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Hepatoma-derived growth factor participates in Helicobacter Pylori-induced neutrophils recruitment, gastritis and gastric carcinogenesis

Abstract

Helicobacter pylori (Hp) infection and overexpression of hepatoma-derived growth factor (HDGF) are involved in gastric carcinogenesis. However, the relationship between Hp-induced gastric diseases and HDGF upregulation is not yet completely clear. This study aimed to elucidate the role of HDGF in Hp-induced gastric inflammation and carcinogenesis. HDGF expression in gastric biopsy and serum from patients was analyzed by immunohistochemical and ELISA analysis, respectively. Hp and gastric cells coculture system was employed to delineate the mechanism underlying HDGF overexpression during Hp infection. The gastric pathologies of wild type and HDGF knockout mice after Hp infection were investigated by immunohistochemical, immunoblot, and immunofluorescence analyses. HDGF level was significantly elevated in patients with Hp infection or intestinal metaplasia (IM, a precancerous lesion), and HDGF overexpression was positively correlated with Hp load, IM, and neutrophil infiltration in gastric biopsy. Consistently, patients with Hp infection or IM had significantly higher serum HDGF level. By using coculture assay, Hp infection led to HDGF upregulation and secretion in gastric cells. In mice model, HDGF ablation significantly suppressed the Hp-induced neutrophil infiltration and inflammatory TNF-α/COX-2 signaling, thereby relieving the tissue damage in stomach. This was further supported by that recombinant HDGF (rHDGF) stimulated the differentiation/chemotaxis of cultured neutrophils and oncogenic behaviors of gastric cells. Time series studies showed that Hp infection elicited an inflammatory TNF-α/HDGF/COX-2 cascade in stomach. HDGF secretion by Hp infection promotes the neutrophils infiltration and relays Hp-induced inflammatory signaling. Thus, HDGF may constitute a novel diagnostic marker and therapeutic target for Hp-induced gastritis and carcinogenesis.

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Acknowledgements

This work was supported by the grants from National Research Program for Biopharmaceuticals (103NPP1002-3, MOST103-2325-B-110-002), from Ministry of Science and Technology (107-2320-B-110-003), from Kaohsiung Medical University Research Center Grant (KMU-TC108A02), from the Center for Infectious Disease and Cancer Research, Kaohsiung Medical University (KMUTP105E20), from Kaohsiung Medical University Research Foundation (KMUOR105), from Kaohsiung Medical University Center for Stem Cell Research (KMUTP105G01), from the NSYSU-KMU Joint Research Project (NSYSUKMU103 -I010, NSYSUKMU-105-P023, NSYSUKMU-106-P020) and Kaohsiung Armed Forces General Hospital (103-6). In addition, the authors thank Dr. Sebastian Franken (Institute of Physiological Chemistry, University of Bonn, Bonn, Germany) for sharing HDGF-KO mice.

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Study concept and design: MHT and DCW; Acquisition of data: THC, STH, CJL, HWL, BCW, SMY, JCW, YCC, PHT; Analysis and interpretation of data: THC, STH, SFY, CJL, HWL; Drafting of the manuscript: THC and STH; Statistical analysis: THC, STH, SFY, CJL, HWL; Obtained funding: MHT, DCW and SCH; Technical support: SFY, SCH, ZHW, YMC, WJW and MLK; Material support: SFY, SCH, ZHW, YMC, WJW and MLK; Study supervision: MHT and DCW.

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Correspondence to Deng-Chyang Wu or Ming-Hong Tai.

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Chu, TH., Huang, ST., Yang, SF. et al. Hepatoma-derived growth factor participates in Helicobacter Pylori-induced neutrophils recruitment, gastritis and gastric carcinogenesis. Oncogene 38, 6461–6477 (2019). https://doi.org/10.1038/s41388-019-0886-3

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