Hesperidin Reversed Long-Term N-methyl-N-nitro-N-Nitroguanidine Exposure Induced EMT and Cell Proliferation by Activating Autophagy in Gastric Tissues of Rats

Gastric cancer is a common malignant tumor worldwide. N-methyl-N-nitro-N-nitroguanidine (MNNG) is one of the most important inducing factors of gastric cancer. Autophagy can affect the occurrence and development of gastric cancer, but the mechanism is not clear. Chemoprevention has been shown to be a rational and very promising approach to the prevention of gastric cancer. Hesperidin is a citrus flavone, an abundant polyphenol in citrus fruits and traditional Chinese medicine. It has an excellent phytochemistry that plays an intervention role in gastric cancer. However, it is unclear whether long-term exposure to MNNG will affect the occurrence of gastric cancer by regulating autophagy and whether hesperidin can play an intervention role in this process. In the present study, we demonstrated that long-term MNNG exposure inhibits autophagy in stomach tissues of rats, promotes the epithelial–mesenchymal transition (EMT) process and cell proliferation and suppresses the activity of the PI3K/AKT pathway. We further found that after rapamycin-activated autophagy, long-term MNNG exposure promoted cell proliferation and EMT were inhibited. In addition, hesperidin promotes autophagy and the activity of the PI3K/AKT pathway, as well as the suppression of proliferation and EMT in the stomach tissues of rats. Our findings indicate that hesperidin reverses MNNG-induced gastric cancer by activating autophagy and the PI3K/AKT pathway, which may provide a new basis for the early prevention and treatment of MNNG-induced gastric cancer.