The extracellular matrix protein mindin attenuates colon cancer progression by blocking angiogenesis via Egr-1-mediated regulation

Abstract

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. Contrary to previous reports, this study used two different enzyme-linked immunosorbent assay (ELISA) kits to 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. 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, chromatin immunoprecipitation (ChIP) DNA and electrophoretic mobility shift assay (EMSA) methods. Egr-1 regulates mindin mRNA and protein expression in CRC cells, 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, migration and angiogenic sprouts 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-1a 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.

Independent prognostic genes and mechanism investigation for colon cancer

“…A previous study shows that matrix metalloproteinase-9 is an important marker for analysis of the postoperative prognosis and risk of metastases in patients with colorectal cancer [ 35 ]. Recently, Wang et al showed that the extracellular matrix protein mindin attenuated colon cancer progression by blocking angiogenesis via Egr-1-mediated regulation [ 36 ]. Despite of extracellular matrix, the digestion function is closed related to cancer preventative activity [ 37 ].…”

Cinobufagin suppresses colorectal cancer angiogenesis by disrupting the endothelial mammalian target of rapamycin/hypoxia‐inducible factor 1α axis

“…This early angiogenic switch emerges in premalignant or in in situ carcinomas. Neovasculature promotes solid tumor growth and metastasis . Therefore, targeting angiogenesis is one of the most conventional approaches for controlling tumor progression.…”

Egr-1 increases angiogenesis in cartilage via binding Netrin-1 receptor DCC promoter

“…Early growth response-1 (Egr-1), also called NGFI-A, is a zinc finger transcription factor and immediate early gene, which plays an important role in angiogenesis [ 14 , 15 ]. Meanwhile, Egr-1 may be involved in the pathogenesis of OA [ 16 , 17 ].…”