The Study Of The Mechanism Of Autocrine Motility Factor (?AMF/PGI) Promoting Tumorigenesis In Endometrial Carcinoma

Endometrial carcinoma(EC)is the one of the most common gynaecologic malignant tumors.Reckoned by FIGO,in the year of 2015,approximately 54870 new cancer cases of EC will be diagnosed and 10170 deaths are expected in America alone,while in China,63400 EC cases will be diagnosed for one year.Compared with the year of 2014,all the figures foregoing tended to be increased.Recently,several studies have indicated that unopposed estrogens contribute to the tumorigenesis and progressive of endometrial carcinoma.However,the molecular and cellular mechanism underlying EC metastasis was poorly defined.Furthermore,specific detection methods in the early stage EC,effective therapy in the late stage EC as well as targeted therapy of endometrial cancer were poor.Thus,it is critical to further develop novel diagnostic and prognostic biomarkers,as well as therapeutic strategies,for ECAMF,autocrine motility factor(AMF),which is also known as phosphoglucose isomerase(PGI),stimulates both direct and random cell migration.Several researchers independently found that secreted AMF/PGI,a tumor secreted cytokine,is involved in regulation oncogenesis and tumor progression in various human cancers.Currently,the specific role of AMF/PGI in human EC remains unclear,and therefore it is of considerable interest to identify novel mechanisms to better understand how EC occurs and disseminates.In this study,we first demonstrated that AMF/PGI is significantly correlated with EC aggressiveness.First,we tested AMF/PGI expression in EC patients.Then,we examined the biological consequences of AMF/PGI downregulation in aggressive human EC cell lines.Moreover,phospho antibody microarrays revealed that the MAPK ERK1/2 signaling pathway is involved in AMF/PGI mediated endometrial cancer and that the re activation of MAPK ERK1/2 signaling with exogenous PGI in co cultured EC cells induced migration,invasion and proliferation.At last,we verified our finding using in vivo mouse models and found that the silencing of AMF/PGI abrogated tumor growth and lowered the level of MAPK ERK1/2 signaling phosphorylation.These results shed light on the mechanisms and pathways by which EC occurs and develops,providing evidence that AMF/PGI is a novel proto oncoprotein of EC and therefore a potential therapeutic target.There are four parts of this study:(1)To investigate the expression of AMF/PGI and AMFR in various uterine endometrial tissues and the level of AMF/PGI in serum by IHC,RT-PCR and ELISA;(2)To determine the role and the mechanism of AMF/PGI in endometrial cancer cells migration,invasion and proliferation by transwell,MTS assay,3D spheroid culture system,flow cytometry analysis,anti phosphoprotein array.(3)To elucidated the inhibition of AMF/PGI in EC cell metastasis and growth and to evaluate the potential of AMF/PGI as a carcinogenic factor in endometrial tumor by bioluminescence imaging and metastasis model which established by injecting EC cells into nude mouse via left ventricular or intraperitoneally.