Salivary Trefoil Factor Family (TFF) Peptides and Their Roles in Oral and Esophageal Protection: Therapeutic Potential

Abstract

Human saliva is a complex body fluid with more than 3000 different identified proteins. Besides rheological and lubricating properties, saliva supports wound healing and acts as an antimicrobial barrier. TFF peptides are secreted from the mucous acini of the major and minor salivary glands and are typical constituents of normal saliva; TFF3 being the predominant peptide compared with TFF1 and TFF2. Only TFF3 is easily detectable by Western blotting. It occurs in two forms, a disulfide-linked homodimer (Mr: 13k) and a high-molecular-mass heterodimer with IgG Fc binding protein (FCGBP). TFF peptides are secretory lectins known for their protective effects in mucous epithelia; the TFF3 dimer probably has wound-healing properties due to its weak motogenic effect. There are multiple indications that FCGBP and TFF3-FCGBP play a key role in the innate immune defense of mucous epithelia. In addition, homodimeric TFF3 interacts in vitro with the salivary agglutinin DMBT1gp340. Here, the protective roles of TFF peptides, FCGBP, and DMBT1gp340 in saliva are discussed. TFF peptides are also used to reduce radiotherapy- or chemotherapy-induced oral mucositis. Thus, TFF peptides, FCGBP, and DMBT1gp340 are promising candidates for better formulations of artificial saliva, particularly improving wound healing and antimicrobial effects even in the esophagus.

Different Molecular Forms of TFF3 in the Human Respiratory Tract: Heterodimerization with IgG Fc Binding Protein (FCGBP) and Proteolytic Cleavage in Bronchial Secretions

“…In the past, homodimeric TFF3 was reported to interact in vitro with the agglutinin Deleted in Malignant Brain Tumor 1/gp340 (DMBT1gp 340 ), a glycoprotein involved in mucosal innate immunity (review: [ 29 ]). Thus, we tested whether TFF3-FCGBP and DMBT1gp 340 co-migrated after native AgGE possibly due to forming a complex ( Figure 5 ).…”

“…Exposed free thiols act as intracellular retention signals for unassembled secretory proteins, which are then subject to degradation [ 26 ]. In line with this, both human intestinal and salivary TFF3 mainly exist as disulfide-linked heterodimers with IgG Fc binding protein (FCGBP) [ 27 , 28 , 29 ].…”

“…In the human and murine stomach, FCGBP even forms heterodimers with TFF1 [ 36 , 37 ], the latter having high similarity with TFF3 [ 3 , 4 ]. FCGBP is ubiquitous in vertebrates [ 38 ] and probably has a general function for the mucosal innate immune defense together with mucins [ 28 , 29 , 39 , 40 ]. For example, FCGBP is a highly up-regulated early defense gene in catfish skin after bacterial infection [ 41 ].…”

Spatiotemporally deciphering the mysterious mechanism of persistent HPV‐induced malignant transition and immune remodelling from HPV‐infected normal cervix, precancer to cervical cancer: Integrating single‐cell RNA‐sequencing and spatial transcriptome

“…Three (SPRR3, CEACAM7, APOBEC3A) might stimulate cervical lesion progression via a second hit after HPV infection 13–16 . The other three genes (TCN1, TFF3, BPIFB1) were downregulated in HSIL and CA compared with the normal cervix, revealing potentially weakened protection from malignant transition 17–19 . These discoveries indicate that upregulation of those ‘second‐hit’‐related genes or downregulation of progression‐protective genes might initiate precancerous lesions and even CC.…”

“… 13 , 14 , 15 , 16 The other three genes (TCN1, TFF3, BPIFB1) were downregulated in HSIL and CA compared with the normal cervix, revealing potentially weakened protection from malignant transition. 17 , 18 , 19 These discoveries indicate that upregulation of those ‘second‐hit’‐related genes or downregulation of progression‐protective genes might initiate precancerous lesions and even CC. Thus, active therapy should be performed to prevent the malignant transition of cervical epithelial cells.…”