Abstract
Background/Aim Although IL-6-mediated activation of the signal transduction and activator of transcription 3 (STAT3) axis is involved in inflammation and cancer, the role of STAT3 in Helicobacter-associated gastric inflammation and carcinogenesis is unclear. This study investigated the role of STAT3 in gastric inflammation and carcinogenesis and examined the molecular mechanism of Helicobacter-induced gastric phenotypes. Methods To evaluate the contribution of STAT3 to gastric inflammation and carcinogenesis, we used wild-type (WT) and gastric epithelial conditional Stat3-knockout (Stat3Δgec) mice. Mice were infected with Helicobacter felis and euthanized at 18 months postinfection. Mouse gastric organoids were treated with recombinant IL-6 (rIL-6) or rIL-11 and a JAK inhibitor (JAKi) to assess the role of IL-6/STAT3 signaling in vitro. Results Inflammation and mucous metaplasia were more severe in WT mice than in Stat3Δgec mice. The epithelial cell proliferation rate and STAT3 activation were increased in WT mice. Application of rIL-6 and rIL-11 induced expression of intestinal metaplasia-associated genes, such as Tff2; this induction was suppressed by JAKi administration. Conclusions Loss of STAT3 signaling in the gastric mucosa leads to decreased epithelial cell proliferation, atrophy, and metaplasia in the setting of Helicobacter infection. Therefore, activation of STAT3 signaling may play a key role in Helicobacter-associated gastric carcinogenesis.
Highlights
Helicobacter pylori infection, a major risk factor for gastric cancer, drives the initiation and progression of mucosal atrophy, intestinal metaplasia, and dysplasia toward gastric cancer via intracellular signaling pathways, such as the interleukin-6- (IL-6-) IL-11-JAK/STAT pathway [1,2,3]
Because gastric carcinogenesis results from prolonged gastritis due to long-term Helicobacter infection, we investigated the role of signal transduction and activator of transcription 3 (STAT3) in gastric carcinogenesis using Stat3Δgec mice with long-term Helicobacter infection [22,23,24]
Stat3Δgec mice were healthy, and no evidence of growth disturbance was detected during the observation period in the absence of H. felis infection
Summary
Helicobacter pylori infection, a major risk factor for gastric cancer, drives the initiation and progression of mucosal atrophy, intestinal metaplasia, and dysplasia toward gastric cancer via intracellular signaling pathways, such as the interleukin-6- (IL-6-) IL-11-JAK/STAT pathway [1,2,3]. The IL-6 family of cytokines binds to the α-subunit of their specific receptors, associates with gp130 homodimers at the cell membrane, and activates the SHP-2/ERK and JAK/STAT signaling pathways [4,5,6]. STAT3 activation in malignancy, suggesting a role for inflammation in carcinogenesis [9,10,11]. Inflammation can initiate carcinogenesis in various organs, and continuous activation of STAT3 plays an important role in the initiation of inflammation and cellular transformation in gastric cancer and in several other cancers [8, 14]. Activation of STAT3 induced by Helicobacter has been reported in gastric cancer cell lines and H. felis-infected mice [21], the precise role of STAT3 in Helicobacter-induced gastric inflammation and metaplasia is unclear. We used a gastric organoid culture system to assess the mechanism(s) underlying inflammation-associated metaplasia and cancer
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