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.
Highlights
Epithelial ovarian cancer (EOC) is the second most common type of gynecologic cancer and a leading cause of gynecological cancer deaths in the United States
Immunohistochemical (IHC) staining using the human EOC tissue array (CJ2 provided by SUPER BIO CHIPS, Seoul/South Korea) showed that higher intensity staining of ST3GalI (Figure 1B) positively correlated with lower overall survival rate (Figure1C)
We further investigated the association of ST3GalI expression with EOC progression
Summary
Epithelial ovarian cancer (EOC) is the second most common type of gynecologic cancer and a leading cause of gynecological cancer deaths in the United States. In 2016, there were 14,240 EOC related deaths and 22,280 new cases diagnosed in the United States [1]. Despite intensive treatment with cytoreductive surgery and postoperative adjuvant chemotherapy with/without antiangiogenesis agents, EOC has the highest mortality rate among gynecological cancers because it is diagnosed in an advanced stage and has high recurrence rate [2,3,4]. EOC is characterized by advanced-stage presentation, multiple organ metastases, peritoneal dissemination and refractory ascites at diagnosis [6]. The development of novel biomarkers is urgently required for accurate and early prediction of metastasis and treatment outcomes in EOC patients
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