NF-kB-dependent activation of STAT3 by H. pylori is suppressed by TFF1

Mohammed Soutto, Nadeem Bhat, Shayan Khalafi, Shoumin Zhu, Julio Poveda, Monica Garcia-Buitrago, Alexander Zaika, Wael El-Rifai

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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: 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: 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: 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.

Original languageEnglish (US)
Article number444
JournalCancer Cell International
Volume21
Issue number1
DOIs
StatePublished - Dec 2021

Keywords

  • Gastric cancer
  • H. pylori-induced
  • Helicobacter pylori
  • Inflammation
  • NFκB
  • STAT3
  • TFF1

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Fingerprint

Dive into the research topics of 'NF-kB-dependent activation of STAT3 by H. pylori is suppressed by TFF1'. Together they form a unique fingerprint.

Cite this