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Androgen-induced alterations in endometrial proteins crucial in recurrent miscarriages

Tanzil Ur Rahman _, Kamran Ullah, Meng-Xi Guo, Hai-Tao Pan, Juan Liu, Jun Ren, Lu-Yang Jin, Yu-Zhong Zhou, Yi Cheng, Jian-Zhong Sheng and He-Feng Huang

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Oncotarget. 2018; 9:24627-24641. https://doi.org/10.18632/oncotarget.24821

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Tanzil Ur Rahman1,2,*, Kamran Ullah1,2,5,*, Meng-Xi Guo1,2, Hai-Tao Pan4, Juan Liu1, Jun Ren1,2, Lu-Yang Jin1,2, Yu-Zhong Zhou1,2, Yi Cheng1,2, Jian-Zhong Sheng1,2,3 and He-Feng Huang1,3

1The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, China

2Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, China

3The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

4Shaoxing Women and Children's Hospital, Shaoxing, China

5Department of Zoology, University of Swabi, Anbar, Khyber Pakhtunkhwa, Pakistan

*These authors contributed equally to this work

Correspondence to:

Jian-Zhong Sheng, email: [email protected]

He-Feng Huang, email: [email protected]

Keywords: androgen; recurrent miscarriage; PCOS

Received: July 03, 2017     Accepted: March 02, 2018     Published: May 15, 2018


High androgen level impairs endometrial receptivity in women experiences the recurrent miscarriage. The mechanism of androgen actions on endometrium is still uncertain. We hypothesized that androgen has a direct effect on the endometrium in women with recurrent miscarriage. In the present study, we assess the impact of androgen (A2) at high concentration (10–7 M) on Ishikawa cells compared with the physiological concentration of androgen (10–9 M). To go into deeper analysis, we use global stable isotopes labeled profiling tactic using iTRAQ reagents, followed by 2D LC-MS/MS. We determine 175 non-redundant proteins, and 18 of these were quantified. The analysis of differentially expressed proteins (DEPs) identified 8 up-regulated proteins and 10 down-regulated in the high androgen group. These DEPs were examined by ingenuity pathway (IPA) analysis and established that these proteins might play vital roles in recurrent miscarriage and endometrium receptivity. In addition, proteins cyclin-dependent kinase inhibitor 2a (CDKN2a), endothelial protein C receptor (EPCR), armadillo repeat for velocardiofacial (ARVCF) were independently confirmed using western blot. Knockdown of CDKN2a significantly decreased the expression level of CDKN2a protein in ishikawa cells, and decreased migration (p < 0.01), invasion (p < 0.05), proliferation (p < 0.05), and the rate of Jar spheroid attachment (p < 0.05) to Ishikawa cell monolayer. The present results suggest that androgen at high concentration could alter the expression levels of proteins related to endometrium development and embryo implantation, which might be a cause of the impaired endometrial receptivity and miscarriage.

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