Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

JAK/STAT3 Pathway in Human Intestinal Epithelial Cells During Trefoil Factor 3(TFF3) Mediated Cell Migration

Author(s): Mengmeng Zhuang, Juan Le, Bo Zhu, Wenwen Zhang, Hao Yan, Pan Zhang, Ting Wang and Yong Sun*

Volume 17, Issue 8, 2020

Page: [993 - 1000] Pages: 8

DOI: 10.2174/1570180817666200204104420

Price: $65

Abstract

Objectives: Trefoil factor family is expressed in several tissues of the body and provides gastric and intestinal protection and healing. This research aims to indicate the mechanism involved in its function.

Methods: The intestinal epithelial cells were pretreated with JAK inhibitor AG490 or the concentration of 60ug/ml human recombinant trefoil factor, while the levels of phospho-STAT3, E-cadherin and N-cadherin were detected by Western Blotting. The levels of Matrix Metalloproteinases, Ecadherin and N-cadherin were evaluated by quantitative real time PCR. The cell migration was assessed by the transwell assay and the scratch assay. The immunofluorescence method was performed to detect the reduction of molecular E-cadherin.

Results: hTFF3 activates the JAK/STAT3 pathway in HT-29 cells. The effect of JAK/STAT3 pathway mechanism on cell migration promoted by hTFF3. TFF3 promoting cell migration is associated with increased gene transcription of MMPs. hTFF3 alters E-cadherin expression. hTFF3 activates the expression of N-cadherin and down-regulates E-cadherin expression in HT-29 Cells.

Conclusion: We have shown that TFF3 activated the JAK/STAT3 pathway. TFF3 increased the level of Matrix Metalloproteinases and N-cadherin, decreased that of E-cadherin, while AG490 had the opposite effect. TFF3 accelerated cell migration and the AG490 relieved the migrating rate to control the levels. TFF3 activated JAK/STAT3 pathway which was associated with intestinal epithelial cell migration.

Keywords: Trefoil factor 3, JAK/STAT3 pathway, cell migration, cell adhesion, N-cadherin, E-cadherin.

« Previous Next »
Graphical Abstract

[1]
Thim, L. Trefoil peptides: from structure to function. Cell. Mol. Life Sci., 1997, 53(11-12), 888-903.
[http://dx.doi.org/10.1007/s000180050108] [PMID: 9447240]
[2]
Hoffmann, W. Trefoil factor family (TFF) peptides and chemokine receptors: a promising relationship. J. Med. Chem., 2009, 52(21), 6505-6510.
[http://dx.doi.org/10.1021/jm9008136] [PMID: 19888754]
[3]
Jagla, W.; Wiede, A.; Hinz, M.; Dietzmann, K.; Gülicher, D.; Gerlach, K.L.; Hoffmann, W. Secretion of TFF-peptides by human salivary glands. Cell Tissue Res., 1999, 298(1), 161-166.
[http://dx.doi.org/10.1007/s004419900087] [PMID: 10555550]
[4]
Wiede, A.; Hinz, M.; Canzler, E.; Franke, K.; Quednow, C.; Hoffmann, W. Synthesis and localization of the mucin-associated TFF-peptides in the human uterus. Cell Tissue Res., 2001, 303(1), 109-115.
[http://dx.doi.org/10.1007/s004410000297] [PMID: 11235998]
[5]
Poulsom, R.; Hanby, A.M.; Lalani, E.N.; Hauser, F.; Hoffmann, W.; Stamp, G.W. Intestinal trefoil factor (TFF 3) and pS2 (TFF 1), but not spasmolytic polypeptide (TFF 2) mRNAs are co-expressed in normal, hyperplastic, and neoplastic human breast epithelium. J. Pathol., 1997, 183(1), 30-38.
[http://dx.doi.org/10.1002/(SICI)1096-9896(199709)183:1<30::AID-PATH1085>3.0.CO;2-K] [PMID: 9370944]
[6]
Vestergaard, E.M.; Nexo, E.; Wendt, A.; Guthmann, F. Trefoil factors in human milk. Early Hum. Dev., 2008, 84(10), 631-635.
[http://dx.doi.org/10.1016/j.earlhumdev.2008.04.001] [PMID: 18502057]
[7]
Wiede, A.; Jagla, W.; Welte, T.; Köhnlein, T.; Busk, H.; Hoffmann, W. Localization of TFF3, a new mucus-associated peptide of the human respiratory tract. Am. J. Respir. Crit. Care Med., 1999, 159(4 Pt 1), 1330-1335.
[http://dx.doi.org/10.1164/ajrccm.159.4.9804149] [PMID: 10194185]
[8]
Kouznetsova, I.; Kalinski, T.; Peitz, U.; Mönkemüller, K.E.; Kalbacher, H.; Vieth, M.; Meyer, F.; Roessner, A.; Malfertheiner, P.; Lippert, H.; Hoffmann, W. Localization of TFF3 peptide in human esophageal submucosal glands and gastric cardia: differentiation of two types of gastric pit cells along the rostro-caudal axis. Cell Tissue Res., 2007, 328(2), 365-374.
[http://dx.doi.org/10.1007/s00441-006-0350-x] [PMID: 17216196]
[9]
Jagla, W.; Wiede, A.; Dietzmann, K.; Rutkowski, K.; Hoffmann, W. Co-localization of TFF3 peptide and oxytocin in the human hypothalamus. FASEB J., 2000, 14(9), 1126-1131.
[http://dx.doi.org/10.1096/fasebj.14.9.1126] [PMID: 10834934]
[10]
Paulsen, F.; Varoga, D.; Paulsen, A.; Tsokos, M. Trefoil factor family (TFF) peptides of normal human Vater’s ampulla. Cell Tissue Res., 2005, 321(1), 67-74.
[http://dx.doi.org/10.1007/s00441-005-1131-7] [PMID: 15909165]
[11]
Suemori, S.; Lynch-Devaney, K.; Podolsky, D.K. Identification and characterization of rat intestinal trefoil factor: tissue- and cell-specific member of the trefoil protein family. Proc. Natl. Acad. Sci. USA, 1991, 88(24), 11017-11021.
[http://dx.doi.org/10.1073/pnas.88.24.11017] [PMID: 1763017]
[12]
Podolsky, D.K.; Lynch-Devaney, K.; Stow, J.L.; Oates, P.; Murgue, B.; DeBeaumont, M.; Sands, B.E.; Mahida, Y.R. Identification of human intestinal trefoil factor. Goblet cell-specific expression of a peptide targeted for apical secretion. J. Biol. Chem., 1993, 268(9), 6694-6702.
[PMID: 8454642]
[13]
Sun, Y.; Wu, W.; Zhang, Y.; Lv, S.; Wang, S.; Peng, X. Intestinal trefoil factor produced in Escherichia coli promotes the healing of rat burn-induced acute gastric mucosal lesions. J. Trauma, 2008, 65(1), 163-169.
[http://dx.doi.org/10.1097/TA.0b013e318076b49f] [PMID: 18580528]
[14]
Rivat, C.; Rodrigues, S.; Bruyneel, E.; Piétu, G.; Robert, A.; Redeuilh, G.; Bracke, M.; Gespach, C.; Attoub, S. Implication of STAT3 signaling in human colonic cancer cells during intestinal trefoil factor 3 (TFF3) -- and vascular endothelial growth factor-mediated cellular invasion and tumor growth. Cancer Res., 2005, 65(1), 195-202.
[PMID: 15665295]
[15]
Nam, S.T.; Seok, H.; Kim, D.H.; Nam, H.J.; Kang, J.K.; Eom, J.H.; Lee, M.B.; Kim, S.K.; Park, M.J.; Chang, J.S.; Ha, E.M.; Shong, K.E.; Hwang, J.S.; Kim, H. Clostridium difficile toxin A inhibits erythropoietin receptor-mediated colonocyte focal adhesion through inactivation of Janus Kinase-2. J. Microbiol. Biotechnol., 2012, 22(12), 1629-1635.
[http://dx.doi.org/10.4014/jmb.1207.07063] [PMID: 23221524]
[16]
Babyatsky, M.W.; deBeaumont, M.; Thim, L.; Podolsky, D.K. Oral trefoil peptides protect against ethanol- and indomethacin-induced gastric injury in rats. Gastroenterology, 1996, 110(2), 489-497.
[http://dx.doi.org/10.1053/gast.1996.v110.pm8566596] [PMID: 8566596]
[17]
Chinery, R.; Playford, R.J. Combined intestinal trefoil factor and epidermal growth factor is prophylactic against indomethacin-induced gastric damage in the rat. Clin. Sci. (Lond.), 1995, 88(4), 401-403.
[http://dx.doi.org/10.1042/cs0880401] [PMID: 7789040]
[18]
Dignass, A.; Lynch-Devaney, K.; Kindon, H.; Thim, L.; Podolsky, D.K. Trefoil peptides promote epithelial migration through a transforming growth factor beta-independent pathway. J. Clin. Invest., 1994, 94(1), 376-383.
[http://dx.doi.org/10.1172/JCI117332] [PMID: 8040278]
[19]
Firmbach-Kraft, I.; Byers, M.; Shows, T.; Dalla-Favera, R.; Krolewski, J.J. tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene, 1990, 5(9), 1329-1336.
[PMID: 2216457]
[20]
Kawamura, M.; McVicar, D.W.; Johnston, J.A.; Blake, T.B.; Chen, Y.Q.; Lal, B.K.; Lloyd, A.R.; Kelvin, D.J.; Staples, J.E.; Ortaldo, J.R. Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc. Natl. Acad. Sci. USA, 1994, 91(14), 6374-6378.
[http://dx.doi.org/10.1073/pnas.91.14.6374] [PMID: 8022790]
[21]
Wilks, A.F.; Harpur, A.G.; Kurban, R.R.; Ralph, S.J.; Zürcher, G.; Ziemiecki, A. Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol. Cell. Biol., 1991, 11(4), 2057-2065.
[http://dx.doi.org/10.1128/MCB.11.4.2057] [PMID: 1848670]
[22]
Ghoreschi, K.; Laurence, A.; O’Shea, J.J. Janus kinases in immune cell signaling. Immunol. Rev., 2009, 228(1), 273-287.
[http://dx.doi.org/10.1111/j.1600-065X.2008.00754.x] [PMID: 19290934]
[23]
Steelman, L.S.; Pohnert, S.C.; Shelton, J.G.; Franklin, R.A.; Bertrand, F.E.; McCubrey, J.A. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 2004, 18(2), 189-218.
[http://dx.doi.org/10.1038/sj.leu.2403241] [PMID: 14737178]
[24]
Decker, T.; Müller, M.; Stockinger, S. The yin and yang of type I interferon activity in bacterial infection. Nat. Rev. Immunol., 2005, 5(9), 675-687.
[http://dx.doi.org/10.1038/nri1684] [PMID: 16110316]
[25]
Madan, E.; Prasad, S.; Roy, P.; George, J.; Shukla, Y. Regulation of apoptosis by resveratrol through JAK/STAT and mitochondria mediated pathway in human epidermoid carcinoma A431 cells. Biochem. Biophys. Res. Commun., 2008, 377(4), 1232-1237.
[http://dx.doi.org/10.1016/j.bbrc.2008.10.158] [PMID: 18996091]
[26]
O’Shea, J.J.; Lahesmaa, R.; Vahedi, G.; Laurence, A.; Kanno, Y. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat. Rev. Immunol., 2011, 11(4), 239-250.
[http://dx.doi.org/10.1038/nri2958] [PMID: 21436836]
[27]
Stark, G.R.; Cheon, H.; Wang, Y. responses to cytokines and interferons that depend upon JAKs and STATs. Cold Spring Harb. Perspect. Biol., 2018, 10(1) a028555
[http://dx.doi.org/10.1101/cshperspect.a028555] [PMID: 28620095]
[28]
Su, Y.; Yang, J.; Besner, G.E. HB-EGF promotes intestinal restitution by affecting integrin-extracellular matrix interactions and intercellular adhesions. Growth Factors, 2013, 31(1), 39-55.
[http://dx.doi.org/10.3109/08977194.2012.755966] [PMID: 23305395]
[29]
Xu, H.; Inagaki, Y.; Seyama, Y.; Du, G.; Wang, F.; Kokudo, N.; Tang, W. Expression of KL-6/MUC1 in pancreatic cancer tissues and its potential involvement in tumor metastasis. Oncol. Rep., 2011, 26(2), 371-376.
[PMID: 21617869]
[30]
Gagliano, N.; Pettinari, L.; Aureli, M.; Martinelli, C.; Colombo, E.; Costa, F.; Carminati, R.; Volpari, T.; Colombo, G.; Milzani, A.; Dalle-Donne, I.; Gioia, M. Malignant phenotype of renal cell carcinoma cells is switched by ukrain administration in vitro. Anticancer Drugs, 2011, 22(8), 749-762.
[http://dx.doi.org/10.1097/CAD.0b013e328346c7f7] [PMID: 21799470]
[31]
Takeichi, M. Cadherin cell adhesion receptors as a morphogenetic regulator. Science, 1991, 251(5000), 1451-1455.
[http://dx.doi.org/10.1126/science.2006419]

Rights & Permissions Print Cite
Article Metrics
6
1
© 2024 Bentham Science Publishers | Privacy Policy