The Extracellar Matrix Protein Mindin Attenuates Colorectal Cancer Progression By Blocking Angiogenesis Via Egr-1-mediated Regulation

Mindin,a secreted,highly conserved extracellular matrix(ECM)protein,exerts a broad spectrum of effects on the innate immune system.However,its function in colorectal cancer(CRC)progression is not well established,and its upstream regulation mechanisms remain unclear.This study show that the serum level of Mindin was significantly decreased in CRC patients and that this decreased level is more significantly associated with the early stages of the disease by Elisa.To explore the regulation of Mindin,we used a bioinformatics approach to predict potential transcription factors and determined that early growth response factor(Egr)-1 directly regulates Mindin expression at the transcriptional level using dual luciferase,ChIP DNA and EMSA methods.Egr-1 regulates Mindin mRNA and protein expression in CRC cells SW480 and HCT15,and the protein expression of both Egr-1 and Mindin was significantly decreased in tumor lesions of patients compared with adjacent control tissues.Mindin is essential for Egr-1-mediated inhibition of endothelial cell tube formation,and Mindin inhibits endotheliocyte proliferation and migration in vitro.Overexpression of Mindin suppressed xenograft tumor growth by blocking angiogenesis instead of directly suppressing CRC cell proliferation.Mechanically,Mindin inhibits the hypoxia-induced HIF-la and VEGFA protein expression in CRC cells and the phosphorylation of VEGFR-2 in endothelial cells.The results suggest that the serum level of Mindin can be used as a novel biomarker for early detection of CRC and that the Egr-1/Mindin axis is a potential therapeutic target for the inhibition of angiogenesis in CRC development.