Protein Kinase C and ERK Activation Are Required for TFF- peptide-stimulated Bronchial Epithelial Cell Migration and Tumor Necrosis Factor-α-induced Interleukin-6 (IL-6) and IL-8 Secretion

Graneß, Angela; Chwieralski, Caroline E.; Reinhold, Dirk; Thim, Lars; Hoffmann, Werner

doi:10.1074/jbc.m200468200

Cited by 91 publications

(78 citation statements)

References 65 publications

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“…Also, the tumor cells inside the metastatic lymph nodes of the TFF2-positive patients were strongly positive for TFF2, indicating that TFF2-positive cell lineage metastasized to the regional lymph nodes and the metastatic phenotype could be attributable to the TFF2 expression by the tumor cells. This finding further strengthens the conclusions of previous in vitro studies stating that TFF2 is intricately related with cancer cell motility and invasion (Efstathiou et al, 1999;Emami et al, 2001;Graness et al, 2002;Playford et al, 1995). In an in vitro wound-induced cell migration assay using confluent rat intestinal epithelial cells, Dignass et al (1994) showed that application of TFF2 enhanced migration of cells into the wound approximately 4-fold.…”

Section: Discussionsupporting

confidence: 76%

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Expression of Cytoplasmic TFF2 Is a Marker of Tumor Metastasis and Negative Prognostic Factor in Gastric Cancer

Dhar

Wang

Maruyama

et al. 2003

Laboratory Investigation

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SUMMARY:Trefoil factor family 2 (TFF2) is a small peptide constitutively expressed in the gastric mucosa, where it plays a protective role in restitution of gastric mucosa. TFF2 has also been shown to be expressed in some gastric cancers, but its role in tumor metastasis and patient prognosis has not been examined. In this study, we examined TFF2 expression at both the mRNA and protein levels and correlated these results with the clinicopathologic characteristics and prognosis of gastric cancer patients. Among the 144 curatively resected samples, 43 (30%) were positive for TFF2. TFF2 expression was preferentially observed in the infiltrating tumor cells sparing the superficial cells. Significantly increased expression of TFF2 was noted in large tumors of the diffuse type. An increased prevalence of TFF2 expression was also found in tumors with advanced T and N stage and in patients with lymphatic and venous invasion. Accordingly, patients with TFF2-expressing tumors had a significantly worse disease-free survival, and in multivariate analysis, this finding remained significant as an independent prognostic factor. Taken together, our results suggest that TFF2 expression may play a role in gastric cancer invasion and as such could be a useful target for therapeutic intervention. (Lab Invest 2003, 83:1343-1352.

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Section: Discussionsupporting

confidence: 76%

“…However, it is possible that TFF2 might contribute to tumor progression in other ways, such as cell migration, angiogenesis, or immune suppression. Indeed, several studies have supported a role with respect to cell migration and possibly invasion (Efstathiou et al, 1999;Emami et al, 2001;Graness et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Expression of Cytoplasmic TFF2 Is a Marker of Tumor Metastasis and Negative Prognostic Factor in Gastric Cancer

Dhar

Wang

Maruyama

et al. 2003

Laboratory Investigation

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“…Human intestinal trefoil factor (TFF3, gene symbol hITF) is a member of a family of polypeptides characterized by containing at least one copy of the trefoil motif, a 3-leaved structure formed by three conserved disulfides within a 40-amino acid segment [1,2]. Trefoil peptides are expressed mainly in gastrointestinal and other selected epithelial tissues and are packaged along with mucins and secreted [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Trefoil factor 3 overexpression in prostatic carcinoma: Prognostic importance using tissue microarrays

et al. 2004

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“…Experimental induction of ulceration in the rat stomach leads to rapid up-regulation of TFF2 expression with high levels observed 30 min after ulceration with persistence for up to 10 days (1). TFF2 is secreted into the mucus layer of the gastrointestinal tract of mammals where it stabilizes the mucin gel layer and stimulates migration of epithelial cells (2)(3)(4), suggesting an important role in restitution and in maintenance of the integrity of the gut. Exogenous administration of recombinant TFF2, either orally or intravenously, provides mucosal protection in several rodent models of acute gastric or intestinal injury (5,6).…”

mentioning

confidence: 99%

Secreted Trefoil Factor 2 Activates the CXCR4 Receptor in Epithelial and Lymphocytic Cancer Cell Lines

Dubeykovskaya

Dubeykovskiy

Solal-Cohen

et al. 2009

Journal of Biological Chemistry

106

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The secreted trefoil factor family 2 (TFF2) protein contributes to the protection of the gastrointestinal mucosa from injury by strengthening and stabilizing mucin gels, stimulating epithelial restitution, and restraining the associated inflammation. Although trefoil factors have been shown to activate signaling pathways, no cell surface receptor has been directly linked to trefoil peptide signaling. Here we demonstrate the ability of TFF2 peptide to activate signaling via the CXCR4 chemokine receptor in cancer cell lines. We found that both mouse and human TFF2 proteins (at ϳ0.5 M) activate Ca 2؉ signaling in lymphoblastic Jurkat cells that could be abrogated by receptor desensitization (with SDF-1␣) or pretreatment with the specific antagonist AMD3100 or an anti-CXCR4 antibody. TFF2 pretreatment of Jurkat cells decreased Ca 2؉ rise and chemotactic response to SDF-1␣. In addition, the CXCR4-negative gastric epithelial cell line AGS became highly responsive to TFF2 treatment upon expression of the CXCR4 receptor. TFF2-induced activation of mitogen-activated protein kinases in gastric and pancreatic cancer cells, KATO III and AsPC-1, respectively, was also dependent on the presence of the CXCR4 receptor. Finally we demonstrate a distinct proliferative effect of TFF2 protein on an AGS gastric cancer cell line that expresses CXCR4. Overall these data identify CXCR4 as a bona fide signaling receptor for TFF2 and suggest a mechanism through which TFF2 may modulate immune and tumorigenic responses in vivo.

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Protein Kinase C and ERK Activation Are Required for TFF- peptide-stimulated Bronchial Epithelial Cell Migration and Tumor Necrosis Factor-α-induced Interleukin-6 (IL-6) and IL-8 Secretion

Abstract: TFF-peptides (formerly P-

Cited by 91 publications

References 65 publications

Expression of Cytoplasmic TFF2 Is a Marker of Tumor Metastasis and Negative Prognostic Factor in Gastric Cancer

Expression of Cytoplasmic TFF2 Is a Marker of Tumor Metastasis and Negative Prognostic Factor in Gastric Cancer

Trefoil factor 3 overexpression in prostatic carcinoma: Prognostic importance using tissue microarrays

Secreted Trefoil Factor 2 Activates the CXCR4 Receptor in Epithelial and Lymphocytic Cancer Cell Lines

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