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Helicobacter pylori infection promotes Aquaporin 3 expression via the ROS–HIF-1α–AQP3–ROS loop in stomach mucosa: a potential novel mechanism for cancer pathogenesis

Oncogene volume 37, pages 3549–3561 (2018)Cite this article

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Abstract

Helicobacter pylori (H. pylori) is the major stomach carcinogen, but the molecular mechanism responsible for the pathogenesis of cancer development mediated by H. pylori infection is still unclear. Aquaporin 3 (AQP3), overexpressed in gastric carcinoma, has a crucial role in gastric carcinogenesis and progression. However, the triggers and precise regulations for AQP3 upregulation during gastric carcinogens also remain unknown. Here we report that H. pylori infection-mediated carcinogenesis may be mechanistically depended on the upregulation of AQP3 expression via reactive oxygen species (ROS) pathway activation in the stomach. The retrospective analyses of clinical samples from patients with gastric carcinoma and other different stages of gastric diseases indicated that AQP3 expression was positively associated with gastric mucosal disease progression and H. pylori infection status as well. Furthermore, H. pylori infection significantly upregulated AQP3 and HIF-1α expression and increased ROS amount in human gastric epithelial AGS and GES-1 cells. Blockage of ROS with inhibitors, NAC and DPI, markedly decreased the expression of AQP3 and HIF-1α in both AGS and GES-1 cells simultaneously. Furthermore, the increased AQP3 in cells was mechanistically due to the transcriptional regulation by HIF-1α. In addition, H. pylori infection exerted production of proinflammatory cytokines IL-6, IL-8, and TNF depending on AQP3 level. Importantly, these in vitro novel findings were further investigated in vivo in a mouse H. pylori infectious model. Our current studies identify the mechanistic link between H. pylori infection and AQP3 upregulation in the pathogenesis of gastric carcinoma, which involves the activation of the ROS–HIF-1α axis and the exacerbated ROS–HIF-1α–AQP3–ROS loop.

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Acknowledgements

We are grateful to Prof. Wenxi Wu (Department of General Surgery, First Affiliated Hospital, Nanjing Medical University) for his helpful suggestions and critical review of the manuscript.

Funding

This project was partially supported by the National Natural Science Foundation of China (Grant No. 81272711 to LS, the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, JX10231801 to LS), and the Key Medical Talents Program of Jiangsu Province (ZDRCA2016014 to LS).

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Author notes

  1. These authors contributed equally: Jianfei Wen, Yao Wang, Cheng Gao.

Authors and Affiliations

  1. Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, 210029, Nanjing, China

    Jianfei Wen, Yao Wang, Cheng Gao & Lizong Shen

  2. Department of Gastroenterology, First Affiliated Hospital, Nanjing Medical University, 210029, Nanjing, China

    Guoxin Zhang

  3. Department of Geriatrics, Second Affiliated Hospital, Nanjing Medical University, 210003, Nanjing, China

    Qiang You

  4. Department of Pathology, First Affiliated Hospital, Nanjing Medical University, 210029, Nanjing, China

    Weiming Zhang & Zhihong Zhang

  5. School of Public Health, Nanjing Medical University, 211166, Nanjing, China

    Shoulin Wang

  6. Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA

    Guangyong Peng

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Wen, J., Wang, Y., Gao, C. et al. Helicobacter pylori infection promotes Aquaporin 3 expression via the ROS–HIF-1α–AQP3–ROS loop in stomach mucosa: a potential novel mechanism for cancer pathogenesis. Oncogene 37, 3549–3561 (2018). https://doi.org/10.1038/s41388-018-0208-1

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