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Expression of early growth response 1 affects miR-106a/signal transducer and activator of transcription 3 regulating cognitive impairment in ovariectomized mice

Cong, Jing MD, MSc1; Wang, Chaojun MD, MSc1; Pu, Danhua MD1; Liu, Jiayin MD, PhD1; Hu, Gang MD, PhD2; Gao, Chao MSc1; Wu, Jie MD, PhD1

doi: 10.1097/GME.0000000000000234
Original Articles

Objective: This study aims to investigate the effects of early growth response 1 (Egr1) on miR-106a/signal transducer and activator of transcription 3 (STAT3) regulating cognitive impairment in an ovariectomy model.

Methods: Using the Morris water maze test, we assessed escape latency and time spent in a quadrant among mice at 6, 8, and 12 weeks after ovariectomy and their age-matched controls (n = 15 each group). Egr1, miR-106a, and STAT3 messenger RNA expression (n = 7) in the hippocampus and cortex of mice at 6, 8, and 12 weeks after ovariectomy was detected by quantitative real-time polymerase chain reaction, whereas Egr1, phospho-STAT3 (p-STAT3), and STAT3 protein expression (n = 8) was evaluated by Western blot analysis. Moreover, alterations in miR-106a and STAT3 expression were investigated in neuroblastoma (SH-SY5Y) cells transfected with a human Egr1 interference fragment (si-Egr1) or an Egr1-overexpressing plasmid (GV141-Egr1), respectively.

Results: Escape latency was significantly increased and time spent in a platform quadrant was reduced in mice at 12 weeks after ovariectomy compared with age-matched controls. Egr1 and miR-106a expression was obviously increased in the hippocampus and cortex at 12 weeks after ovariectomy, whereas STAT3 levels were decreased compared with 12-week controls. After SH-SY5Y cell transfection with the si-Egr1 fragment, miR-106a levels decreased and STAT3/p-STAT3 levels increased, whereas cotransfection of the miR-106a mimic caused a significant decrease in STAT3 levels. MiR-106a messenger RNA expression was significantly increased and STAT3/p-STAT3 protein levels were decreased by Egr1 overexpression, whereas simultaneous transfection with the miR-106a inhibitor inhibited alterations in STAT3 levels.

Conclusions: This study suggests that Egr1 decreases STAT3 expression via miR-106a in ovariectomized mice with cognitive impairment, indicating that Egr1 represents a potential target for therapeutic intervention in postmenopausal cognitive decline.

From the 1State Key Laboratory of Reproductive Medicine, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University; and 2Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China.

Received November 19, 2013; revised and accepted February 12, 2014.

J.C. and C.W. contributed equally to this work.

Funding/support: This study was supported by grants from the Chinese National Natural Science Foundation (81170540), Jiangsu Province Science and Technology Commission for Natural Science Foundation (BK2011846), and Jiangsu Key Laboratory of Neurodegeneration (SJ11KF06).

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Jie Wu, MD, PhD, State Key Laboratory of Reproductive Medicine, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. E-mail: jie.wuyale@gmail.com

© 2014 by The North American Menopause Society.