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

Tian Huei Chu, Shih Tsung Huang, Sheau Fang Yang, Chia Jung Li, Hung Wei Lin, Bi Chuang Weng, Shih Ming Yang, Shih Chung Huang, Jian Ching Wu, Yi Chen Chang, Zhi Hong Wen, Yi Ming Arthur Chen, Wen Jeng Wu, Mei Lang Kung, Po Han Tai, Deng Chyang Wu, Ming Hong Tai

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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.

Original languageEnglish
Pages (from-to)6461-6477
Number of pages17
JournalOncogene
Volume38
Issue number37
DOIs
Publication statusPublished - Sep 12 2019
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    Chu, T. H., Huang, S. T., Yang, S. F., Li, C. J., Lin, H. W., Weng, B. C., Yang, S. M., Huang, S. C., Wu, J. C., Chang, Y. C., Wen, Z. H., Chen, Y. M. A., Wu, W. J., Kung, M. L., Tai, P. H., Wu, D. C., & Tai, M. H. (2019). Hepatoma-derived growth factor participates in Helicobacter Pylori-induced neutrophils recruitment, gastritis and gastric carcinogenesis. Oncogene, 38(37), 6461-6477. https://doi.org/10.1038/s41388-019-0886-3