Helicobacter pylori Subdues Cytokine Signaling to Alter Mucosal Inflammation via Hypermethylation of Suppressor of Cytokine Signaling 1 Gene During Gastric Carcinogenesis

Abstract

Helicobacter pylori infection has been associated with the onset of gastric mucosal inflammation and is known to perturb the balance between T-regulatory (Treg) and T-helper 17 (Th17) cells which causes a spurt of interleukin 17 (IL17) and transforming growth factor-β (TGF-β) from Th17 and Treg cells within the gastric milieu. IL17 instigates a surge of interleukin 6 (IL6) from T-helper 1 (Th1) and T-helper 2 (Th2) cells. Further, H. pylori infection is known to stimulate the atypical DNA methylation in gastric mucosa. However, the precise role of cytokine signaling in induction of epigenetic modifications during gastric carcinogenesis is vaguely understood. In this study, patient samples from were examined using real-time polymerase chain reaction (qPCR), PCR, methylation-specific (MS)-PCR, and enzyme-linked immunosorbent assays. We found that H. pylori infection augments the production of interleukin 10 (IL10), IL6, and TGF-β in the gastric milieu and systemic circulation. Together with the IL6/IL10 mediated hyperactivation of the JAK/STAT pathway, H. pylori infection causes the inactivation of suppressor of cytokine signaling 1 (SOCS1) gene through the hypermethylation of the promoter region. This study signifies that H. pylori-mediated epigenetic silencing of SOCS1 in concert with inflammatory cytokines miffs hyperactivation of the JAK/STAT cascade during gastric carcinogenesis.

Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within

“…The JAK proteins are relatively large kinases with more than 1,100 amino acids with a molecular mass between 120–130 KDa ( Shahjahani et al, 2020 ). The JAK/STAT signaling is relatively simple and is activated by binding of extracellular ligands to the receptors that phosphorylated intracellular JAKs associated with them ( Jan et al, 2021 ). Phosphorylated JAKs in turn create the docking site for downstream substrates, including both the receptor and the STATs ( Bousoik and Montazeri Aliabadi, 2018 ).…”

Investigating the Active Substance and Mechanism of San-Jiu-Wei-Tai Granules via UPLC-QE-Orbitrap-MS and Network Pharmacology

“…As a hallmark cytokine of Th17 cells, IL-17 plays a critical role in the host's defence against bacterial infection [ 53 ]. H. pylori infection perturbs the balance between T-regulatory and Th17 cells, which causes a spurt of IL-17 and gives rise to CG [ 54 ]. Gastric cancer exhibits alterations in the ErbB receptor family and ErbB-related signalling pathways [ 55 ]; in particular, the expression level of ErbB2 is increased in gastric cancer, and ErbB2 targeted therapies for gastric cancer have proved highly beneficial [ 56 ].…”

Digesting the Role of JAK-STAT and Cytokine Signaling in Oral and Gastric Cancers

“…STAT3 is also known to promote the formation of new blood vessels by increasing expression levels of VEGF in GC ( 60 ). A recent study also highlighted the role of H. pylori in the epigenetic silencing of SOCS1 in GC through hypermethylation of the promotor region, which in addition to inflammatory cytokines, further amplifies JAK-STAT signaling in this cancer ( 204 ). Collectively, multiple human GC studies have intimated a role for JAK-STAT signaling, in particular STAT3 in multiple cell types associated with tumorigenic phenomena, such as inflammation, EMT transition and metastasis ( 60 ).…”