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Int J Clin Exp Pathol 2013;6(10):2030-2038

Original Article
NME1 suppression of endometrial stromal cells promotes angiogenesis in the
endometriotic milieu via stimulating the secretion of IL-8 and VEGF

Kai-Kai Chang, Li-Bing Liu, Li-Ping Jin, Yu-Han Meng, Jun Shao, Ying Wang, Jie Mei, Ming-Qing Li, Da-Jin Li

Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College,
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China. Equal contributors.

Received June 23, 2013; Accepted August 1, 2013; Epub September 15, 2013; Published October 1, 2013

Abstract: Nonmetastatic gene 23-H1 (NME1, also known as nm23-H1) is a wide-spectrum tumor metastasis suppressor gene that plays an
important role in suppressing the proliferation, adhesion and invasion of endometrial stromal cells (ESCs). The present study is undertaken to
explore the mechanism by which NME1 in ESCs from endometriosis modulates the angiogenesis and herein participates in the pathogenesis
of endometriosis. The expression of NME1 in the primary ESCs from normal endometrium without endometriosis was higher than that from
eutopic endometrium and ectopic lesion with endometriosis. Silencing NME1 stimulated the secretion of angiogenic factors interleukin-8 (IL-8)
and vascular-endothelial growth factor (VEGF) of the eutopic ESCs from women with endometriosis, and these effects could be abrogated by
MAPK/ERK1/2 or AKT inhibitor. In addition, the supernatant of NME1-silenced ESCs increased the expression of angiogenesis-relative
molecules CD62E and CD105, and promoted angiogenesis of human umbilical vein endothelial cells (HUVECs). Anti-human IL-8 or VEGF
neutralizing antibody reversed the effect on angiogenesis of HUVECs induced by NME1-silenced ESCs. Our current results suggest that the
abnormal lower expression of NME1 in ESCs secrete more IL-8 and VEGF through activation of MAPK/ERK1/2 and AKT signal pathways,
up-regulate the level of CD62E and CD105, and finally lead to numerous angiogenesis of vascular endothelial cells in the endometriotic milieu,
which is beneficial to the origin and development of endometriosis. (IJCEP1307037).

Keywords: NME1, ESCs, HUVECs, angiogenesis, endometriosis

Address correspondence to: Dr. Ming-Qing Li or Dr. Da-Jin Li, Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics
and Gynecology, Fudan University Shanghai Medical College, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases,
No. 413, Zhaozhou Road, Shanghai 200011, China. Tel: 86-21-63457331; Fax: 86-21-63457331; E-mail: mqli1311@gmail.com (Ming-Qing Li);
djli@shmu.edu.cn (Da-Jin Li)