Intestinal trefoil factor confers colonic epithelial resistance to apoptosis

Abstract

Intestinal trefoil factor (ITF) is an essential regulator of colonic epithelial restitution, the rapid migration of colonocytes over mucosal wounds. High levels of ITF are frequently present in colorectal cancers and derived cell lines. Mucosal restitution requires the detachment of epithelium from substrate, which would be expected to induce apoptosis. However, mice deficient in ITF showed an increase in colonocyte apoptosis unaccompanied by changes in expression of receptor-related (TNFR͞Fas) or stressrelated (Bcl-family) cell death regulators. An ITF-expressing colonic (HT-ITF1) cell line was resistant to apoptosis induced by serum starvation and ceramide. Exogenous ITF also protected another human colonic carcinoma-derived cell line (HCT116) and a nontransformed rat intestinal epithelial cell line (IEC-6) from apoptosis. This effect was abrogated by wortmannin and tyrphostin A25, indicating the potential involvement of phosphatidylinositol 3-kinase and epidermal growth factor (EGF) receptor activation. Expression of phosphorylated Akt, which lies downstream of phosphatidylinositol 3-kinase activation, was elevated in this HT-29-ITF line. p53-dependent cell death in the AGS human gastric cancer cell line after etoposide was similarly inhibited by transient expression of ITF but not a C-terminal truncation mutant of ITF, and it required functional phosphatidylinositol 3-kinase and EGF receptor. These findings support a central role for ITF in the maintenance of intestinal mucosal continuity, and conversely demonstrate the potential for ITF expression to confer resistance of colorectal tumors to therapy.cell survival ͉ signal transduction ͉ cell adhesion ͉ colonic neoplasm ͉ cultured tumor cells R estitution, the ability of epithelial cells to spread and migrate across the basement membrane to cover shallow defects, is the key initial step in repair of mucosal injury and can achieve restoration of mucosal continuity over broad areas of damage within hours (1-3). This resurfacing, which is independent of proliferation, is followed over a period of days by a remodeling phase of epithelial proliferation and differentiation. Brisk restitution after injury is desirable both to limit fluid and electrolyte losses and to prevent diffusion of foreign antigens from the gastrointestinal lumen into local and systemic immune compartments. Both these aspects underlie the morbidity after therapeutic abdominal irradiation, and they limit dose and dose intervals (4).The trefoil peptide family, comprising the intestinal peptide ITF and the gastric peptides SP and pS2, play a critical role in epithelial restitution within the mammalian gastrointestinal tract. These small (7-12-kDa) protease-resistant proteins are abundantly secreted onto the mucosal surface by specialized mucus-secreting cells of the gut. They are rapidly up-regulated at the margins of mucosal injury, and they are believed to promote epithelial cell migration (5, 6). Colonic restitution is absent in mice made ITF deficient by homologous recombination (7), renderi...

Trefoil factor 3: a novel serum marker identified by gene expression profiling in high-grade endometrial carcinomas

“…Nevertheless, little is known about whether TFF3 directly contributes to the malignant behaviour of cancer cells. In this regard, TFF3 has been shown to regulate cancer progression by increasing tumour metastasis acting as anti-apoptotic, scattering, pro-invasive, and angiogenic agent on cancer cells (Taupin et al, 2000;Emami et al, 2001;Rodrigues et al, 2003). Trefoil factor 3 expression in the human uterus has been analysed by several investigators with conflicting results.…”

Identification of murine and human XCP1 genes as C/EBP-ε-dependent members of FIZZ/Resistin gene family

“…A number of structurally similar cysteine-bridged proteins, such as defensins and trefoil factors, are active upon secretion and processing, which preserves only the cysteine-bridged C-terminal domain (Selsted et al, 1992;Ganz, 1999;Taupin et al, 2000). Our computer analysis of the XCP protein sequence has identified the presence of a 20-amino-acid N-terminal transmembrane region.…”

“…The predicted structure of mXCP1 and hXCP1 proteins was also reminiscent of cysteine-bridged family of proteins that appear to share a general architecture, such as a-defensins (Selsted et al, 1992;Ganz, 1999), b-defensins (Huttner et al, 1994;Yount et al, 1995;Yang et al, 1999), trefoil factors Taupin et al, 2000), prostate stem cell antigen (PSCA), RIG-E and several other proteins that have a signal sequence at their amino terminus and a cysteinecrosslinked carboxy terminal-secreted domain (Figure 1). Our computer analysis failed to predict protease cleavage sites next to the signal sequences, leaving it uncertain whether XCP1 protein detaches from the cell membrane (secreted) or remains anchored there.…”

Induction of the adenoma-carcinoma progression and Cdc25A-B phosphatases by the trefoil factor TFF1 in human colon epithelial cells

“…Recent studies incriminate TFF1 and other TFFs in the neoplastic progression of the digestive system, according to their scattering, proinvasive and proangiogenic activities in vitro and in vivo (Emami et al, 2001;Rodrigues et al, 2001Rodrigues et al, , 2003bRivat et al, 2005). All TFF members are implicated in cancer cell survival, suggesting that they participate to the aggressive behavior and metastatic potential of colon cancer cells (Taupin et al, 2000;BossenmeyerPourie et al, 2002;Yio et al, 2005). These studies suggest that divergent effects are associated with the status of TFF1 in the gastrointestinal mucosa during normal development, chronic inflammation, and neoplastic progression.…”