J Cancer 2022; 13(2):401-412. doi:10.7150/jca.65403 This issue

Research Paper

Chronic stress model simulated by salbutamol promotes tumorigenesis of gastric cancer cells through β2-AR/ERK/EMT pathway

YanJie Lu1,2#, Ying Zhang1#, HanZheng Zhao3, Qingshan Li4, Ying Liu1, YanZhen Zuo2, Qian Xu2, Hongyan Zuo1,5, Yang Li1,5✉, YuHong Li1,2✉

1. Department of Pathology, Chengde Medical College, Chengde, Hebei, China.
2. Cancer Research Laboratory, Chengde Medical College, Chengde, Hebei, China.
3. Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
4. Department of oncology, The First Affiliated Hospital of Chengde Medical College, Chengde, Hebei, China.
5. Beijing Institute of Radiation Medicine, Beijing, China.
# These authors have contributed equally to this work.

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Citation:
Lu Y, Zhang Y, Zhao H, Li Q, Liu Y, Zuo Y, Xu Q, Zuo H, Li Y, Li Y. Chronic stress model simulated by salbutamol promotes tumorigenesis of gastric cancer cells through β2-AR/ERK/EMT pathway. J Cancer 2022; 13(2):401-412. doi:10.7150/jca.65403. Available from https://www.jcancer.org/v13p0401.htm

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Abstract

Graphic abstract

Chronic stress induced by long-term anxiety and depression can promote the malignant progression of gastric cancer. β2-adrenergic receptor (β2-AR) is a critical mediator for chronic stress-induced multiple processes of tumor cells. However, the function of chronic stress in gastric cancer and its potential mechanisms in vivo and in vitro, especially at the cellular level, remain unknown. Here, we provide further evidence that chronic stress affected behavior and hypothalamus pituitary adrenal axis related hormone levels in mice. Furthermore, immunofluorescence showed that emotion affected the expression of epithelial-mesenchymal transition (EMT) markers in patients' tissues. To address this, salbutamol, a specific agonist of β2-AR, was utilized for simulating chronic stress and demonstrating the mechanism of stress in tumor progression at the molecular level both in vivo and in vitro. Salbutamol significantly induced EMT, migration and invasion via ERK (Extracellular-signal-regulated kinase) phosphorylation, and the effects were reversed by the β2-AR antagonist ICI-118,551. The promoting effects of salbutamol on EMT, migration and invasion were inhibited by phosphorylation inhibitor of ERK PD98059 in vitro. Analysis of xenograft models revealed that salbutamol significantly promoted tumor growth and adrenal volume, while ICI-118,551 inhibited these effects. In addition, salbutamol increased the expression of mesenchymal marker N-cadherin and decreased epithelial marker E-cadherin in transplanted tumor tissue. In conclusion, salbutamol simulates a chronic stress model, which promotes tumorigenesis of gastric cancer cells through β2-AR/ERK/EMT pathway.

Keywords: chronic stress, salbutamol, gastric cancer, β2-AR, ERK, epithelial-mesenchymal transition