Vitamin D–binding protein enhances epithelial ovarian cancer progression by regulating the insulin-like growth factor-1/akt pathway and Vitamin D receptor transcription

Yu Fang Huang, Yi Hui Wu, Wen Fang Cheng, Shu Ling Peng, Wan Lin Shen, Cheng Yang Chou

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2 Citations (Scopus)

Abstract

Purpose: Malignant ascites of epithelial ovarian cancer (EOC) helps identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D–binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC. Experimental Design: We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines. Results: Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor–binding protein-2/Akt axis, and induced suppression of vitamin D–responsive genes. A NF-kB p65-binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation. Conclusions: This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC.

Original languageEnglish
Pages (from-to)3217-3228
Number of pages12
JournalClinical Cancer Research
Volume24
Issue number13
DOIs
Publication statusPublished - 2018 Jul 1

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Calcitriol Receptors
Somatomedins
Vitamins
Proteins
Ascites
Ovarian Neoplasms
Ovarian epithelial cancer
Neoplasms
Biomarkers
NF-kappa B
Aggression

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "Vitamin D–binding protein enhances epithelial ovarian cancer progression by regulating the insulin-like growth factor-1/akt pathway and Vitamin D receptor transcription",
abstract = "Purpose: Malignant ascites of epithelial ovarian cancer (EOC) helps identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D–binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC. Experimental Design: We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines. Results: Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor–binding protein-2/Akt axis, and induced suppression of vitamin D–responsive genes. A NF-kB p65-binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation. Conclusions: This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC.",
author = "Huang, {Yu Fang} and Wu, {Yi Hui} and Cheng, {Wen Fang} and Peng, {Shu Ling} and Shen, {Wan Lin} and Chou, {Cheng Yang}",
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T1 - Vitamin D–binding protein enhances epithelial ovarian cancer progression by regulating the insulin-like growth factor-1/akt pathway and Vitamin D receptor transcription

AU - Huang, Yu Fang

AU - Wu, Yi Hui

AU - Cheng, Wen Fang

AU - Peng, Shu Ling

AU - Shen, Wan Lin

AU - Chou, Cheng Yang

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Purpose: Malignant ascites of epithelial ovarian cancer (EOC) helps identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D–binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC. Experimental Design: We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines. Results: Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor–binding protein-2/Akt axis, and induced suppression of vitamin D–responsive genes. A NF-kB p65-binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation. Conclusions: This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC.

AB - Purpose: Malignant ascites of epithelial ovarian cancer (EOC) helps identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D–binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC. Experimental Design: We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines. Results: Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor–binding protein-2/Akt axis, and induced suppression of vitamin D–responsive genes. A NF-kB p65-binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation. Conclusions: This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC.

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