TFF2 (trefoil family factor2) inhibits apoptosis in breast and colorectal cancer cell lines

Siu, Lai-San; Romańska, Hanna; Abel, Paul; Baus-Lončar, Mirela; Kayademir, Tuncay; Stamp, Gordon; Lalani, El–Nasir

doi:10.1016/j.peptides.2003.11.023

Cited by 27 publications

(11 citation statements)

References 19 publications

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“…While the explanation(s) for this defective barrier function remains undefined, one possibility is that TFF2 −/− mice have defective expression/function of gap-junction proteins due to the role of TFF2 in the regulation of cell adhesion molecule expression (34). Alternatively, TFF2 deficiency could result in excess intestinal epithelial cell death because several TFF family members block apoptosis (35, 36). Irrespective of the exact mechanism, our evidence for decreased barrier function in naive TFF2 mice may partially explain why TFF2 −/− mice have increased susceptibility to chemical and infection-induced models of gastritis and colitis (11).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, dysregulation of this protein has been documented in a variety of disease contexts. Elevated TFF2 levels are associated with several different types of cancer (35, 37–39) and may predict the stage of tumor progression (40). Furthermore, administration of rTFF2 accelerates the rate of tissue repair in models of burn injury (41), ocular damage (10), gastritis and colitis (12, 42).…”

Section: Discussionmentioning

confidence: 99%

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Trefoil Factor 2 Negatively Regulates Type 1 Immunity against Toxoplasma gondii

McBerry

Egan

Rani

et al. 2012

The Journal of Immunology

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Interleukin 12 (IL-12)-mediated Type 1 inflammation confers host-protection against the parasitic protozoan Toxoplasma gondii. However, production of interferon gamma (IFN-γ), another Type 1 inflammatory cytokine, also drives lethality from excessive injury to the intestinal epithelium. As mechanisms that restore epithelial barrier function following infection remain poorly understood, this study investigated the role of Trefoil factor 2 (TFF2), a well-established regulator of mucosal tissue repair. Paradoxically, TFF2 antagonized IL-12 release from DC’s and macrophages, which protected TFF2 deficient mice (TFF2−/−) from T. gondii pathogenesis. Dysregulated intestinal homeostasis in naïve TFF2−/− mice correlated with increased IL-12/23p40 levels and enhanced T cell recruitment at baseline. Infected TFF2−/− mice displayed low rates of parasite replication and reduced gut immunopathology, whereas WT mice experienced disseminated infection and lethal ileitis. p38 MAPK activation and IL-12p70 production was more robust from TFF2−/− CD8+ DC compared to WT CD8+ DC and treatment of WT DC with rTFF2 suppressed TLR-induced IL-12/23p40 production. Neutralization of IFN-γ and IL-12 in TFF2−/− animals abrogated resistance shown by enhanced parasite replication and infection-induced morbidity. Hence, TFF2 regulated intestinal barrier function and Type 1 cytokine release from myeloid phagocytes, which dictated the outcome of oral T. gondii infection in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Trefoil Factor 2 Negatively Regulates Type 1 Immunity against Toxoplasma gondii

McBerry

Egan

Rani

et al. 2012

The Journal of Immunology

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“…The importance of TFF2 in mediating these effects was supported by the finding that recombinant TFF2 restored the apoptotic and migratory phenotype in cells expressing WTp53 and that downregulation of TFF2 sensitized gastric cancer cells to p53-dependent chemotherapeutic drug-induced apoptosis. Previous studies have suggested that TFF2 can promote cell migration and branch cell morphogenesis (11) and can inhibit apoptosis in cancer cell lines (42). It is also known that the control of cell migration and induction of apoptosis are important tumor suppressor functions of p53 (38).…”

Section: Discussionmentioning

confidence: 99%

p53 inhibition of AP1-dependent TFF2 expression induces apoptosis and inhibits cell migration in gastric cancer cells

Alfred²,

Ai³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Overexpression of trefoil factor 2 (TFF2) is associated with increased cell migration, resistance to apoptosis, and possibly increased gastric cancer invasion. Dysregulation of p53 is frequently observed in preneoplastic conditions of the stomach. Here, we investigated the effect of p53 on the expression and function of TFF2 in gastric cancer cell lines. Gene expression was determined by reverse transcription-polymerase chain reaction, and promoter activity was assessed by dual luciferase reporter assays. Apoptosis was detected by flow cytometry, and cell migration was evaluated by the Boyden chamber assay. Exogenous expression of p53 dose dependently inhibited endogenous TFF2 mRNA, protein, and promoter activity and resulted in induction of cell apoptosis and inhibition of cell migration. Downregulation of TFF2 by small interfering RNA sensitized gastric cancer cells to drug-induced p53-dependent apoptosis. Addition of human TFF2 peptide reversed p53-dependent apoptosis and inhibition of cell migration. The p53-responsive element was mapped to an AP-1-like cis-element at -182 bp upstream of the TFF2 transcription start site. Mutation of this AP-1-like element abrogated p53-mediated inhibition of TFF2 promoter activity. Gel shift and chromatin immunoprecipitation assays demonstrated that c-Jun and c-Fos bind to this AP-1-like element. Ectopic expression of c-Jun/c-Fos or p300 or treatment of cells with phorbol 12-myristate 13-acetate (PMA) stimulated endogenous TFF2 mRNA expression and promoter activity, and p53 inhibited the effects of AP-1 and PMA on TFF2. p53 induces cell apoptosis and inhibits cell migration in part by downregulating TFF2 expression through an AP-1-like site, suggesting that TFF2 may be an important downstream target of p53.

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“…(12) Blockade of its paralog, TFF2, in highly expressing colon cancers has also been demonstrated to induce apoptosis in vitro . (20) In addition to sporadic lesions, mRNA and protein expression of trefoil factors are also strongly upregulated in the tumors of those with serrated polyposis syndromes. (18) Taken together with our findings, these data support a general role for TFF1 and TFF2 as tumor promoters.…”

Section: Discussionmentioning

confidence: 99%

TFF2–CXCR4 Axis Is Associated with BRAF V600E Colon Cancer

Gala

Austin

Ogino

et al. 2015

Cancer Prevention Research

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Oncogene-induced senescence (OIS), a tumor suppressive mechanism that is induced by the replicative and metabolic stress of oncogene activation, is a key barrier in the development of BRAF V600E colon cancer. Inhibition of this mechanism has been observed through epigenetic changes observed in sporadic serrated polyps, as well as through the germline mutations associated with those who develop serrated polyposis. We hypothesize upregulated autocrine factors exist that are specific to the serrated pathway and also promote bypass of oncogene-induced senescence. To identify such autocrine factors, we integrate analyses of microarrays of sessile serrated polyps and two large colon cancer cohorts, the Cancer Genome Atlas (TCGA) (n = 153) and French national Cartes d’Identité des Tumeurs (CIT) program (n = 462), with enhanced gene annotation through natural language processing techniques of the existing medical corpus. We reproducibly associate higher expression of the ligand-receptor axis of TFF2 and CXCR4 with BRAF V600E mutant colon cancer (P = 3.0 × 10−3 and 0.077, respectively for TCGA; P = 3.0 × 10−8 and 5.1 × 10−7 for CIT). Given well-described oncogenic roles of TFF2 and CXCR4 in colon cancer, and availability of CXCR4 inhibitors for other clinical indications, this ligand-receptor axis may represent an actionable target for prevention and treatment of this molecular subtype of colorectal cancer.

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TFF2 (trefoil family factor2) inhibits apoptosis in breast and colorectal cancer cell lines

Cited by 27 publications

References 19 publications

Trefoil Factor 2 Negatively Regulates Type 1 Immunity against Toxoplasma gondii

Trefoil Factor 2 Negatively Regulates Type 1 Immunity against Toxoplasma gondii

p53 inhibition of AP1-dependent TFF2 expression induces apoptosis and inhibits cell migration in gastric cancer cells

TFF2–CXCR4 Axis Is Associated with BRAF V600E Colon Cancer

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