title: ATM may be a protective factor in endometrial carcinogenesis with the progesterone pathway.
abstract: The purpose of the study was to explore the role and mechanism of ataxia-telangiectasia mutated (ATM) protein in endometrial carcinogenesis. A reverse-phase protein array (RPPA) was used to analyze the expression of ATM signal pathway proteins in Ishikawa and progesterone-insensitive Ishikawa. ATM expression was detected in endometrium specimens by immunohistochemistry, including 8 cases with proliferative endometrium, 6 cases with secretory endometrium, 10 cases with simple hyperplasia (SH), 13 cases of complex hyperplasia (CH), 11 cases of endometrial atypical hyperplasia (EAH), and 83 cases with type I endometrial cancer. The relationship between ATM expression and other clinicopathological indicators was also examined in type I endometrial cancer patients. The mechanisms of ATM were explored in vitro with the endometrial cell lines Ishikawa and RL95-2. A cell counting kit-8 (CCK-8) test and Western blot analysis were performed to test proliferation and protein expression. Statistical analysis was performed with SPSS19.0. The significance level was set at 0.05. ATM was increased with medroxyprogesterone acetate (MPA) stimulation in Ishikawa in RPPA. ATM expression gradually decreased in endometrial hyperplasic lesions compared with the normal proliferative and secretory endometrium and was the lowest in type I endometrial cancer. ATM expression was negatively correlated with pathological grades in type I endometrial cancer. In vitro, ATM silencing retarded proliferation inhibition in Ishikawa and RL95-2 treated with MPA. ATM silencing could down-regulate the MPA-stimulated signal proteins, including Chk2, P53, and caspase-3 in vitro. MPA might exert its role through activating the ATM-associated pathway, ATM-Chk2-P53-caspase-3 (active), preserving normal endometrium and protecting it from malignancies. ATM might be a promising indicator for endometrial hyperplasia and cancer.
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, People's Republic of China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Shan
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xuezhen
authors.initials: X
authors.lastname: Luo
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Ning
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Yu
authors.forename: Youji
authors.initials: Y
authors.lastname: Feng
authors.forename: Chao
authors.initials: C
authors.lastname: Gu
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Chen
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011374:Progesterone / Q000235:genetics* / Q000378:metabolism; D065840:Protective Factors; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011374:Progesterone; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D053148:Caspase 3