J. Microbiol. Biotechnol. J. Microbiol. Biotechnol. (2017), 27(4), 668–677 https://doi.org/10.4014/jmb.1609.09028 Research Article jmb Review Benzoic Acid Enhances Embryo Implantation through LIF-Dependent Expression of Integrin αVβ3 and αVβ5 Hee-Jung Choi 1† , Tae-Wook Chung 1† , Mi-Ju Park 1 , Hyung Sik Kim 2 , Sooseong You 3 , Myeong Soo Lee 3 , Bo Sun Joo 1 , Kyu Sup Lee 4 , Keuk-Jun Kim 5 , Gabbine Wee 6 , Choong-Yong Kim 6 , Cheorl-Ho Kim 7 , and Ki-Tae Ha 1 * School of Korean Medicine and Healthy Aging Korean Medicine Research Center, Pusan National University, Yangsan 50612, Republic of Korea Laboratory of Molecular Toxicology, School of Pharmacy, SungKyunKwan University, Suwon 16419, Republic of Korea Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea Department of Obstetrics and Gynecology, Pusan National University Hospital, Busan 49241, Republic of Korea Department of Clinical Pathology, DaeKyeung University, Gyeongsan 38547, Republic of Korea Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea Department of Biological Science, Sungkyunkwan University, Suwon 16419, Republic of Korea Introduction Embryo implantation is a crucial step in the reproductive process, requiring communication between the fully developed trophoblast and the receptive endometrium [1, 2]. The main factors regulating endometrial receptivity include cytokines, growth factors, and receptors, which influence physiological changes in the endometrium [3]. Among these factors related to endometrial receptivity, leukemia inhibitory factor (LIF) plays a key role in successful embryo implantation [4-6]. As shown in previous clinical studies, genetic mutation or low expression of LIF is a cause of recurrent implantation failure [7, 8]. Moreover, inhibition of LIF activity through treatment with anti-LIF antibodies or LIF receptor antagonists effectively blocks embryo implantation [9-12]. Among various adhesion molecules, integrins are known to mediate embryo attachment to the endometrium. Previous studies have shown that in women with unexplained infertility, diminished expression of integrins in the endometrium is frequently observed [13-15]. Thus, we supposed that LIF and integrins are important molecular targets that could be used to develop alternative treatments for improving endometrial receptivity. Received: September 19, 2016 Revised: October 27, 2016 Accepted: January 9, 2017 First published online January 12, 2017 *Corresponding author Phone: +82-51-510-8464; Fax: +82-51-510-8620; E-mail: hagis@pusan.ac.kr These authors contributed equally to this work. upplementary data for this paper are available on-line only at http://jmb.or.kr. pISSN 1017-7825, eISSN 1738-8872 Copyright © 2017 by The Korean Society for Microbiology and Biotechnology Embryo implantation is the crucial step for a successful pregnancy. Diverse factors, including adhesion molecules, growth factors, and cytokines are important for embryo implantation through improving endometrial receptivity. Benzoic acid (BA), a component of various plants, has been shown to have antifungal and antioxidant effects. However, the effect of BA on embryo implantation remains unknown. Here, we showed the contribution of BA for the enhancement of endometrial receptivity through the leukemia inhibitory factor (LIF)- dependent increase of integrin αV, β3, and β5 expression. Furthermore, in vivo study using a mifepristone-induced implantation failure model showed that BA definitely improves the numbers of implantation embryos. Taken together, we suggest that BA has a novel function for embryo implantation through the up-regulation of LIF-mediated integrins, and may be a candidate for therapeutic medicine to increase the pregnancy rate. Keywords: Benzoic acid, leukemia inhibitory factor, integrin, adhesion, endometrial receptivity, implantation S S