mucosal restitution and adenocarcinogenesis. CD147, a membrane protein, was identified as a binding partner for TFF3. Via binding to CD147, TFF3 enhanced CD147-CD44s interaction, resulting in signal transducer and activator of transcription 3 (STAT3) activation and prostaglandin G/H synthase 2 (PTGS2) expression, which were indispensable for TFF3-induced migration, proliferation, and invasion. PTGS2-derived PGE2 bound to prostaglandin E2 receptor EP4 subtype (PTGER4) and contributed to TFF3-stimulated CRC progression. Solution NMR studies of the TFF3-CD147 interaction revealed the key residues critical for TFF3 binding and the induction of PTGS2 expression. The ability of TFF3 to enhance mucosal restitution was weakened by a PTGS2 inhibitor. Blockade of TFF3-CD147 signaling using competitive inhibitory antibodies or a PTGS2 inhibitor reduced CRC lung metastasis in mice. Our findings bring strong evidence that CD147 is a novel receptor for TFF3 and PTGS2 signaling is critical for TFF3-induced mucosal restitution and CRC progression, which widens and deepens the understanding of the molecular function of trefoil factors.

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Section: Introductionmentioning

confidence: 99%

CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression

Cui

Wang

Song

et al. 2021

Sig Transduct Target Ther

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“…Trefoil factors (TFFs) include a family of three mucinassociated peptides secreted by goblet cells in the intestinal mucosa [11]. They have a key role in maintaining mucosal barrier integrity [12] and are up-regulated at the site of mucosal damage [13,14].…”

Section: Introductionmentioning

confidence: 99%

Trefoil Factor 3 is Highly Predictive of Complete Mucosal Healing Independently and in Combination with C-Reactive Protein in Patients with Ulcerative Colitis

Nakov

Velikova

Nakov

et al. 2019

JGLD

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Aim: In the current study we aimed to evaluate the role of trefoil factor 3 (TFF3) as a marker for complete mucosal healing (MH) in patients with ulcerative colitis (UC). Methods: We enrolled 116 consecutive UC patients. Trefoil factor 3 levels were measured by ELISA and were compared to the clinical activity, assessed by Lichtiger Index, fecal calprotectin (FCP) and C-reactive protein (CRP) levels. Colonoscopy was performed in all the patients and the findings were graded according to Mayo endoscopic score (EMS) and UC endoscopic index of severity (UCEIS). Results: Trefoil factor 3 levels were significantly correlated with Lichtiger Index (r=0.736, p<0.001), EMS (r=0.811, p<0.001), UCEIS (r=0.820, p<0.001), FCP (r=0.696, p<0.001) and CRP (r=0.405, p<0.001). The TFF3 cut-off level of 6.74 ng/ml indicated complete MH (EMS=0; UCEIS=0) with a sensitivity and specificity of 0.879 and 0.869, respectively (area under the curve, AUC 0.927; 95% confidence interval, 0.877–0.976). The DeLong’s test revealed no significant difference between the AUC of TFF3+CRP and the AUC of FCP (Z=1.717, p=0.086), AUC of TFF3+FCP (Z=1.908, p=0.056), and AUC of TFF3+CRP+FCPP (Z=1.915, p=0.056). However, the AUC of TFF3+CRP showed significant difference compared with the AUC of TFF3 (Z=2.210, p=0.027) and the AUC of CRP (Z=3.145, p=0.002) for predicting complete MH. Conclusions: Trefoil factor 3 levels correlated significantly with clinical activity, endoscopic indices, CRP and FCP in our patients. TFF3 is a highly predictive marker of complete MH independently and in combination with CRP in patients with UC.

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“…TFF peptides have a stable triple-loop structure that may have apparent resistance to protease hydrolysis, acid digestion, and heat treatment; thus, TFFs can maintain biological activity in the complex environment of the digestive tract [20,21]. Commonly, TFF1 and TFF2 are expressed mainly in the mucosal epithelial cells of the gastric body and antrum, and TFF3 is expressed in goblet cells of the small intestine and the colon [22,23]. However, under pathological conditions, the site-speci c expression of TFFs is absent, and TFFs can be detected in any damaged mucosae as their expression is up-regulated to participate in gastrointestinal epithelial reconstruction and mucosal repair process [24,25].…”

Section: Discussionmentioning

confidence: 99%

Trefoil Factors as Screening Biomarkers for Gastric Cancer and Premalignant Lesions: A Cross-Sectional Population-Based Cohort Study

Zan¹,

Chen²,

Guo³

et al. 2021

Preprint

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Background: The lack of effective biomarkers for screening gastric cancer (GC) and premalignant lesions (PMLs) is a significant roadblock in the prevention and early intervention of GC. We aimed to identify noninvasive biomarkers to improve the screening of high-risk populations. Methods: We evaluated 25,000 adults residing in Wuwei. We collected baseline characteristics, GC risk indicators, including trefoil factors (TFF1–3), endoscopy diagnosis, and pathological information. We analyzed the data to determine the association of risk biomarkers with the progression of GC and the prediction capacities of these biomarkers using odds ratio (OR)-adjusted models and receiver operating characteristic (ROC) curve analyses. Results: TFF1 and TFF2 serum levels showed incremental changes from the PMLs to the GC group, with the highest serum TFF3 levels reported in the intestinal metaplasia group. TFF1 and TFF2 had significant predictive values in the PMLs and GC in the three OR-adjusted models but not in the non-atrophic gastritis group. Similar results were obtained after adjusting for all biomarkers and risk factors wherein the ORs (95 % confidence intervals) of TFF1 and TFF2 in the GC group were 2.71 (1.57–4.67) and 2.87 (1.75–4.71), respectively (P < 0.001). The combination of TFF1–3 showed the largest area under the curve across all four groups (chronic atrophic gastritis [0.74], intestinal metaplasia [0.79], low-grade intraepithelial neoplasia/dysplasia [0.79], and GC [0.84]), making it the best-fit ROC. Conclusions: TFF1, TFF2, and the combination of TFF1–3 can serve as sensitive, specific, and noninvasive biomarkers for detecting GC and PMLs, facilitating the early identification of these lesions.

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Identification of human intestinal trefoil factor. Goblet cell-specific expression of a peptide targeted for apical secretion.

Cited by 234 publications

References 29 publications

CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression

CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression

Trefoil Factor 3 is Highly Predictive of Complete Mucosal Healing Independently and in Combination with C-Reactive Protein in Patients with Ulcerative Colitis

Trefoil Factors as Screening Biomarkers for Gastric Cancer and Premalignant Lesions: A Cross-Sectional Population-Based Cohort Study

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