The trefoil factor 1 participates in gastrointestinal cell differentiation by delaying G1-S phase transition and reducing apoptosis

Abstract

Trefoil factor (TFF)1 is synthesized and secreted by the normal stomach mucosa and by the gastrointestinal cells of injured tissues. The link between mouse TFF1 inactivation and the fully penetrant antropyloric tumor phenotype prompted the classification of TFF1 as a gastric tumor suppressor gene. Accordingly, altered expression, deletion, and/or mutations of the TFF1 gene are frequently observed in human gastric carcinomas. The present study was undertaken to address the nature of the cellular and molecular mechanisms targeted by TFF1 signalling. TFF1 effects were investigated in IEC18, HCT116, and AGS gastrointestinal cells treated with recombinant human TFF1, and in stably transfected HCT116 cells synthesizing constitutive or doxycycline-induced human TFF1. We observed that TFF1 triggers two types of cellular responses. On one hand, TFF1 lowers cell proliferation by delaying G1-S cell phase transition. This results from a TFF1-mediated increase in the levels of cyclin-dependent kinase inhibitors of both the INK4 and CIP subfamilies, leading to lower E2F transcriptional activity. On the other hand, TFF1 protects cells from chemical-, anchorage-free–, or Bad-induced apoptosis. In this process, TFF1 signalling targets the active form of caspase-9. Together, these results provide the first evidence of a dual antiproliferative and antiapoptotic role for TFF1. Similar paradoxical functions have been reported for tumor suppressor genes involved in cell differentiation, a function consistent with TFF1.

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

“…Previous studies have demonstrated that both TFF1 and Cdc25A are involved in the regulation of cell proliferation and apoptosis (Bossenmeyer-Pourie et al, 2002;Kang et al, 2004;Leisser et al, 2004). Consistent with this, we next examined the impact of TFF1 ectopic expression on cell survival in TFF1-transformed colon epithelial cells, using the potent apoptosis inducer thapsigargin (TG).…”

“…The transforming functions of TFFs in the digestive tract and other solid tumors are supported by their positive actions on tumor cell invasion, angiogenesis and survival (Emami et al, 2001;Bossenmeyer-Pourie et al, 2002;Rodrigues et al, 2003a, b). To our knowledge, the status and biological significance of TFF1 at the adenoma and carcinoma transitions in the intestine has not been elucidated.…”

Expression of Clara cell 10-kDa protein and trefoil factor family 1 in patients with chronic rhinosinusitis and nasal polyps

“…TFF1 delays the transition from G1 to the S-phase in the cell cycle, thus regulating tumor inhibition, mucosal protection, cell apoptosis and differentiation (30). The expression of TFF1 in inflammation and malignant tumors indicates the status of prognosis and is significantly negatively correlated with the therapeutic effect of hormone therapy (29,31).…”

Expression of Tight-Junction Protein Claudin-7 Is an Early Event in Gastric Tumorigenesis

“…7,8 Recent reports support the notion that Tff1 may be a candidate tumor suppressor gene that may be involved in development and/or progression of human gastric cancers. 6,7,9 The Tff1 knockout (Ϫ/Ϫ) mouse model was first reported in 1996 as a model for spontaneous development of intestinal-type gastric dysplasia and cancer, similar to human disease. 10 Thus, the Tff1Ϫ/Ϫ mouse model provides a window to look into molecular alterations that are associated with precancerous lesions and understand the development of gastric cancers.…”