IGFBP-3透過調控TSP-1的表現以抑制腫瘤的血管新生

Abstract

Insulin-like growth factor binding protein 3 (IGFBP-3) is known as an antiproliferative and an invasion-suppressor protein. In human ovarian endometrioid carcinoma (OEC) OVTW59, highly invasive subline P4 showed lower IGFBP-3 gene expression than the original P0 cell line (Oncogene 2008; 27:2137-47). By cDNA microarray analysis of differential gene expression between IGFBP-3 re-expression in P4-pKG3226-hIGFBP-3 transfectant and the control line, thrombospondin-1 (TSP-1) was identified to be significantly co-expression with IGFBP-3. TSP-1 is a known endogenous inhibitor of angiogenesis. We further established a tetracycline-inducible IGFBP-3 expressing OEC cell line using pBIG2i plasmid. This cell line showed 4-fold increase in IGFBP-3 expression 2 hours after tetracycline treatment in associated with a paraellel increase in TSP-1. In human umbilical vein endothelial cell (HUVECs) tube formation assay, IGFBP-3 expression was associated with a decrease in capillary tube formation. This reaction was reversed after anti-TSP-1 treatment. By chick embryo chorioallantoic membrane (CAM) assay, IGFBP-3 expression showed a significant decrease in capillary formation. Heterotransplantation of IGFBP-3-transfectants showed significant decrease in tumor growth 5 days after IGFBP-3 induction. The dormancy state of tumor growth persisted for about 10 days. Xenograft tumors in this period showed a decrease in micro vessel density and an increase in tumor apoptosis. In conclusion, we have identified a novel association between IGFBP-3 and TSP-1. IGFBP-3 could acts through the regulation of TSP-1 to decrease angiogenesis formation, and resulted in the dormancy state of cancer growth. By impairing the processes of angiogenesis, IGFBP-3 could then play as a tumor suppressor gene in ovarian cancer. Both IGFBP-3 and TSP-1 may serve for the molecular targeted therapy in patients with ovarian endometroid cancer.