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

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.

Trefoil factors share a lectin activity that defines their role in mucus

The trefoil factors (TFFs) are disulfide-rich mucosal peptides that protect the epithelium by promoting cell migration and increasing the viscoelasticity of the mucosa. Here we show that all TFFs are divalent lectins that recognise the GlcNAc-α-1,4-Gal disaccharide, which terminates type-III mucin-like O-glycans. Structural, mutagenic and biophysical data support a model of mucus viscoelasticity that features non-covalent cross-linking of glycoproteins by TFFs.

Deoxynivalenol Inhibits Porcine Intestinal Trefoil Factors Expression in Weanling Piglets and IPEC-J2 Cells

Trefoil factors (TFFs) are regulatory peptides playing critical roles in mucosal repair and protection against a variety of insults within the gastrointestinal tract. This work aimed to explore the effects of deoxynivalenol (DON) on intestinal TFFs expression using in vivo and in vitro models. In an animal trial, twenty-four 28-d-old barrows (Duroc × Landrace × Large White; initial body weight = 7.6 ± 0.7 kg) were randomly divided into three treatments for 28 days, including a control diet (0.61 mg DON/kg feed), and two levels of DON-contaminated diets containing 1.28 and 2.89 mg DON/kg feed, respectively. Piglets exposed to DON had lower mRNA expression of TFF1, TFF2, TFF3, as well as Claudin-4 in the intestine (P < 0.05). Dietary DON exposure decreased the protein levels of TFF2 and TFF3 in the jejunum as demonstrated by western blot and immunohistochemistry. In intestinal porcine epithelial cells (IPEC-J2), DON depressed the mRNA expression of TFF2, TFF3, and Claudin-4. Overexpression of sterile alpha motif (SAM) pointed domain E26 transformation‐specific (ETS) factor (SPDEF) was found to attenuate DON-induced suppression of TFFs in IPEC-J2 cells. Altogether, our work shows, for the first time, that dietary DON exposure depresses the expression of intestinal TFFs in piglets. Given the fundamental role of TFFs in intestinal mucosal homeostasis, our observations indicate that the DON content in animal feed should be strictly controlled based on the existing regulation for DON.