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Metabolic Syndrome Develops Cardia Cancer via Nuclear Factor-E2-related Factor 2-Programmed Death-Ligand 1 Signaling

Keisuke Kusano,K. Uno,Toru Tamahara,N. Asano,Koichiro Sudo,Mizuki Tanabe,Koya Ogasawara,Takeshi Kanno,T. Koike,Ritsuko Shimizu,A. Masamune

Published 2025 in Cellular and Molecular Gastroenterology and Hepatology

ABSTRACT

Background & Aims The incidence of gastric cardia adenocarcinoma (GCA) and metabolic syndrome (MetS) have increased concurrently. Lipopolysaccharide (LPS) may be a biomarker for GCA development and treatment resistance of immune checkpoint inhibitors. We aimed to elucidate whether high-fat diet (HFD)-related endotoxemia progresses GCA via programmed death-ligand 1 (PD-L1) signaling. Methods We studied K19-Wnt1/C2mE mice fed HFD or control diet with or without systemic administration of Escherichia coli LPS ± clodronate liposomes (CLs). To clarify the role of nuclear factor E2-related factor 2 (Nrf2) in tumorigenesis, we generated Nrf2-deficient K19-Wnt1/C2mE mice. We performed further experiments using MKN7 and THP-1 cells. Results In the HFD + LPS group of K19-Wnt1/C2mE mice, tumor growth with increase in tumor cell proliferation and macrophage infiltration was observed with gut dysbiosis, gut mucosal barrier damage, endotoxemia, and insulin resistance. The expression of 8-OHdG, NAD(P)H quinone oxidoreductase 1 (Nqo1), Tumor necrosis factor (TNF)-a, phosphorylated nuclear factor-kappa B (p-NFκB), and PD-L1 was upregulated in tumors. TNF-α expression was observed in tumor cells and stromal macrophages. These effects were abolished in the HFD + LPS + CL group. In the Nrf2-deficient K19-Wnt1/C2mE mice, tumors shrank as TNF-α and PD-L1 expression decreased, without improvement of gut barrier damage and endotoxemia. LPS stimulation of phorbol 12-myristate 13-acetate-treated THP-1 cells induced the expression of TNF-α, which activated NFκB-PD-L1 signaling in cocultured MKN7 cells. LPS stimulation of MKN7 cells increased the expression of NQO1, phosphorylated NFκB, and PD-L1, and NRF2 directly regulated CD274 transcription. Conclusions HFD-related metabolic endotoxemia may promote GCA progression via PD-L1 induction in tumor cells directly through Nrf2 signaling activated by LPS and through NFκB signaling by TNF-α from LPS-activated macrophages in tumor microenvironment.

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