Mechanism of N-Methyl-N-Nitroso-Urea-Induced Gastric Precancerous Lesions in Mice.
Mechanism of N-Methyl-N-Nitroso-Urea-Induced Gastric Precancerous Lesions in Mice.
复制标题
DOI：
10.1155/2022/3780854
复制
发表时间：
2022
影响因子：
--
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Zhang SX;Tian W;Liu YL;Ni JH;Zhang D;Pan HF;Zhao ZM;Ai B;Chen ZS;Lin LZ;Liu W
胃癌前病变的早期诊断和治疗是降低胃癌发病率和致残率的关键。本研究旨在研究N-甲基-N-亚硝基脲（MNU）诱导的小鼠GPL，并阐明肿瘤发生的潜在机制。本研究利用MNU诱导的胃粘膜损伤小鼠模型，通过苏木精-伊红染色和阿辛蓝染色观察胃粘膜的组织病理学变化。采用实时定量聚合酶链反应检测胃黏膜中miR-194- 5 p的表达水平。应用透射电镜观察MNU对胃主细胞和壁细胞的影响。采用免疫组化法检测HIF-1α、vWF、Ki-67、P53的表达，Western blot法检测LKB 1-AMPK和AKT-FoxO 3信号通路关键基因蛋白表达的变化。结果表明，缺氧条件下GPL胃组织中miR-194- 5 p表达上调，miR-194- 5 p高表达与胃癌发生密切相关。从机制上讲，miR-194- 5 p通过LKB 1-AMPK和AKT-FoxO 3途径加速与代谢重编程相关的活动。此外，与miR-194- 5 p相似，AMPK和AKT的高表达水平也与GPL的代谢重编程相关。此外，我们揭示了miR-194- 5 p、p-AMPKα、p-AKT和FoxO 3a表达水平之间的相关性。这些发现表明miR-194- 5 p/FoxO 3通路对于GPL中代谢重编程的逆转是重要的。因此，探索调控miR-194- 5 p/FoxO 3a通路的策略可能为GPL的预防和治疗提供有效的策略。
Early diagnosis and treatment of gastric precancerous lesions (GPL) are key factors for reducing the incidence and morbidity of gastric cancer. The study is aimed at examining GPL in mice induced by N-methyl-N-nitroso-urea (MNU) and to illustrate the underlying mechanisms of tumorigenesis. In this study, we utilized an in vivo MNU-induced GPL mouse model, and histopathological changes of the gastric mucosa were observed by hematoxylin and eosin (H&E-stain) and alcian blue (AB-PAS-stain). The level of miR-194-5p in the gastric mucosa was determined by real-time polymerase chain reaction. We used transmission electron microscopy to observe the effects of MNU on gastric chief cells and parietal cells. We performed immunohistochemical detection of HIF-1α, vWF, Ki-67, and P53, while the changes in the protein expression of key genes in LKB1-AMPK and AKT-FoxO3 signaling pathways were detected by western blot analysis. We demonstrated that the miR-194-5p expression was upregulated under hypoxia in GPL gastric tissues, and that a high miR-194-5p expression level closely related with tumorigenesis. Mechanistically, miR-194-5p exerted the acceleration of activities related to metabolic reprogramming through LKB1-AMPK and AKT-FoxO3 pathways. Furthermore, similar to miR-194-5p, high expression levels of AMPK and AKT were also related to the metabolic reprogramming of GPL. Moreover, we revealed the correlation between the expression levels of miR-194-5p, p-AMPKα, p-AKT, and FoxO3a. These findings suggest that miR-194-5p/FoxO3 pathway is important for the reversal of metabolic reprogramming in GPL. Thus, exploring strategies to regulate the miR-194-5p/FoxO3a pathway may provide an efficient strategy for the prevention and treatment of GPL.