Intestinal trefoil factor controls the expression of the adenomatous polyposis coli–catenin and the E-cadherin–catenin complexes in human colon carcinoma cells

Abstract

Intestinal trefoil factor 3 (TFF3) is a member of the trefoil family of peptides, small molecules constitutively expressed in epithelial tissues, including the gastrointestinal tract. TFF3 has been shown to promote migration of intestinal epithelial cells in vitro and to enhance mucosal healing and epithelial restitution in vivo. In this study, we evaluated the effect of recombinant TFF3 (rTFF3) stimulation on the expression and cellular localization of the epithelial (E)-cadherin-catenin complex, a prime mediator of Ca 2؉ dependent cell-cell adhesion, and the adenomatous polyposis coli (APC)-catenin complex in HT29, HCT116, and SW480 colorectal carcinoma cell lines. Stimulation by rTFF3 (10 ؊9 M and 10 ؊8 M) for 20-24 hr led to cell detachment and to a reduction in intercellular adhesion in HT29 and HCT116 cells. In both cell lines, E-cadherin expression was down-regulated. The expression of APC, ␣-catenin and ␤-catenin also was decreased in HT29 cells, with a translocation of APC into the nucleus. No change in either cell adhesion or in the expression of E-cadherin, the catenins, and APC was detected in SW480 cells. In addition, TFF3 induced DNA fragmentation and morphological changes characteristic of apoptosis in HT29. Tyrphostin, a competitive inhibitor of protein tyrosine kinases, inhibited the effects of TFF3. Our results indicate that by perturbing the complexes between E-cadherin, ␤-catenin, and associated proteins, TFF3 may modulate epithelial cell adhesion, migration, and survival.

Intestinal trefoil factor binds to intestinal epithelial cells and induces nitric oxide production: priming and enhancing effects of mucin

“…Moreover we found that mucin-primed IEC cells are more sensitive to ITF stimulation, speculating that the up-regulation of ITF-binding molecules might be physiologically relevant. Several groups have proposed the existence of a receptor-like molecule that is able to mediate ITF action [1,2,18,[22][23][24][25][26]. Further isolation and characterization of ITF-BP will shed light on the molecular mechanism of ITF action and intestinal epithelial cell biology.…”

“…Previous studies showed that : (1) specific ITF-binding sites exist in the gastric epithelium, crypt cells of small intestine and colon [22][23][24] ; (2) ITF-binding protein (ITF-BP) is a 50 kDa glycosylated intestinal membrane protein [22] ; (3) stimulation by ITF for 24 h (at concentrations as low as 1 nM) leads to cell detachment and to a decreased intracellular adhesion in human carcinoma cells [25] ; (4) ITF (100 nM) leads to the inhibition of extracellular signal-related protein kinase and the mitogenactivated protein kinase pathways in IEC-6 cells through the activation of tyrosine or dual-specific phosphatase [2] ; (5) ITF (10 nM) modulates EGF effects on intestinal epithelial ion transport [26] ; and (6) ITF effect is mediated by signal transduction pathways linked to the protein tyrosine kinase\tyrosine phosphatase pathway [2,18,25]. These observations strongly suggest that a receptor-like membrane protein might mediate the action of ITF.…”

Genes that co-cluster with estrogen receptor alpha in microarray analysis of breast biopsies

“…It is expressed in estrogen-responsive but not in estrogen-nonresponsive breast cancer cell lines and may play a role in promoting cell migration by controlling the expression of APC and E-cadherin-catenin complexes. 20,21 As discussed previously, TFF1 is a fairly well established predictive biomarker for estrogen therapy responsiveness TFF1. mRNA levels are reportedly increased by estradiol but not by progesterone, dexamethasone, or dihydrotestosterone.…”

Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment

“…We therefore postulate that specific signals from the tumor microenvironment, e.g., by stromal cells, the extracellular matrix, or cytokines, which were already shown to have strong influence on the malignant phenotype of breast cancer (28), also regulate intracellular ␤-catenin distribution and subsequently the behavior of colon tumor cells. For instance, trefoil factors are described to induce nuclear translocation of ␤-catenin in colon carcinoma cells (29). A possible direct influence of the extracellular matrix was demonstrated by showing that activation of integrin linked kinase leads to transcriptional repression of the E-cadherin gene and nuclear accumulation of ␤-catenin (30).…”