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

Oncogene volume 37, pages 601–615 (2018)Cite this article

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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.

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Acknowledgements

The National Natural Science Foundation of China (No. 81570496, 81370505, 81370591 and 91229201) and 973 programs (2015CB553800) in China supported this study.

Author contributions

Bayasi Guleng and Jian-Lin Ren designed the experiments; Li-fen Wang, Yuan-sheng Liu, Ping Li, Bing Yang, Xiao-Shen Cheng, Chuan-Xing Xiao, Jing-Jing Liu and Shao Li performed the experiments; Guleng B and Li-fen Wang wrote the paper.

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Author notes

  1. L-F Wang, Y-S Liu and B Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China

    L-F Wang, Y-S Liu, B Yang, P Li, X-S Cheng, C-X Xiao, J-J Liu, J-L Ren & B Guleng

  2. Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China

    P Li

  3. MOE Key Laboratory of Bioinformatics, Tsinghua University, Beijing, China

    S Li

  4. Faculty of Clinical Medicine, Medical College of Xiamen University, Xiamen, China

    B Guleng

  5. State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China

    B Guleng

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Wang, LF., Liu, YS., Yang, B. et al. The extracellular matrix protein mindin attenuates colon cancer progression by blocking angiogenesis via Egr-1-mediated regulation. Oncogene 37, 601–615 (2018). https://doi.org/10.1038/onc.2017.359

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