{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTrefoil factor 3 (TFF3) is emerging as a valuable diagnostic and prognostic biomarker in a range of clinical settings. Minimally invasive sampling devices—such as the Cytosponge coupled with immunohistochemical analysis of TFF3—have been successfully employed to screen for Barrett’s esophagus, a premalignant condition associated with esophageal adenocarcinoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In other studies, altered TFF3 mRNA and protein expression levels have been linked to the progression of thyroid and other endocrine‐related tumors, while epigenetic profiles involving its promoter are emerging as promising discriminators among cancer subtypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its diagnostic utility, TFF3 exerts potent mucosal protective effects. It plays a central role in promoting epithelial restitution and barrier regeneration in various tissues—including the gastrointestinal tract, airways, oral mucosa, cornea, and even the urinary system—by enhancing cell migration and modulating tight junction integrity. For example, in vitro and in vivo models demonstrate that TFF3 increases the migratory capacity of normal oral keratinocytes and accelerates corneal wound healing, while also participating in the regulation of tight junction proteins to preserve mucosal integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA growing body of evidence highlights the oncogenic properties of TFF3 in diverse cancer types. TFF3 has been shown to stimulate STAT3 activation, thereby promoting cellular invasion and metastasis in colorectal and breast cancers, and mediating anti‐estrogen resistance through enhanced estrogen receptor transcriptional activity. In prostate cancer, its expression appears tightly linked to genetic rearrangements that further augment tumor cell aggressiveness, and in hepatocellular carcinoma, TFF3 overexpression contributes to enhanced cell proliferation and chemoresistance. Moreover, TFF3 modulation of inflammatory signaling pathways (for example via TLR4/NF‐κB) further supports its role in tumor progression and in fostering an environment conducive to malignant dissemination."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the mechanistic level, TFF3 exerts its diverse functions through multiple, interrelated signaling pathways. Structural analyses reveal that TFF3 dimerization confers enhanced biological activity over the monomer, while its modulation of cell adhesion molecules—such as down‐regulation of E-cadherin and alteration in claudin composition—facilitates epithelial cell migration and epithelial–mesenchymal transition. In parallel, epigenetic regulation of the TFF3 gene and its interplay with other secreted mucin-associated proteins further refine its role in both physiological repair processes and pathological conditions including inflammatory bowel disease, cholangiocarcinoma, and even pancreatic beta-cell replication. These molecular insights underscore TFF3’s capacity to orchestrate complex responses in tissue repair and cancer progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Caryn S Ross-Innes, Irene Debiram-Beecham, Maria O'Donovan, et al. 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