Trefoil factors — new markers of gastrointestinal mucosal barrier

Cover Page


Cite item

Full Text

Abstract

Trefoil factors (TFFs) are peptides containing a cloverleaf-like structure, which are synthesized in diverse organs including various regions of the human brain (presumably involved in nervous system development and differentiation), thyroid gland, mammary gland, uterus, prostate gland, conjunctiva, respiratory tract, salivary glands, and gall bladder, which peaks in diverse gastrointestinal tract mucosa: TFF-1 — in the stomach, TFF-2 — in the stomach and duodenum, and TFF-3 — in the gut. An increasing body of studies indicate not only about a widely distributed trefoil factors in vivo but also points at their important regulatory functions. In particular, TFFs affect cell adhesion by enhancing epithelial cell migration. Recovery of reversibly damaged epithelial structures called restitution is also facilitated due to TFF-related antiapoptotic effect (anoikis resistance). In contrast, TFF-mediated proangiogenic effects can promote tumor angiogenesis, whereas their immunomodulatory effects include an influence on expression of pro-inflammatory and defense factors (including nitric oxide, cytokines, and defensins). Moreover, TFFs interacting with mucin may increase mucus viscosity, thereby protecting the mucosal layers against ulcerogenic agents. However, bronchial asthma maybe aggravated by elevating mucus viscosity in the respiratory tract due to TFF-2. In addition, TFF expression level is associated with pathogenesis of inflammatory diseases in the gastrointestinal tract. It was shown that modality of changes in TFF level might differ depending on anatomical location and severity of lesions. Changing TFF level plays an important role in oncogenesis. For instance, gastric and colorectal cancer is accompanied by upregulated TFF-1 expression. Importantly, TFF amount is considered as a diagnostic predictor due to being associated with carcinogenesis stage, metastasis as well as sensitivity to chemotherapy in gastrointestinal cancer. In addition, a role potentially played by TFFs in other malignancies including retinoblastoma, breast cancer, and thyroid carcinoma has been extensively examined. Thus, an expanding range of experimental and clinical data evidence that trefoil factors maybe considered as a promising marker of gastrointestinal and oncology diseases.

About the authors

A. V. Shestopalov

Pirogov Russian National Research Medical University; Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology; Center of the Strategic Planning

Email: al-shest@yandex.ru

Alexander V. Shestopalov - PhD, MD (Medicine), Professor, Vice Director of the High School of Molecular and Experimental Medicine at Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology; Head of the Department of Biochemistry and Molecular Biology, Pirogov Russian National Research Medical University; Professor of the Center of the Strategic Planning.

117997, Moscow, Samory Mashela str., 1.

Phone: +7 (495) 287-65-70.

Russian Federation

A. S. Dvornikov

Pirogov Russian National Research Medical University

Email: bio-tav@yandex.ru

PhD, MD (Medicine), Dean of the Medical Faculty, Pirogov Russian National Research Medical University.

Russian Federation

O. V. Borisenko

Pirogov Russian National Research Medical University

Email: borisenko_olga07@mail.ru

PhD, MD (Medicine), Associate Professor, Department of Biochemistry and Molecular Biology, Pirogov Russian National Research Medical University.

Russian Federation

A. V. Tutelyan

Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology; Central Research Institute of Epidemiology of the Federal Service for Surveillance on Customer Rights Protection and Human Wellbeing

Author for correspondence.
Email: bio-tav@yandex.ru

RAS Corresponding Member, PhD, MD (Medicine), Professor, Head of the Department of Molecular Immunology, Infectology and Pharmacotherapy, and the Laboratory of Molecular Visualization, Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology; Head of the Laboratory of Infections Associated with the Provision of Medical Care, Central Research Institute of Epidemiology of the Federal Service for Surveillance on Customer Rights Protection and Human Wellbeing.

Russian Federation

References

  1. Шестопалов А.В., Мирошниченко Ю.А., Рымашевский А.Н. Содержание муцинов (MUC 5 AC, MUC 6) и трефоилового пептида-3 (TFF-3) в эндометрии и цервико-вагинальном секрете у женщин с физиологической беременностью // Фундаментальные исследования. 2013. T. 12, № 1. С. 104–106.
  2. Шестопалов А.В., Трофименко О.В., Шестопалова М.А. Уровень трефоиловых пептидов (TFF-1 и TFF-2) у детей с хроническими гастродуоденитами // Фундаментальные исследования. 2012. T. 10, № 2. С. 363–366.
  3. Aamann L., Vestergaard E.M., Gronberg H. Trefoil factors in inf lammatory bowel disease. World J. Gastroenterol., 2014, vol. 20, no. 12, pp. 3223–3230. doi: 10.3748/wjg.v20.i12.3223
  4. Aihara E., Engevik K.A., Montrose M.H. Trefoil factor peptides and gastrointestinal function. Ann. Rev. Phys., 2017, vol. 79, pp. 357–380. doi: 10.1146/annurev-physiol-021115-105447
  5. Andoh A., Kinoshita K., Rosenberg I., Podolsky D.K. Intestinal Trefoil Factor Induces Decay-Accelerating Factor Expression and Enhances the Protective Activities Against Complement Activation in Intestinal Epithelial Cells. J. Immunol., 2001, vol. 167, pp. 3887–3893. doi: 10.4049/jimmunol.167.7.3887
  6. Barrera G.J., Tortolero G.S. Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins. Bratislavské Lekárske Listy, 2016, vol. 117, no. 6, pp. 332–339.
  7. Belovari T., Bijelić N., Tolušić Levak M., Baus Lončar M. Trefoil factor family peptides TFF1 and TFF3 in the nervous tissue of developing mouse embryo. Bosn. J. Med. Sci., 2015, vol. 15, no. 1, pp. 33–37. doi: 10.17305/bjbms.2015.251
  8. Bossenmeyer-Pourié C., Kannan R., Ribieras S., Wendling C., Stoll I., Thim L., Tomasetto C., Rio M.C. The trefoil factor 1 participates in gastrointestinal cell differentiation by delaying G1-S phase transition and reducing apoptosis. J. Cell. Biol., 2002, vol. 157, pp. 761–770. doi: 10.1083/jcb200108056
  9. Busch M., Dünker N. Trefoil factor family peptides—friends or foes? Biomol. Concepts, 2015, vol. 6, no. 5–6, pp. 343–359. doi: 10.1515/bmc-2015-0020
  10. Chan V.Y., Chan M.W., Leung W.K., Leung P.S., Sung J.J., Chan F.K. Intestinal trefoil factor promotes invasion in non-tumorigenic Rat-2 fibroblast cell. Regul. Pept., 2005, vol. 127, pp. 87–94. doi: 10.1016/j.regpep.2004.10.016
  11. Chen Y.H., Lu Y., De Plaen I.G., Wang L.Y., Tan X.D. Transcription factor NF-kappaB signals antianoikic function of trefoil factor 3 on intestinal epithelial cells. Biochem. Biophys. Res. Commun., 2000, vol. 274, pp. 576–582. doi: 10.1006/bbrc.2000.3176
  12. Choudhary A., Smitha C.N., Suresh D.K. Trefoils: an unexplored natural protective shield of oral cavity. J. Oral Biol. Craniofac. Res., 2015, vol. 5, no 3, pp. 226–231. doi: 10.1016/j.jobcr.2015.06.009
  13. Dhar D.K., Wang T.C., Tabara H., Tonomoto Y., Maruyama R., Tachibana M., Kubota H., Naqasue N. Expression of trefoil factor family members correlates with patient prognosis and neoangiogenesis. Clin. Cancer Res., 2005, vol. 11, pp. 6472–6478. doi: 10.1158/1078-0432.CCR-05-0671
  14. Eder P., Stawczyk-Eder K., Korybalska K., Czepulis N., Luczak J., Lykowska-Szuber L., Krela-Kazmierczak I., Linke K., Witowski J. Trefoil factor-3 is not a useful marker of mucosal healing in Crohn’s disease treated with anti-TNF-α antibodies. World J. Gastroenterol., 2017, vol. 23, no. 1, pp. 135–140. doi: 10.3748/wjg.v23.i1.135
  15. Emami S., Le Floch M., Bruyneel E., Thim L., May F., Westley B., Rio M., Mareel M., Gespach C. Induction of scattering and cellular invasion by trefoil peptides in src- and RhoA-transformed kidney and colonic epithelial. FASEB J., 2001, vol. 15, pp. 351–361. doi: 10.1096/fj.00-0355com
  16. Esposito R., Morello S., Vllahu M. Eletto D., Porta A., Tosco A. Gastric TFF1 expression from acute to chronic Helicobacter infection. Front Cell Infect. Microbiol., 2017, vol. 7, pp. 434. doi: 10.3389/fcimb.2017.00434
  17. Feng G., Zhang Y., Yuan H., Bai R., Zheng J., Zhang J., Song M. DNA methylation of tretoil factor 1 (TFF1) is associated with the tumorogenesis of gastric carcinoma. Mol. Med. Rep., 2014, vol. 9, no. 1, pp. 109–117. doi: 10.3892/mmr.2013.1772
  18. Fitzgerald A.J., Pu M., Marchbank T., Westley B.R., May F.E., Boyle J., Yadollahi-Farsani M., Ghosh S., Playford R.J. Synergistic effects of systemic trefoil factor family 1 (TFF1) peptide and epidermal growth factor in a rat model of colitis. Peptides, 2004, vol. 25, pp. 793–801. doi: 10.1016/j.peptides.2003.12.022
  19. Frisch S.M., Screaton R.A. Anoikis mechanisms. Curr. Opin. Cell. Biol., 2001, vol. 13, pp. 555–562.
  20. Furuta G.T., Turner J.R., Taylor C.T., Hershberg R.M., Comerford K., Narravula S., Podolsky D.K., Colgan S.P. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J. Exp. Med., 2001, vol. 193, pp. 1027–1034.
  21. Giraud A.S., Pereira P.M., Thim L., Parker L.M., Judd L.M. TFF-2 inhibits iNOS/NO in monocytes, and nitrated protein in healing colon after colitis. Peptides, 2004, vol. 25, no. 5, pp. 803–809. doi: 10.1016/j.peptides.2004.01.019
  22. Gouyer V., Wiede A., Buisine M.P. Dekeyser S., Moreau O., Lesuff leur T., Hoffman W., Huet G. Specific secretion of gel-forming mucins and TFF peptides in HT-29 cells of mucin-secreting phenotype. Biochim. Biophys. Acta, 2001, vol. 1539, pp. 71–84.
  23. Greeley M.A., Van Winkle L.S., Edwards P.C. Plopper C.G. Airway trefoil factor expression during naphthalene injury and repair. Toxicol Sci., 2010, vol. 113, no. 2, pp. 453–467. doi: 10.1093/toxsci/kfp268
  24. Große-Kreul J., Busch M., Winter C., Pikos S., Stephan H., Dünker N. Forced trefoil factor family peptide 3 (TFF3) expression reduces growth, viability, and tumorigenicity of human retinoblastoma cell lines. PLoS One, 2016, vol. 11, no. 9, pp. e0163025. doi: 10.1371/journal.pone.0163025
  25. Hensel K.O., Boland V., Postberg J., Zilbauer M., Heuschkel R., Vogel S., Gödde D., Wirth S., Jenke A.C. Differential expression of mucosal trefoil factors and mucins in pediatric inf lammatory bowel diseases. Sci. Rep., 2014, vol. 4, pp. 7343. doi: 10.1038/srep07343
  26. Henze D., Doecke W.D., Hornung D., Aqueusop I., von Ahsen O., Machens K., Schmitz A.A., Gashaw I. Endometriosis leads to an increased trefoil factor 3 concentration in the peritoneal cavity but does not alter systemic levels. Reprod. Sci., 2017, vol. 24, no. 2, pp. 258–267. doi: 10.1177/1933719116653676
  27. Hoffmann W., Jagla W., Wiede A. Molecular medicine of TFF-peptides: from gut to brain. Histol. Histopathol., 2001, vol. 16, no. 1, pp. 319–334.
  28. Huang Y.G., Li Y.F., Pan B.L., Wang L.P., Zhang Y., Lee W.H., Zhang Y. Trefoil Factor 1 gene alterations and expression in colorectal carcinomas. Tumori, 2013, vol. 99, no. 6, pp. 702–707. doi: 10.1177/030089161309900610
  29. Kinoshita K., Taupin D.R., Itoh H., Podolsky D.K. Distinct pathways of cell migration and antiapoptotic response to epithelial injury: structure-function analysis of human intestinal trefoil factor. Mol. Cell. Biol., 2000, vol. 20, pp. 4680 –4690.
  30. Kjellev S., Nexø E., Thim L., Poulsen S.S. Systemically administered trefoil factors are secreted into the gastric lumen and increase the viscosity of gastric contents. Br. J. Pharmacol., 2006, vol. 149, pp. 92–99. doi: 10.1038/sj.bjp.0706840
  31. Le J., Zhang D.Y., Zhao Y., Qui W., Wang P., Sun Y. ITF promotes migration of intestinal epithelial cells through crosstalk between the ERK and JAK/STAT3 pathways. Sci. Rep., 2016, vol. 6, pp. 33014. doi: 10.1038/srep33014
  32. Li Q., Wang K., Su C., Fang J. Serum trefoil factor 3 as a protein biomarker for diagnosis of colorectal cancer. Technol. Cancer Res. Treat., 2017, vol. 16, no. 4, pp. 440 –445. doi: 10.1177/1533034616674323
  33. Lin N., Xu L.F., Sun M. The protective effect of trefoil factor 3 on the intestinal tight junction barrier is mediated by toll-like receptor 2 via a PI3K/Akt dependent mechanism. Biochem. Biophys. Res. Commun., 2013, vol. 440, no. 1, pp. 143–149. doi: 10.1016/j.bbrc.2013.09.049
  34. Madsen J., Nielsen O., Tornøe I., Thim L., Holmskov U. Tissue localization of human trefoil factors 1, 2, and 3. J. Histochem. Cytochem., 2007, vol. 55, pp. 505–513. doi: 10.1369/jhc.6A7100.2007
  35. Markićević M., Džodić R., Buta M., Kanjer K., Mandušić V., Nešković-Konstantinović Z., Nikolić-Vukosavljević D. Trefoil factor 1 in early breast carcinoma: a potential indicator of clinical outcome during the first 3 years of follow-up. Int. J. Med. Sci., 2014, vol. 11, no. 7, pp. 663–673. doi: 10.7150/ijms.8194
  36. Mhawech-Fauceglia P., Wang D., Samrao D., Liu S., DuPont N.C., Pejovic T. Trefoil factor family 3 (TFF3) expression and interaction with estrogen receptor (ER) in endometrial adenocarcinoma. Gynecol. Oncol., 2013, vol. 130, no. 1, pp. 174–180. doi: 10.1016/j.ygyno.2013.03.030
  37. Muskett F.W., May F.E., Westley B.R., Feeney J. Solution structure of the disulfide-linked dimer of human intestinal trefoil factor (TFF3): the intermolecular orientation and interactions are markedly different from those of other dimeric trefoil proteins. Biochemistry, 2003, vol. 42, pp. 15139–15147. doi: 10.1021/bi030182k
  38. Ortiz-Masiá D., Hernández C., Quintana E., Velázquez M., Cebrián S., Riaño A., Calatayud S., Esplugues J.V., Barrachina M.D. iNOS-derived nitric oxide mediates the increase in TFF2 expression associated with gastric damage: role of HIF-1. FASEB J., 2010, vol. 24, no. 1, pp. 136–145. doi: 10.1096/fj.09-137489
  39. Paterson R.W., Barlett J.W., Blennow K., Fox N.C., Alzheimer’s Disease Neuroimaging Initiative, Shaw L.M., Trojanowski J.Q., Zetterberg H., Schott J.M. Cerebrospinal f luid markers including trefoil factor 3 are associated with neurodegeneration in amyloid-positive individuals. Transl. Psychiatry, 2014, vol. 4, no. 7, pp. e419. doi: 10.1038/tp.2014.58
  40. Rodrigues S., Nguyen Q.D., Faivre S., Bruyneel E., Thim L., Westley B., May F., Flatau G., Mareel M., Gespach C., Emami S. Activation of cellular invasion by trefoil peptides and src is mediated by cyclooxygenase- and thromboxane A2 receptor-dependent signaling pathways. FASEB J., 2001, vol. 15, pp. 1517–1528.
  41. Rodrigues S., Van Aken E., Van Bocxlaer S., Attoub S., Nguyen Q.D., Bruyneel E., Westley B.R., May F.E., Thim L., Mareel M., Gespach C., Emami S. Trefoil peptides as proangiogenic factors in vivo and in vitro: implication of cyclooxygenase-2 and EGF receptor signaling. FASEB J., 2003, vol. 17, pp. 7–16. doi: 10.1096/fj.02-0201com
  42. Royce S.G., Lim C., Muljadi R.C., Samuel C.S., Ververis K., Karagiannis T.C., Giraud A.S., Tang M.L. Trefoil factor-2 reverses airway remodeling changes in allergic airways disease. Am. J. Respir. Cell. Mol. Biol., 2013, vol. 48, no. 1, pp. 135–144. doi: 10.1165/ rcmb.2011-0320OC
  43. Soriano-Izquierdo A., Gironella M., Massaguer A., May F.E., Salas A., Sans M., Poulsom R., Thim L., Piqué J.M., Panés J. Trefoil peptide TFF2 treatment reduces VCAM-1 expression and leukocyte recruitment in experimental intestinal inf lammation. J. Leukoc. Biol., 2004, vol. 75, pp. 214–223. doi: 10.1189/jlb.0803396
  44. Soutto M., Peng D., Katcha A., Chen Z., Piazuelo M.B., Washington M.K., Belkhiri A., Correa P., El-Rifai W. Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis. Gut, 2015, vol. 64, no. 7, pp. 1028–1039. doi: 10.1136/gutjnl-2014-307191
  45. Srivastava S., Kedia S., Kumar S., Pratap Mouli V., Dhingra R., Sachdev V., Tiwari V., Kurrey L., Pradhan R., Ahuja V. Serum trefoil factor 3 is a biomarker for mucosal healing in ulcerative colitis patients with minimal disease activity. J. Crohns Colitis, 2015, vol. 9, no. 7, pp. 575–579. doi: 10.1093/ecco-jcc/jjv075
  46. Thim L., Madsen F., Poulsen S.S. Effect of trefoil factors on the viscoelastic properties of mucus gels. Eur. J. Clin. Invest., 2002, vol. 32, pp. 519–527.
  47. Vandenbroucke K., Hans W., Van Huysse J., Neirynck S., Demetter P., Remaut E., Rottiers P., Steidler L. Active delivery of trefoil factors Lactococcus lactis prevents and by genetically modified heals acute colitis in mice. Gastroenterology, 2004, vol. 127, pp. 502–513.
  48. Wiils-Karp M., Rani R., Dienger K., Lewkowich I., Fox J.G., Perkins C., Lewis L., Finkelman F.D., Smith D.E., Bryce P.J., Kurt-Jones E.A., Wang T.C., Sivaprasad U., Hershey G.K., Herbert D.R. Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J. Exp. Med., 2012, vol. 209, no 3, pp. 607–622. doi: 10.1084/ jem.20110079
  49. Xiao L., Liu Y.P., Xiao C.X., Ren J.L., Guleng B. Serum TFF3 may be a pharmacodynamic marker of responses to chemotherapy in gastrointestinal cancers. BMC Clin. Pathol., 2014, vol. 14, pp. 26. doi: 10.1186/1472-6890-14-26
  50. Xue G., Huang J., Zhang H., Zhang W., Wu J., Shang X. The expression and significance of trefoil factor 3 and SDF-1/CXCR4 biological axis in papillary thyroid carcinoma. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi, 2014, vol. 28, pp. 108–112.
  51. Xue L., Aihara E., Wang T.C., Montrose M.H. Trefoil factor 2 requires Na/H exchanger 2 activity to enhance mouse gastric epithelial repair. J. Biol. Chem., 2011, vol. 286, no. 44, pp. 38375–38382. doi: 10.1074/jbc.M111.268219
  52. Zhu Y.Q., Tan X.D. TFF3 modulates NF-kappaB and a novel negative regulatory molecule of NF-kappa B in intestinal epithelial cells via a mechanism distinct from TNF-α. Am. J. Physiol. Cell Physiol., 2005, vol. 289, pp. C1085–C1093. doi: 10.1152/ajpcell.00185.200.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2019 Shestopalov A.V., Dvornikov A.S., Borisenko O.V., Tutelyan A.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 64788 от 02.02.2016.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies