J Cancer 2021; 12(14):4121-4133. doi:10.7150/jca.52658

Research Paper

Chronic stress accelerates the process of gastric precancerous lesions in rats

Jiayi Zheng1,2, Weiwu Cai1,4, Xuen Lu1,3, Wei He1,4, Ding Li5, Haoyu Zhong1,3, Liangjun Yang1,2, Siyi Li1,4, Haishan Li1,6, Sereen Rafee7, Ziming Zhao8, Qi Wang1,4, Huafeng Pan1,2,4✉

1. Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
2. Institute of Gastroenterology, Guangzhou University of Chinese Medicine, China.
3. Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China.
4. Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China.
5. The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
6. Second Clinical Medical College of Guangzhou university of Chinese Medicine.
7. Rutgers University Graduate School of Biomedical Sciences, Newark, NJ, USA.
8. Guangdong Province Engineering Technology Research Institute of Traditional Chinese Medicine, Guangzhou, China.

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Citation:
Zheng J, Cai W, Lu X, He W, Li D, Zhong H, Yang L, Li S, Li H, Rafee S, Zhao Z, Wang Q, Pan H. Chronic stress accelerates the process of gastric precancerous lesions in rats. J Cancer 2021; 12(14):4121-4133. doi:10.7150/jca.52658. Available from https://www.jcancer.org/v12p4121.htm

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Abstract

Background: Gastrointestinal cancers account for 20% of all deaths worldwide. Gastric cancer (GC) patients are susceptible to psychological change, especially depression which is commonly induced by chronic stress. Gastric precancerous lesions (GPL) is an important prodromal stage in the occurrence of gastric cancer. Chronic stress influences the prognosis of GC and may influence the process of GPL as well.

Methods: Sixty SD rats were randomly divided into a control group, GPL group, and GPL+CUMS group. In the GPL group, 200μg/mL N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) free drinking method combined with intermittent fasting was applied to establish the GPL animal model. Based on this, we combined the GPL rats with chronic unpredicted mild stress (CUMS) to establish a comprehensive model. We then evaluated their behavior by open field tests and sucrose preference tests. We tested the IL-6, IL-10, TNF-α, Ghrelin, Leptin and Somatostatin (SS) levels in serum and observed the expression of Ghrelin and Gastrokine 2(GKN2) in the gastric mucosa of rats with tumors by immunofluorescence.

Results: Our results showed that GPL and GPL+CUMS rats all displayed a significantly decreased total distance and mean velocity traveled in the open field test. The percentages of sucrose preference were significantly decreased in the GPL+CUMS group compared to the control group. In addition, IL-6 and TNF-α were significantly increased in both the GPL and GPL+CUMS groups. Furthermore, the GPL+CUMS group showed significantly increased TNF-α levels in serum compared to the GPL rats. Our results showed that the expression of NF-κB, p53, and BCL-2 were significantly increased while BAX was reduced in the GPL and GPL+CUMS groups. Moreover, Ghrelin and Leptin levels in serum were significantly decreased in the GPL and GPL+CUMS groups. SS levels in serum were significantly increased in the GPL+CUMS group. Additionally, we found that the GPL+CUMS rats with tumors not only had strong expression of GKN2 on the luminal side and the lamina propria of the gastric mucosa and tumor, but also had expression of Ghrelin on the luminal side of the gastric mucosa. The areas that showed strong expression of GKN2 and Ghrelin, are all located around the blood vessels in the tumor.

Conclusions: GPL rats under chronic stress would aggravate the conditions of GPL, shorten the process of GPL, and increase the risk of tumorigenesis. In addition, the close monitoring of the mental health of cancer survivors and precancerous lesion patients is suggested to be of great significance in the prevention and treatment of cancer.

Keywords: gastric precancerous lesions (GPL), chronic stress, animal model, depression