NF-kB-dependent activation of STAT3 by H. pylori is suppressed by TFF1.
Gastric cancer
H. pylori-induced
Helicobacter pylori
Inflammation
NFκB
STAT3
TFF1
Journal
Cancer cell international
ISSN: 1475-2867
Titre abrégé: Cancer Cell Int
Pays: England
ID NLM: 101139795
Informations de publication
Date de publication:
21 Aug 2021
21 Aug 2021
Historique:
received:
03
05
2021
accepted:
08
08
2021
entrez:
22
8
2021
pubmed:
23
8
2021
medline:
23
8
2021
Statut:
epublish
Résumé
H. pylori infection is the main risk factor for gastric cancer. In this study, we investigated H. pylori-mediated activation of STAT3 and NF-κB in gastric cancer, using in vitro and in vivo models. To investigate the activation of NF-κB and STAT3 by H. pylori strains we used in vitro and in vivo mouse models, western blots, immunofluorescence, ChIP Assay, luciferase and quantitative real-time PCR assays. Following infection with H. pylori in vitro, we found an earlier phosphorylation of NF-kB-p65 (S536), followed by STAT3 (Y705). Immunofluorescence, using in vitro and in vivo models, demonstrated nuclear localization of NF-kB and STAT3, following H. pylori infection. NF-kB and STAT3 luciferase reporter assays confirmed earlier activation of NF-kB followed by STAT3. In vitro and in vivo models demonstrated induction of mRNA expression of IL-6 (p < 0.001), VEGF-α (p < 0.05), IL-17 (p < 0.001), and IL-23 (p < 0.001). Using ChIP, we confirmed co-binding of both NF-kB-p65 and STAT3 on the IL6 promoter. The reconstitution of Trefoil Factor 1 (TFF1) suppressed activation of NF-kB with reduction in IL6 levels and STAT3 activity, in response to H. pylori infection. Using pharmacologic (BAY11-7082) and genetic (IκB super repressor (IκBSR)) inhibitors of NF-kB-p65, we confirmed the requirement of NF-kB-p65 for activation of STAT3, as measured by phosphorylation, transcription activity, and nuclear localization of STAT3 in in vitro and in vivo models. Our findings suggest the presence of an early autocrine NF-kB-dependent activation of STAT3 in response to H. pylori infection. TFF1 acts as an anti-inflammatory guard against H. pylori-mediated activation of pro-inflammatory networks.
Sections du résumé
BACKGROUND
BACKGROUND
H. pylori infection is the main risk factor for gastric cancer. In this study, we investigated H. pylori-mediated activation of STAT3 and NF-κB in gastric cancer, using in vitro and in vivo models.
METHODS
METHODS
To investigate the activation of NF-κB and STAT3 by H. pylori strains we used in vitro and in vivo mouse models, western blots, immunofluorescence, ChIP Assay, luciferase and quantitative real-time PCR assays.
RESULTS
RESULTS
Following infection with H. pylori in vitro, we found an earlier phosphorylation of NF-kB-p65 (S536), followed by STAT3 (Y705). Immunofluorescence, using in vitro and in vivo models, demonstrated nuclear localization of NF-kB and STAT3, following H. pylori infection. NF-kB and STAT3 luciferase reporter assays confirmed earlier activation of NF-kB followed by STAT3. In vitro and in vivo models demonstrated induction of mRNA expression of IL-6 (p < 0.001), VEGF-α (p < 0.05), IL-17 (p < 0.001), and IL-23 (p < 0.001). Using ChIP, we confirmed co-binding of both NF-kB-p65 and STAT3 on the IL6 promoter. The reconstitution of Trefoil Factor 1 (TFF1) suppressed activation of NF-kB with reduction in IL6 levels and STAT3 activity, in response to H. pylori infection. Using pharmacologic (BAY11-7082) and genetic (IκB super repressor (IκBSR)) inhibitors of NF-kB-p65, we confirmed the requirement of NF-kB-p65 for activation of STAT3, as measured by phosphorylation, transcription activity, and nuclear localization of STAT3 in in vitro and in vivo models.
CONCLUSION
CONCLUSIONS
Our findings suggest the presence of an early autocrine NF-kB-dependent activation of STAT3 in response to H. pylori infection. TFF1 acts as an anti-inflammatory guard against H. pylori-mediated activation of pro-inflammatory networks.
Identifiants
pubmed: 34419066
doi: 10.1186/s12935-021-02140-2
pii: 10.1186/s12935-021-02140-2
pmc: PMC8380333
doi:
Types de publication
Journal Article
Langues
eng
Pagination
444Subventions
Organisme : NCI NIH HHS
ID : R01 CA138833
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA206564
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA249949
Pays : United States
Organisme : BLRD VA
ID : IK6 BX006300
Pays : United States
Organisme : BLRD VA
ID : I01 BX002115
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
Lab Invest. 2002 Oct;82(10):1319-26
pubmed: 12379766
Biomed Res Int. 2015;2015:737621
pubmed: 26064948
Environ Health Perspect. 1994 Jun;102(6-7):590-1
pubmed: 9679121
Autophagy. 2010 Nov;6(8):1125-38
pubmed: 20930550
Clin Cancer Res. 2005 Apr 1;11(7):2518-25
pubmed: 15814628
Cancer Res. 1992 Dec 15;52(24):6735-40
pubmed: 1458460
Cell Mol Gastroenterol Hepatol. 2016 Dec 27;3(2):183-191
pubmed: 28275685
Oncoscience. 2014 Jul 03;1(6):468-475
pubmed: 25594045
Cancer Res. 2019 Apr 1;79(7):1600-1611
pubmed: 30696658
Gut. 2015 Jul;64(7):1028-39
pubmed: 25107557
J Infect Dis. 2009 Sep 1;200(5):745-55
pubmed: 19604117
Innate Immun. 2017 Feb;23(2):165-174
pubmed: 27913793
Gastroenterology. 2011 Mar;140(3):879-91
pubmed: 21111741
Protein Cell. 2013 Mar;4(3):176-85
pubmed: 23483479
Int J Mol Sci. 2017 Aug 03;18(8):
pubmed: 28771198
J Biol Chem. 2001 Nov 30;276(48):44856-64
pubmed: 11546774
Science. 1996 Oct 11;274(5285):259-62
pubmed: 8824193
Gastroenterology. 2009 May;136(6):1863-73
pubmed: 19457415
Nat Rev Cancer. 2010 Jun;10(6):403-14
pubmed: 20495574
Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10646-51
pubmed: 16027366
Science. 1994 Apr 1;264(5155):95-8
pubmed: 8140422
Crit Rev Oncol Hematol. 2017 Dec;120:141-150
pubmed: 29198328
Oncotarget. 2017 Dec 14;9(6):7204-7218
pubmed: 29467962
Cancer. 2003 Nov 15;98(10):2184-91
pubmed: 14601088
Gastroenterology. 1999 Jan;116(1):90-6
pubmed: 9869606
Helicobacter. 2016 Oct;21(5):405-16
pubmed: 26910614
Front Immunol. 2018 Mar 20;9:563
pubmed: 29662489
Nat Rev Cancer. 2009 Nov;9(11):798-809
pubmed: 19851315
Oncol Lett. 2017 Feb;13(2):543-548
pubmed: 28356927
Cancer Res. 2006 Feb 1;66(3):1346-53
pubmed: 16452188
Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1023-8
pubmed: 22203967
Drug Des Devel Ther. 2015 Jun 08;9:2941-6
pubmed: 26089643
Nature. 1997 Aug 7;388(6642):539-47
pubmed: 9252185
J Clin Invest. 2011 May;121(5):1753-67
pubmed: 21490402
Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(4):196-219
pubmed: 28413197
J Clin Invest. 2009 Sep;119(9):2475-87
pubmed: 19729845
World J Gastroenterol. 2014 May 21;20(19):5660-5
pubmed: 24914325
Gastroenterology. 2000 Sep;119(3):691-8
pubmed: 10982763
Mol Nutr Food Res. 2016 Jun;60(6):1448-57
pubmed: 27079734
Cancer Res. 2001 Oct 1;61(19):6996-7001
pubmed: 11585723
Cancer Res. 2009 Jan 15;69(2):632-9
pubmed: 19147578
Oncotarget. 2014 Jul 30;5(14):5663-73
pubmed: 25015107
Cancer. 2015 Dec 15;121(24):4348-58
pubmed: 26372254
Oncotarget. 2016 May 31;7(22):32031-45
pubmed: 27074565
Biochemistry. 2005 Dec 6;44(48):15705-14
pubmed: 16313173
Cell Commun Signal. 2015 Jul 11;13:30
pubmed: 26160167
Onco Targets Ther. 2018 Apr 11;11:2063-2073
pubmed: 29695914
Sci Rep. 2018 Feb 16;8(1):3201
pubmed: 29453360
Mol Microbiol. 2018 Dec;110(5):761-776
pubmed: 30230643
Nat Commun. 2019 Jul 10;10(1):3039
pubmed: 31292446
BMC Gastroenterol. 2013 Feb 12;13:29
pubmed: 23402362
Gut Microbes. 2013 Nov-Dec;4(6):482-93
pubmed: 23989802
Cell. 2010 Mar 19;140(6):883-99
pubmed: 20303878