| Today,esophageal cancer is the sixth most common cause of cancer deaths worldwide and the fourth in China.There are different incidences of esophageal cancer in different regions and races in the world,therefore,environmental factors and genetic factors are both associated with the incidence of esophageal cancer.Esophageal cancer mainly divides into two pathological types of esophageal squamous cell carcinoma(ESCC)and adenocarcinoma(EAC),which esophageal squamous cell carcinoma accounts for about 90%of its incidence.High-prevalence areas of ESCC including the central region of China and Central Asia.In the field of etiology of esophageal cancer in China,nitrosamines,moldy foods and deficiency of trace elements were confirmed as the important chemical etiology of esophageal cancer science the etiology study in high ESCC incidence area in Linzhou of Henan Province during 1970s and 1980s.Among various nitrosamines,NMBzA,isolated from the high ESCC incidence area in Linxian County,is the most potent chemical carcinogen used in inducing rat esophageal carcinogenesis model.Lesions induced by NMBzA in the rat esophagus are histologically similar to human cancers of ESCC origin.So,this animal model has important sense in the study of the occurrence,development and chemoprevention of ESCC.By the studies of epithelial arising solid tumours like different colony-forming capacity in vitro,we have a better understanding of the heterogeneity of tumors today.The theory of cancer stem cells provides a theoretical basis for explaining the heterogeneity of tumor cells.At present,the finding of ESCC stem cell markers is still in the exploratory stage,and the high specificity markers still need more studies.Metformin is the most commonly used drug for type 2 diabetes mellitus.Recently,some epidemiological studies showed that metformin may reduce the incidence of a variety of solid tumors,which also including esophageal cancer.However,there are no studys show the molecular mechanism of metformin prevent the incidence and the development of esophageal cancer.In the present study,we established and optimized two models of NMBzA induced rat esophageal carcinogenesis at first.Using the serial pathological specimens from hyperplasia,atypical hyperplasia to carcinogenesis,we studied the expression of esophageal stem cell markers in rat and esophageal squamous cell carcinoma stem cell markers in human beings by immunohistochemistry.Secondly,we revealed the molecular mechanisms of metformin on chemoprevention of the NMBzA-induced(S.C.)rat esophageal carcinogenesis model.The AMPK/mTOR signal transduction pathway is the main targets of metformin in inhibiting the occurrence and development of ESCC in this animal model.Finally,through the experiments in vitro,we confirmed that metformin inhibits the proliferation,blocks the cell cycle at G0/G1 phase and promotes cell apoptosis of human immortalized esophageal epithelial cells and esophageal cancer cells.The inhibited expression of Bcl-2 and cyclin D1 in the above cells were the main mechanisms to induce the above phenomenons.In addition,the migration ability,the colony formation and tumor-spheres formation of esophageal cancer cells were significantly inhibited by metformin,which is related to the AMPK/mTOR,PI3K/Akt and Stat3 signaling pathway and the down-regulation of stem cell-related gene.In summary,our studies optimized the NMBzA induced rat esophageal carcinogenesis model and provided samples for revealing the mutation and overexpression of important genes in the development and progression of ESCC and studying the origin of stem cellsin ESCC.We confirmed the molecular mechanisms of metformin on prevention and treatment of ESCC by in vivo and in vitro experiments and provided theoretical basises for the prevention and treatment of precancerous lesions of esophageal cancer. |
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