Effect Of P53 On Pancreatic Cancer-diabetes Development By Regulating Transglutaminase 2 In Resistance To Glucose Metabolic Stress

Objective: Pancreatic cancer is a kind of malignant tumor of gastrointestinal which is difficult to diagnosis early,easy to transfer,is generally not sensitive to radiotherapy and chemotherapy,five year survival rate is of not more than 5%[1,2].The incidence of pancreatic cancer associated diabetes may be associated with the development of pancreatic cancer,but the pathogenesis of pancreatic cancer associated diabetes has not been fully understood [3].The microenvironment of pancreatic cancer cells is considered to be strictly selected,cell microenvironment stress resistance and adaptation of pancreatic cancer depends on many complicated mechanisms,and pancreatic cancer environment changes may affect other cells(such as pancreatic islet beta cell function and growth [4].In this study,we will investigate the key molecules regulating the stress microenvironment of pancreatic cancer cells,and explain the mechanism of the formation of pancreatic cancer associated diabetes.Methods and results: This study confirmed alone TG2 or p53 interference can reduce glucose stress resistance in pancreatic cancer cells,but also glucose deprivation stress resistance still exist after interfere with p53 and TG2 in pancreatic cancer cells by CCK8 experiments.In the absence of glucose stress,interference p53 can inhibit the up regulation of TG2 by western.Therefore,it is speculated that the function of TG2 in the microenvironment resistance of pancreatic cancer depends on the status of p53.In addition,we confirmed Bcl-2 elevated was responsible to glucose deprivation stress resistance mechanism of transfected shp53+sh TG2 pancreatic cancer cells by western,and flow cytometry experiments showed increased intracellular ROS was responsible to the mechanism of glucose deprivation stress resistance in sh Ctrl,shp53,sh TG2 transfected pancreatic cancer cells.The transfected shp53+sh TG2 pancreatic cancer cell line which the cell itself changes in the growth process of its microenvironment may affect adjacent tissue function,such as pancreatic beta cells,thereby affecting the changes of blood glucose in patients with pancreatic cancer.In this study,we used the cultured supernatant of shp53+sh TG2 pancreatic cancer cell lines treated pancreatic beta cells,in 72 h,96h after the culture in vitro.The results confirmed that the survival rate of min6 cells decreased by 30% by CCK8.In order to investigate the specific signal transduction pathway of pancreatic beta cells,we detected the changes of beta cell gene after treated by shp53+sh TG2 pancreatic cancer cell line by gene chip technology.In vivo experiments,we constructed a luciferase labeled pancreatic cancer in nude mice model,and performed the glucose tolerance test(IGTT)and insulin sensitivity test(ITT)in nude mice.The results of in vivo test showed that the shp53+sh TG2 group of nude mice began to appear impaired glucose tolerance in 4W,sh TG2 began to appear in the 6W glucose tolerance,shp53 and sh Ctrl group had no significant difference.Conclusion: p53 regulates TG2 through ROS and Bcl-2 signaling pathway to resist the glucose stress in pancreatic cancer,and the changes of pancreatic cancer caused by p53 and TG2 have an effect on the growth and function of pancreatic beta cells.