Trefoil Factor Peptides in Gastrointestinal Oncology

Trefoil factor peptides constitute a small family of secreted proteins, TFF1, TFF2 and TFF3, which play pivotal roles in maintaining gastrointestinal mucosal integrity through promotion of epithelial restitution, modulation of immune responses and lectin-mediated binding to glycan structures. In benign mucosa, these peptides support rapid repair of injury and contribute to barrier function. Emerging evidence has revealed dualistic roles for TFF1 and TFF3 in gastrointestinal oncology. TFF1 functions as a gastric tumour suppressor through regulation of pro-inflammatory signalling and activation of p53-dependent pathways, whereas aberrant expression or silencing can drive STAT3-mediated neoplastic transformation. Conversely, TFF3 is frequently upregulated in advanced lesions, where it can enhance cell migration, invasion and metastasis by engaging receptor tyrosine kinases and modulating cancer stem-like phenotypes. Beyond individual activities, TFF peptides form homo- and heterodimers, for instance with FCGBP or gastrokine-2, influencing mucin stability and innate immunity. Lectin activities enable specific carbohydrate interactions that may dictate localisation and receptor binding, linking mucosal protection to tumour progression. Collectively, TFF peptides represent a nexus between homeostatic repair mechanisms and tumourigenic signalling pathways, underscoring their potential as biomarkers and therapeutic targets in gastrointestinal cancer. Practical applications under investigation include peptide delivery systems for mucosal healing and targeted inhibitors to counteract pro-oncogenic activities.

Research from Nature Portfolio

Loss of TFF1 expression has been shown to precipitate a pro-inflammatory cascade in gastric epithelium through unchecked IL-6-STAT3 signalling, driving low-grade dysplasia towards adenocarcinoma. Restoration of TFF1 in model organoids and cancer cell lines disrupts formation of the IL-6Rα–GP130 receptor complex, suppresses STAT3 phosphorylation and abrogates transcription of pro-tumourigenic gene sets. This work provides mechanistic clarity on how TFF1 silencing contributes to gastric neoplasia and highlights the IL-6–STAT3 axis as a targetable vulnerability in TFF1-deficient tumours.

Trefoil Factor Peptides in Gastrointestinal Oncology publication trend

The graph below shows the total number of articles in trefoil factor peptides in gastrointestinal oncology across all publications each year (not limited to Nature Index journals).

Technical terms

Trefoil factor peptides: A family of small secreted proteins (TFF1, TFF2, TFF3) involved in mucosal repair and signalling.

Gastric neoplasia: Abnormal growth or tumour formation in the stomach lining, encompassing dysplasia and adenocarcinoma.

STAT3 signalling: A pathway activated by cytokines such as IL-6, leading to phosphorylation of the STAT3 transcription factor and promotion of cell proliferation and survival.

p53: A tumour suppressor protein that regulates cell cycle arrest, apoptosis and genomic stability in response to cellular stress.

Lectin activity: The ability of a protein to bind specific carbohydrate motifs, mediating interactions with glycoconjugates on cell surfaces or mucins.

References

1. Trefoil Factor Family (TFF) Peptides and Their Diverse Molecular Functions in Mucus Barrier Protection and More: Changing the Paradigm. International Journal of Molecular Sciences (2020).
2. Trefoil Factor Family (TFF) Peptides and Their Links to Inflammation: A Re-evaluation and New Medical Perspectives. International Journal of Molecular Sciences (2021).
3. Human Trefoil Factor 2 Is a Lectin That Binds α-GlcNAc-capped Mucin Glycans with Antibiotic Activity against Helicobacter pylori *. Journal of Biological Chemistry (2014).
4. Activation of STAT3 signaling is mediated by TFF1 silencing in gastric neoplasia. Nature Communications (2019).
5. TFF1 activates p53 through down-regulation of miR-504 in gastric cancer. Oncotarget (2014).
6. Different Forms of TFF3 in the Human Endocervix, including a Complex with IgG Fc Binding Protein (FCGBP), and Further Aspects of the Cervico-Vaginal Innate Immune Barrier. International Journal of Molecular Sciences (2024).
7. A Rapid Self−Assembling Peptide Hydrogel for Delivery of TFF3 to Promote Gastric Mucosal Injury Repair. Molecules (2024).
8. Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma. Cell Death & Disease (2025).
9. Pathological and therapeutic roles of bioactive peptide trefoil factor 3 in diverse diseases: recent progress and perspective. Cell Death & Disease (2022).