The Association Between PI3K/Akt/mTOR Signal Pathways And Barrett's Esophagus

Barrett esophagus is the most important complications of gastroesophageal reflux disease and is a precancerous lesion of esophageal adenocarcinoma. In recent years, the incidence of esophageal adenocarcinoma tends to be top in Western countries and the excess risk of progressing to esophageal adenocarcinoma has been estimated to be 30 to 125 fold relative to the risk of the generalpopulation and the pathogenesis of the disease still understood little. It is significantly to study the pathogenesis of the disease and prevent it's progression. Signaling pathways usually play a crucial role in diseases. PI3K/Akt/mTOR signaling pathway is important in vivo, and is one way of the EGFR mediating, the other is RAS/MAPK. The signal was transducted from the extracellular to the intracellular and participates in cell proliferation, apoptosis, differentiation and other functions.The paper was to make an animal model of Barrett esophagus and investigate the expression levels of key genes such as EGFR, Akt, p-Akt, p-mTOR in esophageal tissues to provide basis for Barrett esophagus treatment.Objective:We investigated the expression of EGFR, Akt, p- Akt, and mTOR in nomal esophagus, esophagitis, and Barrett's esophagus by establishing a kind of available animal model of BE to elucidate the roles of these proteins in Barrett's esophagus .Methods:1One hunderd and fouty 8-week-old male Sprague-Dawley rats were randomized into 6 groups, including control (so) group, iron (Fe) group, esophagoduodenal anastomosis (EDA) group,esophagoduodenal anastomosis adding iorn (EDA+Fe) group, esophagogastroduodenal anastomosis (EGDA)group, esophagogastroduodenal anastomosis adding iorn (EGDA+Fe) group. Sham operation was operated in the fomrer two groups and the last four groups underwent surgical operation to produce gastroduodenoesophageal reflux. After 2 weeks, Iron Dextran were injected intraperitoneum of the rats in EDA+Fe group and EGDA+Fe group (30mg/kg, twice per week for 30 weeks). 5 rats of each group were sacrificed at 12 week after operation and others at 32 week, and esophageal samples were taken. Their esophagi were assessed for presence of inflammation, BE, and dysplasia by gross and microscopy observation.2Expression of EGFR, Akt, p-Akt, and p-mTOR were exmained in nomal esophagus, esophagitis, and Barrett's esophagus by immunohistochemical staining of S-P.Results:1MortalityThe mortality of nomal group, iron group, EDA group, EDA+Fe group, EGDA group, EGDA+Fe group were 0%, 0%, 26.7%, 30%, 6.7%, 6.7%, respectively, the mortalities of EDA group, EDA+Fe group, EGDA group, EGDA+Fe group compared with that in the nomal group and iron group were different significantly(P<0.05). The mortalities between EDA group and EDA+Fe group were not different significantly (P>0.05). The mortalities between EGDA group and EGDA+Fe group were not different significantly(P>0.05). And the mortalities between EDA group and EGDA group were different significantly(P<0.05). 2The occurrence of diseases12 weeks after surgery, the iron group, rough esophageal mucosa occurred partly. Chronic inflammation and mild hyperplasia were observed in the esophagus under the light microscope. There were more serious damage in esophageal mucosa in EDA group, EDA+Fe group, EGDA group and EGDA+Fegroup: the disappearance of pink mucosa, rough mucosa, scattered ulcers, hemorrhagic erosive lesions and the most serious damage were band of white bark-like proliferative changes.32 weeks after surgery, the damage was more serious in groups but there were no BE in iron group. EDA group, EDA + Fe group, EGDA group, EGDA + Fe proliferation and the incidence of Barrett's esophagus was 35.3%, 75%, 43.5%, 73.9%. Thehyperplasia and BE in EDA group, EDA + Fe group, EGDA group, EGDA+Fe group were 35.3%, 75%, 43.5%, 73.9%, and 23.5%, 62.5%, 26%, 56.5%, respectively. The incidence of hyperplasia, BE were significantly different between EDA group and EDA + Fe group (P<0.05), and the difference is also significantly beween EGDA group and EGDA+Fe group (P<0.05). The incidence of hyperplasia, BE were not significantly different between EDA group and EGDA group, and the difference is not significantly beween EDA + Fe group and EGDA + Fe group (P<0.05).3Immunohistochemical stainingThe expression of EGFR in NE, RE, and BE were 0.0277±0.0069, 0.0438±0.0025, 0.1799±0.0367, respectively. The expression of EGFR in Barrett esophagus was highest and significantly higher than the other two diseases(P<0.05).The expression of Akt in NE, RE, and BE were 0.0383±0.0048, 0.0986±0.0093, 0.1874±0.0250, respectively. The expression of Akt in Barrett esophagus was highest and significantly higher than the other two diseases(P<0.05).The expression of p-Akt in NE, RE, and BE were 0.0281±0.0017, 0.0592±0.0027, 0.1418±0.0130, espectively. The expression of p-Akt in Barrett esophagus was highest and significantly higher than the other two diseases(P<0.05).The expression of p-mTOR in NE, RE, and BE were 0.0112±0.0017, 0.0674±0.0059, 0.1591±0.0275, espectively. The expression of p-mTOR in Barrett esophagus was highest and significantly higher than the other two diseases(P<0.05).4The correlation of relative expression among EGFR, Akt, and p-Akt was good (r=0.53, P<0.05; r=0.68, P <0.05), but between EGFR and p-mTOR was not so good (r=0.04, P <0.05). Conclusions:1The present study suggests that long time esophageal reflux plus iron could induce the development of BE.2Both EDA plus iron and EGDA plus iron could induce the developmentof BE, there was no significant difference between them.EGDA plus iron coloud simulate the pathogenesis of human GERD better and have lower mortality rates, it can be used to produce animal model of Barrett's esophagus more reliable.3The key genes of PI3K/Akt/mTOR signal pathway were significantly increased in BE, suggesting that the signaling pathway involved in the pathogenesis of Barrett's esophagus.4PI3K/Akt/mTOR signal pathway involved in the pathogenesis of Barrett's esophagus may be related to the reflux materials of the stomach and duodenum, which may promot cell proliferation, inhibit apoptosis, regulate differentiation and other functions. Multi-target treatment of signaling pathway is expected to become an early effective means of Barrett's esophagus.