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ATM may be a protective factor in endometrial carcinogenesis with the progesterone pathway

  • Research Article
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Tumor Biology

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.

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Acknowledgments

This study was supported by the Shanghai Municipal Science Foundation 2011 (Project No 11ZR1404300); the National Natural Science Foundation of China, 2012 (NSFC No 81101953); and the Shanghai Municipal Science Foundation 2013 (Project No 134119a4500).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, People’s Republic of China

    Weiwei Shan, Xuezhen Luo, Chengcheng Ning, Yinhua Yu, Chao Gu & Xiaojun Chen

  2. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China

    Weiwei Shan, Xuezhen Luo, Chengcheng Ning, Yinhua Yu, Chao Gu & Xiaojun Chen

  3. Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, People’s Republic of China

    Chao Wang

  4. Department of Gynecology, Shanghai First People’s Hospital Affiliated to Shanghai Jiao tong University, Shanghai, 200081, China

    Zhenbo Zhang & Youji Feng

  5. Fangxie Road 419#, Huangpu District, Shanghai, People’s Republic of China

    Chao Gu & Xiaojun Chen

Authors
  1. Weiwei Shan
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  2. Chao Wang
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  3. Zhenbo Zhang
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  4. Xuezhen Luo
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  6. Yinhua Yu
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  7. Youji Feng
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Corresponding authors

Correspondence to Chao Gu or Xiaojun Chen.

Additional information

Weiwei Shan and Chao Wang were co-first authors and equally contributed to this article.

Electronic supplementary material

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S1

A total of 183 antibodies were applied in the RPPA analysis. (XLSX 14 kb)

S2

Cell apoptosis in Ishikawa by flow cytometry. Compared to the NC group, NC+MPA and SI+MPA groups had higher apoptosis rates. The comparison was performed with Student’s t-test. NC, negative control. SI, ATM-siRNA, * P < 0.05, **P < 0.01. (GIF 65 kb)

High resolution image (TIFF 1037 kb)

S3

Cell apoptosis in Ishikawa cells by flow cytometry. Compared to the NC group, the SI, NC+MPA and SI+MPA groups had higher apoptosis rates. Student’s t-test was used for the evaluation. NC, negative control. SI, ATM-siRNA, * P < 0.05,**P < 0.01. (GIF 57 kb)

High resolution image (TIFF 1030 kb)

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Shan, W., Wang, C., Zhang, Z. et al. ATM may be a protective factor in endometrial carcinogenesis with the progesterone pathway. Tumor Biol. 36, 1529–1537 (2015). https://doi.org/10.1007/s13277-014-2712-4

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  • DOI: https://doi.org/10.1007/s13277-014-2712-4

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