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Int J Clin Exp Pathol 2013;6(10):1999-2010

Original Article
Cyclosporin A promotes proliferating cell nuclear antigen expression and migration of
human cytotrophoblast cells via the mitgen-activated protein kinase-3/1-mediated
nuclear factor-κB sig-naling pathways

Song-Cun Wang, Min Yu, Yan-Hong Li, Hai-Lan Piao, Chuan-Lin Tang, Chan Sun, Rui Zhu, Ming Qing Li, Li-Ping Jin, Da-Jin Li, Mei-Rong Du
Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College,
Shanghai 200011, China; IVF Center, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011,
China. Equal contributors.

Received August 10, 2013; Accepted September 5, 2013; Epub September 15, 2013; Published October 1, 2013

Abstract: Our previous studies have demonstrated that cyclosporin A (CsA) promotes the proliferation and migration of human trophoblasts via
the mitgen-activated protein kinase-3/1 (MAPK3/1) pathway. In the present study, we further investigated the role of nuclear factor (NF)-κB in the
CsA-induced trophoblast proliferating cell nuclear antigen (PCNA) expression and migration, and its relationship to MAPK3/1 signal. Flow
cytometry was used to analyze the expression of PCNA in trophoblasts. The migration of human primary trophoblasts was determined by
wound-healing assay and transwell migration assay. Western blot analysis was performed to evaluate the activation of NF-κB p65 and NF-κB
inhibitory protein I-κB in human trophoblasts. We found that treatment with CsA promotes PCNA expression and migration of human
trophoblast in a dose-associated manner. Blocking of the MAPK3/1 signal abrogated the enhanced PCNA expression and migration in
trophoblasts by CsA. In addition, CsA increased the phosphorylation of NF-κB p65 and the inhibitor I-κB in human trophoblasts in a time-
related manner. Pretreatment with MAPK3/1 inhibitor U0126 abrogated the phosphorylation of NF-κB p65 and I-κB. Accordingly, the CsA-
induced enhancement of PCNA expression and migration in trophoblasts was also decreased. This CsA-induced enhancement in the
expression and migration of trophoblasts was abolished by pretreatment with pyrrolidine dithiocarbamate, a specific NF-κB inhibitor. Thus, our
results suggest that CsA promotes PCNA expression and migration of human trophoblasts via MAPK-mediated NF-κB activation.
(IJCEP1308019).

Keywords: Cyclosporine A, trophoblast, PCNA, migration, signal transduction pathway

Address correspondence to: Dr. Meirong Du, Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics & Gynecology,
Fudan University, Shanghai Medical College, Shanghai 200011, China. Tel: +86 21 63457331; Fax: +86 21 63457331; E-mail:
dmrlq1973@sina.cn