Intestinal trefoil factor activates the PI3K/Akt signaling pathway to protect gastric mucosal epithelium from damage

Abstract

Abstract.Intestinal trefoil factor (ITF, also named as trefoil factor 3, TFF3) is a member of the TFF-domain peptide family, which plays an essential role in the regulation of cell survival, cell migration and maintains mucosal epithelial integrity in the gastrointestinal tract. However, the underlying mechanisms and associated molecules remain unclear. The aim of this study was to explore the protective effects of ITF on gastric mucosal epithelium injury and its possible molecular mechanisms of action. In the present study, we show that ITF was able to promote the proliferation and migration of GES-1 cells via a mechanism that involves the PI3K/Akt signaling pathway. Western blot results indicated that ITF induced a dose-and time-dependent increase in the Akt signaling pathway. ITF also plays an essential role in the restitution of GES-1 cell damage induced by lipopolysaccharide (LPS). LPS induced the apoptosis of GES-1 cells, decreased cell viability significantly (P<0.01) and led to epithelial tight junction damage, which is attenuated via ITF treatment. The protective effect of ITF on the integrity of GES-1 was abrogated by inhibition of the PI3K/Akt pathway. Taken together, our results demonstrate that ITF promotes the proliferation and migration of gastric mucosal epithelial cells and preserves gastric mucosal epithelial integrity after damage is mediated by activation of the PI3K/Akt signaling pathway. This study suggested that the PI3K/Akt pathway could act as a key intracellular pathway in the gastric mucosal epithelium that may serve as a therapeutic target to preserve epithelial integrity during injury.

Trefoil Factor Peptides and Gastrointestinal Function

“…This effect is accompanied by an increased expression of the tight junction proteins ZO-1, OCCLUDIN, and CLAUDIN-1 and is reversed if TLR2 is knocked down in the Caco-2 cell (144). Effects were mediated by the PI3K/Akt pathway (144), consistent with other findings that the protective effect of TFF3 in gastric mucosal epithelial cell is mediated by activation of this signaling pathway (92). Thus, TFF3 seems able to inhibit inflammatory cytokines in addition to other cellular effects that enhance mucosal defenses.…”

“…TFF peptides were demonstrated to regulate cell survival via ERK/MAPK, PI3K/Akt, phospholipase C (PLC)/PKC, β-catenin, and EGF signaling pathway (34, 78, 87, 89–91). Sun et al (92) showed that in cultured GES-1 cells (normal human gastric epithelial cells), exogenous addition of TFF3 activated the PI3K/Akt pathway known to be involved in gastric epithelial repair. Given the previously noted promiscuity of TFF peptide action, results support the concept that TFF peptides are involved in GI mucusal repair, although TFF3 is normally found only in the intestine and not the stomach.…”

“…TFF2 and TFF3 peptides signal through the ErbB pathways, but it is entirely unknown if this is due to direct interaction of TFF peptides with EGF-R/ErB or if there is an intermediate EGF family ligand involved. There is evidence in vitro that TFF3 can act on EGF-R to activate several downstream signaling pathways, including MAPK and PI3K/Akt (90, 92). In vitro in colonic cancer and in nontransformed intestinal epithelial cell lines, MAPK activation is primarily responsible for the TFF3-mediated initiation of healing (91).…”

Trefoil factors: Gastrointestinal-specific proteins associated with gastric cancer

“…Aside from these, TFF3 activates the PI3K/Akt signaling axis to preserve the integrity of gastric mucosal epithelium [131], as well as accelerating tumorigenesis via the Leptin/ObRb/STAT3 (signal transducers and activators of transcription 3) pathway [108] and promoting the growth and invasion of GC cells through the HIF-1α(hypoxia-inducible transcription factors-1α)/ VEGF(vascular endothelial growth factor)/ STAT3…”

Critical roles of chemokine receptor CCR5 in regulating glioblastoma proliferation and invasion

“…We further investigated the underlying mechanism of CCR5-mediated proliferation and invasion in U87 and U251 cells by western blot analysis. Because PI3K/Akt signaling pathway has been shown to play important roles in cell proliferation, migration, and survival [33,34], we hypothesized that Akt activation might contribute to CCR5-mediated proliferation and invasion in GBMs. To verify our hypothesis, U87 and U251 cells were treated with CCL5, PI3K inhibitor LY294002, or CCR5 siRNA.…”