Ubiquitination of ADRα1d/SerpinA1 complex stimulates hypoxia to induce gastric tumorigenesis with a combination of Helicobacter pylori and chronic stress through IL-1α

Faisal Aziz, Xiang Li, Abhijit Chakraborty, Yaqiu Zheng, Mingxia Xin, Kang Dong Liu, Zigang Dong

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Helicobacter pylori (H. pylori) has been recognized as the class I carcinogen of gastric cancer and several studies have demonstrated that chronic stress may accelerate gastric cancer progression. However, the evidence is not sufficient.

METHODS: Here, we developed a mouse model that combined H. pylori infection with chronic stress. Gastric inflammation promotes gastric tumor development progression. To evaluate the number of pro-inflammatory cells through observing the numbers of activated macrophages and neutrophils in mice gastric tumors compared with untreated mice or only treated with one factor. ADRα1d /SerpinA1 expression and localization were assessed under stress conditions and H. pylori infection, and evaluated by analyzing IL-1α, CD8, platelet, and RBC status using α- or β- blockers against gastritis to prevent gastric cancer.

RESULTS: Further mechanism study showed that stress hormones increase the number of CD8 + lymphocytes by activating ADRβ2 receptors, leading to IL-1α secretion and tumorigenicity. Gastric carcinogenesis also involves gastric muscle contraction mediated through ADRα1d/Serpina1 interaction. Specifically, we showed that the ADRα1d/SerpinA1 complex increases glucose uptake and the development of hypoxia conditions. These responses promote platelet aggregation and muscle contraction. In turn, gastric cancer cells increase lactate production and promote gastric cell proliferation through Muc-13 and IL-1α stimulation.

CONCLUSION: H. pylori infection in combination with chronic stress can lead to gastric cancer, and the synergistic effects of cytokine production (i.e. IL-1α), T lymphocyte dysfunction contributes to gastric carcinogenesis which will offer treatment opportunities for stress-associated gastric cancer and provide new strategies for the prevention and treatment of gastric cancer in clinics.

Original languageEnglish (US)
Pages (from-to)726-740
Number of pages15
JournalGastric Cancer
Issue number4
StatePublished - Jul 2022

Bibliographical note

Funding Information:
The project was supported by the National Natural Science Foundation of China (NSFC), Research Grant Nos. 81750110551, 82073075.

Publisher Copyright:
© 2022, The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.


  • Chronic stress
  • Gastric tumorigenesis
  • Helicobacter pylori (H. pylori)
  • Interleukin-1α
  • Platelets
  • α- or β- blockers

PubMed: MeSH publication types

  • Journal Article


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