Trefoil Factor

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Yun Zhang - One of the best experts on this subject based on the ideXlab platform.

  • increased expression of protease activated receptor 4 and Trefoil Factor 2 in human colorectal cancer
    PLOS ONE, 2015
    Co-Authors: Yong Zhang, Ping Jiang, Yang Xiang, Guoyu Yu, Chuanrao Zhang, Yun Zhang
    Abstract:

    Protease-activated receptor 4 (PAR4), a member of G-protein coupled receptors family, was recently reported to exhibit decreased expression in gastric cancer and esophageal squamous cancer, yet increased expression during the progression of prostate cancer. Trefoil Factor 2 (TFF2), a small peptide constitutively expressed in the gastric mucosa, plays a protective role in restitution of gastric mucosa. Altered TFF2 expression was also related to the development of gastrointestinal cancer. TFF2 has been verified to promote cell migration via PAR4, but the roles of PAR4 and TFF2 in the progress of colorectal cancer are still unknown. In this study, the expression level of PAR4 and TFF2 in colorectal cancer tissues was measured using real-time PCR (n = 38), western blotting (n=38) and tissue microarrays (n = 66). The mRNA and protein expression levels of PAR4 and TFF2 were remarkably increased in colorectal cancer compared with matched noncancerous tissues, especially in positive lymph node and poorly differentiated cancers. The colorectal carcinoma cell LoVo showed an increased response to TFF2 as assessed by cell invasion upon PAR4 expression. However, after intervention of PAR4 expression, PAR4 positive colorectal carcinoma cell HT-29 was less responsive to TFF2 in cell invasion. Genomic bisulfite sequencing showed the hypomethylation of PAR4 promoter in colorectal cancer tissues and the hypermethylation in the normal mucosa that suggested the low methylation of promoter was correlated to the increased PAR4 expression. Taken together, the results demonstrated that the up-regulated expression of PAR4 and TFF2 frequently occurs in colorectal cancer tissues, and that overexpression of PAR4 may be resulted from promoter hypomethylation. While TFF2 promotes invasion activity of LoVo cells overexpressing PAR4, and this effect was significantly decreased when PAR4 was knockdowned in HT-29 cells. Our findings will be helpful in further investigations into the functions and molecular mechanisms of Proteinase-activated receptors (PARs) and Trefoil Factor Factors (TFFs) during the progression of colorectal cancer.

  • promoter hypermethylation and downregulation of Trefoil Factor 2 in human gastric cancer
    Oncology Letters, 2014
    Co-Authors: Ping Jiang, Yun Zhang, Yang Xiang, Guoyu Yu, W Y Feng
    Abstract:

    Trefoil Factor 2 (TFF2) plays a protective role in gastric mucosa and may be involved in the progression of gastric cancer, but the detailed functions and underlying molecular mechanisms are not clear. The present study used a combination of clinical observations and molecular methods to investigate the correlation between abnormal expression of TFF2 and gastric cancer progression. TFF2 expression was evaluated by reverse transcription polymerase chain reaction (RT-PCR), quantitative PCR (qPCR), and western blot and immunohistochemistry analyses. TFF2 methylation levels were analyzed by genomic bisulfite sequencing method. The results showed that TFF2 mRNA and protein expression were decreased in gastric cancer tissues compared with the matched non-cancerous mucosa, and the decreased level was associated with the differentiation and invasion of gastric cancer. Moreover, the average TFF2 methylation level of CpG sites in the promoter region was 70.4% in three gastric cancer tissues, while the level in associated non-neoplastic tissues was 41.0%. Furthermore, the promoter hypermethylation of TFF2 was also found in gastric cancer cell lines, AGS and N87, and gene expression was significantly increased following treatment with a demethylating agent, 5-Aza-2′-deoxycytidine. In conclusion, TFF2 expression was markedly decreased in gastric cancer and promoter hypermethylation was found to regulate the downregulation of TFF2. TFF2 has been suggested as a tumor suppressor in gastric carcinogenesis and metastasis.

  • circulating serum Trefoil Factor 3 tff3 is dramatically increased in chronic kidney disease
    PLOS ONE, 2013
    Co-Authors: Ting-yi Du, Fang Wang, Qing Wang, Yang Xiang, Yun Zhang
    Abstract:

    Objectives Trefoil Factor 3 (TFF3) is a small peptide that plays an important role in mucosal protection, cell proliferation, and cell migration. The aberrant expression of TFF3 is correlated with gastrointestinal inflammation, solid tumors, and other clinical diseases. The objective of this study was to identify the distribution characteristics of serum TFF3 in common clinical diseases.

  • Trefoil Factor 1 gene alternations and expression in colorectal carcinomas
    Tumori, 2013
    Co-Authors: You-guang Huang, Li Yf, Pan Bl, Wang Lp, Yun Zhang
    Abstract:

    Abstract Aberrant expression of the Trefoil Factor family (TFF) has been recognized to be involved in the development and/or progression of various solid tumors. Increased Trefoil Factor 1 (TFF1) expression is found associated with tumor progression in some tumors, and TFF1 missense mutations have been detected in gastric cancer. The aim of the study was to analyze TFF1 alternations and expression in colorectal carcinoma and their correlation with cancer progression and pathological aspects. TFF1 mutations were detected in colorectal carcinomas by DNA sequencing. TFF1 mRNA and protein levels in subsets of the primary tumors were determined using quantitative reverse transcription polymerase chain reaction and immunohistochemistry analyses. The serum level of TFF1 was also detected by enzyme-linked immunosorbent assay for patients with colorectal carcinoma. Five variants were detected in the 5'-untranslation region and intron 1 of TFF1. TFF1 expression was increased in colorectal carcinoma compared to paired distal colonic mucosa. Immunohistochemistry in primary colorectal carcinoma showed no significant differences in tumor TFF1 levels with respect to clinicopathological parameters such as the patient's sex, cancer differentiation, stage and lymph node metastasis. However, serum TFF1 levels were significantly elevated in patients with colorectal carcinoma compared to healthy individuals. The results indicate that TFF1 missense mutations seem to be a rare event in colorectal carcinogenesis. Serum TFF1 may be a potential useful marker for patients with colorectal carcinoma.

  • Aberrant expression of Trefoil Factor 3 is associated with colorectal carcinoma metastasis.
    Journal of Cancer Research and Therapeutics, 2013
    Co-Authors: You-guang Huang, Yun-feng Li, Li-ping Wang, Yun Zhang
    Abstract:

    Background: Recent evidence has indicated that the Trefoil Factor family possesses pivotal roles in the progression of human cancer. Aberrant expression of Trefoil Factor 3 (TFF3) has been reported to correlate with an aggressive tumor phenotype. However, the clinical importance of TFF3 expression in colorectal carcinomas (CRCs) has rarely been addressed. Purpose: To investigate the putative role of TFF3 in colorectal carcinogenesis and progress, and to clarify whether TFF3 could be a serum marker for CRCs. Materials and Methods: Fifty-six CRCs were sequenced for TFF3 mutations; subsets of the primary tumors were subjected to real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry analyses and serum TFF3 was detected by enzyme-linked immunosorbent assay (ELISA) for patients with CRCs. Results: No variants were detected in the code area of TFF3; TFF3 mRNA is increased in CRCs but not up to statistic significance when compared with paired normal colonic mucosa; TFF3 staining by immunohistochemistry in primary CRCs showed that increased expression of TFF3 is associated with lymph node metastases(LNM), and no significant differences were found with respect to patient's sex, cancer cell differentiation and stage. Serum TFF3 is significantly elevated in patients with CRCs, especially CRCs with LNM. Conclusion: The results indicate that TFF3 point mutations seem to be a rare event in colorectal carcinogenesis; TFF3 expression may play a role in promoting lymph node metastases of CRCs and serum TFF3 may be a potential useful marker for patients with CRCs and their metastases.

Daniel K Podolsky - One of the best experts on this subject based on the ideXlab platform.

  • intestinal Trefoil Factor tff3 promotes re epithelialization of corneal wounds
    Journal of Biological Chemistry, 2008
    Co-Authors: Friedrich Paulsen, Daniel K Podolsky, Chee Wai Woon, Deike Varoga, Anne Jansen, Fabian Garreis, Kristin Jager, Philipp Steven, Nick Barker
    Abstract:

    Abstract Disorders of wound healing characterized by impaired or delayed re-epithelialization are a serious medical problem. These conditions affect many tissues, are painful, and are difficult to treat. In this study using cornea as a model, we demonstrate the importance of Trefoil Factor 3 (TFF3, also known as intestinal Trefoil Factor) in re-epithelialization of wounds. In two different models of corneal wound healing, alkali- and laser-induced corneal wounding, we analyzed the wound healing process in in vivo as well as in combined in vivo/in vitro model in wild type (Tff3+/+) and Tff3-deficient (Tff3-/-) mice. Furthermore, we topically applied different concentrations of recombinant human TFF3 (rTFF3) peptide on the wounded cornea to determine the efficacy of rTFF3 on corneal wound healing. We found that Tff3 peptide is not expressed in intact corneal epithelium, but its expression is extensively up-regulated after epithelial injury. Re-epithelialization of corneal wounds in Tff3-/- mice is significantly prolonged in comparison to Tff3+/+ mice. In addition, exogenous application of rTFF3 to the alkali-induced corneal wounds accelerates significantly in in vivo and in combined in vivo/in vitro model wound healing in Tff3+/+ and Tff3-/- mice. These findings reveal a pivotal role for Tff3 in corneal wound healing mechanism and have broad implications for developing novel therapeutic strategies for treating nonhealing wounds.

  • Intestinal Trefoil Factor/TFF3 Promotes Re-epithelialization of Corneal Wounds
    Journal of Biological Chemistry, 2008
    Co-Authors: Friedrich Paulsen, Daniel K Podolsky, Chee Wai Woon, Deike Varoga, Anne Jansen, Fabian Garreis, Kristin Jager, Philipp Steven, Nick Barker
    Abstract:

    Abstract Disorders of wound healing characterized by impaired or delayed re-epithelialization are a serious medical problem. These conditions affect many tissues, are painful, and are difficult to treat. In this study using cornea as a model, we demonstrate the importance of Trefoil Factor 3 (TFF3, also known as intestinal Trefoil Factor) in re-epithelialization of wounds. In two different models of corneal wound healing, alkali- and laser-induced corneal wounding, we analyzed the wound healing process in in vivo as well as in combined in vivo/in vitro model in wild type (Tff3+/+) and Tff3-deficient (Tff3-/-) mice. Furthermore, we topically applied different concentrations of recombinant human TFF3 (rTFF3) peptide on the wounded cornea to determine the efficacy of rTFF3 on corneal wound healing. We found that Tff3 peptide is not expressed in intact corneal epithelium, but its expression is extensively up-regulated after epithelial injury. Re-epithelialization of corneal wounds in Tff3-/- mice is significantly prolonged in comparison to Tff3+/+ mice. In addition, exogenous application of rTFF3 to the alkali-induced corneal wounds accelerates significantly in in vivo and in combined in vivo/in vitro model wound healing in Tff3+/+ and Tff3-/- mice. These findings reveal a pivotal role for Tff3 in corneal wound healing mechanism and have broad implications for developing novel therapeutic strategies for treating nonhealing wounds.

  • chemotherapy and radiotherapy induced intestinal damage is regulated by intestinal Trefoil Factor
    Gastroenterology, 2004
    Co-Authors: Paul L Beck, Josee Wong, Yan Li, Sunita Swaminathan, Ramnik J Xavier, Kathryn L Devaney, Daniel K Podolsky
    Abstract:

    Abstract Background & Aims: Injury to the intestinal mucosa is frequently a dose-limiting complication of radiotherapy and chemotherapy. Approaches to limit the damage to the intestine during radiation and chemotherapy have been largely ineffective. Trefoil Factors are produced throughout the gastrointestinal tract and regulate cell migration, restitution, and repair. Studies were undertaken to define the role of intestinal Trefoil Factor in modulating the intestinal response to chemotherapy and radiation. Methods: The effect of intestinal Trefoil Factor on migration and cell survival in intestinal epithelial monolayer exposed to methotrexate was studied in vitro. Chemotherapy and radiation damage was assessed in wild-type and intestinal Trefoil Factor-null mice in the presence or absence of supplemental intestinal Trefoil Factor administered in drinking water. Results: Radiation and chemotherapy induced a marked reduction in goblet cell number and intestinal Trefoil Factor messenger RNA, as well as intestinal Trefoil Factor promoter activity. Intestinal Trefoil Factor improved intestinal epithelial cell viability and wound repair after chemotherapy exposure in vitro. Intestinal Trefoil Factor-deficient mice (intestinal Trefoil Factor −/− ) were more susceptible to chemotherapy- and radiation-induced mucositis. Oral recombinant intestinal Trefoil Factor reduced the severity of both chemotherapy-induced and chemotherapy/radiotherapy-induced intestinal mucositis. Conclusions: These studies suggest that intestinal Trefoil Factor is involved in protection against and recovery from intestinal mucositis induced by radiation and chemotherapy.

  • A silencer inhibitor confers specific expression of intestinal Trefoil Factor in gobletlike cell lines
    American Journal of Physiology-gastrointestinal and Liver Physiology, 2001
    Co-Authors: Dai Iwakiri, Daniel K Podolsky
    Abstract:

    Intestinal Trefoil Factor (ITF) is selectively expressed in intestinal goblet cells. Previous studies identified cis-regulatory elements in the proximal promoter of ITF, but these were insufficient...

  • intestinal Trefoil Factor confers colonic epithelial resistance to apoptosis
    Proceedings of the National Academy of Sciences of the United States of America, 2000
    Co-Authors: Koichi Kinoshita, Douglas Taupin, Daniel K Podolsky
    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 (TNFR/Fas) or stress-related (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.

Andrew S Giraud - One of the best experts on this subject based on the ideXlab platform.

R J Playford - One of the best experts on this subject based on the ideXlab platform.

  • effect of ectopic expression of rat Trefoil Factor family 3 intestinal Trefoil Factor in the jejunum of transgenic mice
    Journal of Biological Chemistry, 2001
    Co-Authors: Tania Marchbank, Andrew S Giraud, Richard Poulsom, N A Wright, Robert A Goodlad, Steven F Moss, Janusz Jankowski, R J Playford
    Abstract:

    Abstract To further examine the function of the Trefoil Factor family (TFF), the expression of which is up-regulated at sites of injury, we have produced transgenic mice that chronically express rat TFF3 within the jejunum (using a rat fatty acid-binding protein promoter). The expression of rat TFF3 was limited to the villi of the jejunum and had no effect on base-line morphology. Rat TFF3 expression did result, however, in a reduced sensitivity to indomethacin (85 mg/kg subcutaneously), which only caused a 29% reduction in villus height in transgenics versus 51% reduction in controls (p < 0.01). Indomethacin increased initial intestinal epithelial cell proliferation and migration, but the presence of rat TFF3 caused no additional change in proliferation (bromodeoxyuridine), cell migration ([3H]thymidine and bromodeoxyuridine), apoptosis (terminal deoxyuridine nucleotidyl nick end labeling), or E-cadherin immunostaining. In vitrostudies following changes in resistance of intestinal strips in Ussing chambers (voltage-clamp technique) showed increased base-line resistance in the rat TFF3-expressing region (326 ± 60versus 195 ± 48 ohm·cm2 in controls,p < 0.05) and reduced the fall in resistance following HCl exposure by about 40% (p < 0.01). Overexpression of TFF3 stabilizes the mucosa against noxious agents, supporting its role in mucosal protection/repair. It may therefore provide a novel approach to the prevention and/or treatment of intestinal ulceration.

  • combined intestinal Trefoil Factor and epidermal growth Factor is prophylactic against indomethacin induced gastric damage in the rat
    Clinical Science, 1995
    Co-Authors: Rebecca Chinery, R J Playford
    Abstract:

    1. The availability of recombinant epidermal growth Factor provides a potentially exciting development for the treatment of gastrointestinal ulceration. However, because of its potent mitogenic activity, there is a need for strategies which reduce the dose required. Intestinal Trefoil Factor stimulates mucosal healing without increasing proliferation. Studies were undertaken to examine the biological effects of rat intestinal Trefoil Factor and/or human epidermal growth Factor upon gastrointestinal epithelial cell functions pertinent to mucosal protection, using two wounding models. 2. The study of epithelial restitution in vitro demonstrated a marked synergistic effect on the rate of migration of the wound edge when intestinal Trefoil Factor was used in combination with epidermal growth Factor. There was no increased cellular proliferation due to the addition of intestinal Trefoil Factor to the cells when given alone, or to the stimulatory effect of cells treated with epidermal growth Factor. In the rat model of gastric ulceration, the presence of both epidermal growth Factor and intestinal Trefoil Factor protected against the development of indomethacin-induced gastric lesions. 3. We conclude that combination therapy of epidermal growth Factor with intestinal Trefoil Factor could provide a more potent, safer approach to the treatment of human gastrointestinal ulceration.

Werner Hoffmann - One of the best experts on this subject based on the ideXlab platform.

  • Trefoil Factor family unresolved questions and clinical perspectives
    Trends in Biochemical Sciences, 2019
    Co-Authors: Nayara Braga Emidio, Werner Hoffmann, Stuart M Brierley, Markus Muttenthaler
    Abstract:

    The Trefoil Factor family of peptides (TFF1, TFF2, TFF3) with their lectin activities play important roles in mucosal protection and repair. However, major gaps in understanding their molecular function have hampered therapeutic development for gastrointestinal disorders. We provide here a critical overview of the status quo.

  • TFF (Trefoil Factor Family) Peptides
    Handbook of Biologically Active Peptides, 2006
    Co-Authors: Werner Hoffmann
    Abstract:

    ABSTRACT The TFF (Trefoil Factor family) domain is an ancient cysteine-rich shuffled module forming the basic unit for the family of TFF peptides (in short, TFFs). TFFs are secretory products typical of mucin-producing cells of the gastrointestinal (GI) tract. Three mammalian TFFs are known consisting of one (TFF1 and TFF3) or two TFF domains (TFF2); in amphibia the pattern is more complex—xP1 (single TFF domain), xP4.1 and xP4.2 (both consisting of four TFF domains) have been characterized in the GI tract thus far. TFFs play a key role in the maintenance of the GI surface integrity in health and disease by supporting a variety of different mucosal defense and repair mechanisms. Their multiple molecular functions include (1) formation of the mucous barrier, (2) enhancement of rapid mucosal repair (restitution), (3) modulation of mucosal differentiation processes, and (4) modulation of the mucosal immune response. However, TFFs are also connected with oncogenic pathways.

  • rolling in the clover Trefoil Factor family tff domain peptides cell migration and cancer
    FEBS Letters, 1997
    Co-Authors: N A Wright, Werner Hoffmann, William R Otto, Lars Thim
    Abstract:

    Trefoil Factor family (TFF)-domain peptides 1–3 are mucin-associated molecules, largely found in epithelia of gastro-intestinal tissues. Structurally similar, resistant to enzymatic degradation, they are up-regulated around areas of epithelial damage such as ulcers. Transgenic expression or exogenous peptide ameliorates or prevents gastric mucosal damage due to indomethacin and some are rapidly up-regulated after cryogenic burns. A role in promoting cell migration is strongly suggested. Knockout mice lacking TFF1 or TFF3 show significant pathology, with the former developing gastric tumours. A recent Conference Philippe Laudat agreed upon a new nomenclature for these peptides.

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