JAK-STAT1 Signaling Pathway Is an Early Response to Helicobacter pylori Infection and Contributes to Immune Escape and Gastric Carcinogenesis

• Published in: International journal of molecular sciences Vol. 23; no. 8; p. 4147
• Main Authors: Li, Xue, Pan, Kaifeng, Vieth, Michael, Gerhard, Markus, Li, Wenqing, Mejías-Luque, Raquel
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.04.2022; MDPI
• Subjects: Animals; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Carcinogenesis - metabolism; Cell growth; Gastric cancer; Gastric Mucosa - metabolism; Gastritis - pathology; Genes; Helicobacter Infections - complications; Helicobacter Infections - genetics; Helicobacter pylori - metabolism; Humans; Infections; Inflammation; Janus Kinases - metabolism; Kinases; Lymphocytes; Medical prognosis; Mice; Phosphorylation; Signal Transduction - genetics; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Stomach Neoplasms - pathology; gastric cancer; PD-L1; STAT1
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23084147

Helicobacter pylori infection induces a number of pro-inflammatory signaling pathways contributing to gastric inflammation and carcinogenesis and has been identified as a major risk factor for the development of gastric cancer (GC). Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates immune regulatory processes, including tumor-driven immune escape. Programmed death ligand 1 (PD-L1) expressed on gastric epithelium can suppress the immune system by shutting down T cell effector function. In a human cohort of subjects with gastric lesions and GC analyzed by proteomics, STAT1 increased along the cascade of progression of precancerous gastric lesions to GC and was further associated with a poor prognosis of GC (Hazard Ratio (95% confidence interval): 2.34 (1.04–5.30)). We observed that STAT1 was activated in human H. pylori-positive gastritis, while in GC, STAT1, and its target gene, PD-L1, were significantly elevated. To confirm the dependency of H. pylori, we infected gastric epithelial cells in vitro and observed strong activation of STAT1 and upregulation of PD-L1, which depended on cytokines produced by immune cells. To investigate the correlation of immune infiltration with STAT1 activation and PD-L1 expression, we employed a mouse model of H. pylori-induced gastric lesions in an Rnf43-deficient background. Here, phosphorylated STAT1 and PD-L1 were correlated with immune infiltration and proliferation. STAT1 and PD-L1 were upregulated in gastric tumor tissues compared with normal tissues and were associated with immune infiltration and poor prognosis based on the TCGA-STAD database. H. pylori-induced activation of STAT1 and PD-L1 expression may prevent immune surveillance in the gastric mucosa, allowing premalignant lesions to progress to gastric cancer.