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.
Keywords:
3-sialyltransferases type I; epidermal growth factor receptor; epithelial ovarian cancer; soyasaponin I; α2.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Biomarkers, Tumor / antagonists & inhibitors
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Biomarkers, Tumor / metabolism
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Carcinoma, Ovarian Epithelial
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Cell Line, Tumor
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Cell Movement / drug effects
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Drug Synergism
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism*
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Female
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Humans
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Immunohistochemistry
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Immunoprecipitation
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Kaplan-Meier Estimate
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Mice
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Mice, Inbred C57BL
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Microarray Analysis
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Neoplasm Invasiveness / pathology
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Neoplasm Invasiveness / prevention & control
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Neoplasm Staging
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Neoplasms, Glandular and Epithelial / mortality
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Neoplasms, Glandular and Epithelial / pathology*
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Oleanolic Acid / analogs & derivatives
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Oleanolic Acid / pharmacology
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Oleanolic Acid / therapeutic use
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Ovarian Neoplasms / mortality
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Ovarian Neoplasms / pathology*
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Ovary / pathology
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Peritoneal Neoplasms / secondary
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Peritoneum / pathology
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Prognosis
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Saponins / pharmacology
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Saponins / therapeutic use
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Sialyltransferases / antagonists & inhibitors
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Sialyltransferases / metabolism*
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Signal Transduction / drug effects
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Survival Rate
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beta-Galactoside alpha-2,3-Sialyltransferase
Substances
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Antineoplastic Agents
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Biomarkers, Tumor
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Protein Kinase Inhibitors
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Saponins
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soyasaponin I
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Oleanolic Acid
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Sialyltransferases
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EGFR protein, human
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ErbB Receptors
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beta-Galactoside alpha-2,3-Sialyltransferase