Chronic restraint stress promotes gastric epithelial malignant transformation by activating the Akt/p53 signaling pathway via ADRB2

Abstract

The etiology of gastric cancer is associated with infectious, environmental and dietary factors, as well as genetic background. Additionally, emerging evidence has supported the vital role of chronic emotional stress on gastric carcinogenesis; however, the underlying mechanism remains unclear. The present study aimed to investigate the effects of chronic stress and a detrimental diet on gastric malignant epithelial transformation in rats. Therefore, 26 Wistar rats were randomly divided into the following four groups: i) Control; ii) detrimental diet (DD); iii) detrimental diet with chronic restraint (DR) and iv) detrimental diet with chronic restraint and propranolol treatment (DRP). ELISA was performed to detect the serum levels of epinephrine and norepinephrine. Epithelial cell apoptosis was analyzed using the TUNEL assay. The mRNA and protein expression levels of Akt and p53 were detected using reverse transcription quantitative PCR and western blotting, respectively. Pathological changes were analyzed using hematoxylin and eosin staining (H&E). The H&E staining results showed that dysplasia in the gastric mucosa occurred in two of eight rats in the DD group and in four of five rats in the DR group, whereas no dysplasia was detected in the DRP group. The apoptotic ratios of gastric epithelial cells were significantly decreased in all treatment groups compared with the control group. Adrenoceptor β2 (ADRB2) protein expression levels were increased significantly only in the DR group and this effect was significantly reduced in the DRP group. The mRNA expression levels of Akt and p53 were significantly upregulated in the DD group, and Akt mRNA expression was further elevated in the DR group. With regard to protein expression, the levels of Akt and p-Akt were significantly increased in the DR group, whereas these effects were reversed in the DRP group. Furthermore, the ratio of p-p53/p53 protein was significantly reduced in the DD or DR groups, but was reversed in the DRP group. Collectively, the findings of the present study suggested that chronic restraint stress potentially aggravates the gastric epithelial malignant transformation induced by a detrimental diet, at least partially via the Akt/p53 signaling pathway mediated via ADRB2.

Interplay between stress and cancer—A focus on inflammation

“…Furthermore, Feng et al (2012) have demonstrated that increased glucocorticoid concentrations during chronic restraint stress reduced p53 levels and function, which in turn contributed to irradiation-induced tumorigenesis. Most recently, Zong et al (2022) have pointed toward a key role of beta-adrenergic signaling in chronic stress-induced malignant transformation of gastric epithelial cells through the induction of p53 protein degradation. Aside from the impact on tumorigenesis, stress hormones can stimulate the proliferation of cancer cells by activating various signaling pathways and promoting cell division.…”