α2,3-sialyltransferase type I regulates migration and peritoneal dissemination of ovarian cancer cells

// Kuo-Chang Wen 1, 2, 3 , Pi-Lin Sung 1, 2, 3 , Shie-Liang Hsieh 2, 4 , Yu-Ting Chou 5 , Oscar Kuang-Sheng Lee 2, 6, 7, 8 , Cheng-Wen Wu 2, 9 and Peng-Hui Wang 1, 2, 3, 10 1 Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan 2 Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan 3 Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan 4 Genomics Research Center, Academia Sinica, Taipei, Taiwan 5 Institute of Biotechnology and Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan 6 Stem Cell Research Center, National Yang-Ming University, Taipei, Taiwan 7 Taipei City Hospital, Taipei, Taiwan 8 Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan 9 Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan 10 Department of Medical Research, China Medical University Hospital, Taichung, Taiwan Correspondence to: Peng-Hui Wang, email: phwang@vghtpe.gov.tw , phwang@ym.edu.tw , pongpongwang@gmail.com Oscar Kuang-Sheng Lee, email: kslee@vghtpe.gov.tw , oscarlee9203@gmail.com Cheng-Wen Wu, email: ken@ibms.sinica.edu.tw Keywords: α2,3-sialyltransferases type I, epidermal growth factor receptor, epithelial ovarian cancer, soyasaponin I Abbreviations: EOC: Epithelial ovarian cancer; EGFR: Epidermal growth factor receptor; SsaI: soyasaponin I; OS: overall survival; ST: sialyltransferase Received: November 10, 2016 Accepted: February 10, 2017 Published: March 07, 2017 ABSTRACT Epithelial ovarian cancer (EOC) has the highest mortality rate among gynecologic cancers due to advanced stage presentation, peritoneal dissemination, and refractory ascites at diagnosis. We investigated the role of α2,3-sialyltransferase type I (ST3GalI) by analyzing human ovarian cancer datasets and human EOC tissue arrays. We found that high expression of ST3GalI was associated with advanced stage EOC. Transwell migration and cell invasion assays showed that high ST3GalI expression enhanced migration of EOC cells. We also observed that there was a linear relation between ST3GalI expression and epidermal growth factor receptor (EGFR) signaling in EOC patients, and that high ST3GalI expression blocked the effect of EGFR inhibitors. Co-Immunoprecipitation experiments demonstrated that ST3GalI and EGFR were present in the same protein complex. Inhibition of ST3GalI using a competitive inhibitor, Soyasaponin I (SsaI), inhibited tumor cell migration and dissemination in the in vivo mouse model with transplanted MOSEC cells. Further, SsaI synergistically enhanced the anti-tumor effects of EGFR inhibitor on EOC cells. Our study demonstrates that ST3GalI regulates ovarian cancer cell migration and peritoneal dissemination via EGFR signaling. This suggests α2,3-linked sialylation inhibitors in combination with EGFR inhibitors could be effective agents for the treatment of EOC.