Yu-fang huang, yi-hui wu, cheng-yang chou*

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Yu-fang huang, yi-hui wu, cheng-yang chou* Vitamin D Binding Protein Enhances Epithelial Ovarian Cancer Progression by Regulating Insulin-like Growth Factor-1/Akt Pathway and Vitamin D Receptor Transcription Yu-fang huang, yi-hui wu, cheng-yang chou* 黃于芳, 吳怡慧, 周振陽* 成功大學醫學院附設醫院婦產部

Background Vuolo L et al. Front in endocrinol 2012 Siegel et al. Cancer Statistics. 2012 Vuolo L et al. Front in endocrinol 2012

gc-globulin (group-specific component) Fig. 1. (A) Top 10 up-regulation genes expressed in ascites from ovarian cancers in our preliminary proteomic study. (B) Ascitic vitamin D binding protein (DBP) levels between groups of benign gynecologic disease, low malignant potential (LMP) ovarian tumor, and invasive ovarian cancer.

Vitamin D binding protein (DBP) and vitamin D Biologic function of DBP Actin and fatty acid binding Neutrophil chemotaxis Macrophage activation Role in cancer, carginogenesis or cancer outcome? Low circulating DBP concentrations have elevated risk of pancreatic cancer, renal cell carcinoma, and colorectal cancer (CRC) Low serum DBP levels were related to cancer-specific death in lung cancer No investigation for prognosis Biologic function of vitamin D Protective effect against carcinogenesis and cancer progression

Orthotopic animal model This work connecting to the biomarker identification, basic research and translational study Blood samples Ascites samples Cancerous tissues Cell lines ES-2, ES-2/CP Microfluicidic system Orthotopic animal model IHC ELISA Cellular composition Fluid composition DBP in EOC Circulating DBP, IGFBP2 in EOC Mechanism of DBP in enhancing EOC progression Regulation of DBP and tumor progression & ascites formation Cytology Proteomics ELISA Q1 DBP and EOC progression in human? Q2 DBP in ascites, serum, cancerous tissue as a prognostic biomarker of EOC in human? Q3 Elevated DBP level and EOC progression in animal? Q4 Relationship between elevated DBP level and ascites formation in animal? Q5 How does DBP involve in EOC progression? Ascitic DBP in EOC

Q1. DBP and EOC progression in human?

Q2. DBP in ascites, serum, cancerous tissue as a prognostic biomarker of EOC in human?

Fig. 2. Overall survival and progression-free survival Fig. 2. Overall survival and progression-free survival. Kaplan-Meier curves stratified by (A) ascitic DBP, and (B) serum DBP tested by log rank test.

Q3. Elevated DBP level and EOC formation?

Q4. Relationship between elevated DBP level and ascites formation?

Fig 3. DBP knockdown mice have longer survival, less ascites amount, and less tumor cells in ascites.

Fig. 4 DBP knockdown suppressed tumor formation, ascites formation and invasiveness.

Q5. Mechanism of DBP in EOC progression?

Fig. 5 DBP regulates cell invasion ability via VDR/IGF-1/Akt signaling pathway and inhibit expressions of vitamin D responsive genes.

Fig. 6 DBP regulates VDR transcription through inhibits p65 binds to VDR promoter.

Summary In vivo and in vitro investigations demonstrated an important role for DBP in ovarian cancer progression. 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, and DBP overexpression in cancerous tissue was significantly related to chemoresistance. Orthotopic model mice inoculated with ovarian cancer cells in which DBP expression was knocked down by stable expression of short hairpin RNA exhibited significant reductions in tumor formation, malignant cell numbers, DBP levels in ascites, invasiveness, metastasis, and survival compared with controls. In the presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via the 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. An NF-κB p65 binding site in the VDR promoter was identified as a major determinant of DBP-dependent VDR promoter activation.

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