The extracellular matrix protein mindin attenuates colon cancer progression by blocking angiogenesis via Egr-1-mediated regulation
The extracellular matrix protein mindin attenuates colon cancer progression by blocking angiogenesis via Egr-1-mediated regulation
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DOI：
10.1038/onc.2017.359
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发表时间：
2018-02
期刊：
影响因子：
8
通讯作者：
Wang Lf;Yonghong Liu;B. Yang;P. Li;P. Li;Cheng Xs;Changchun Xiao;Jia Liu;Shao Li;
中科院分区：
文献类型：
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作者：
Wang Lf;Yonghong Liu;B. Yang;P. Li;P. Li;Cheng Xs;Changchun Xiao;Jia Liu;Shao Li;
Mindin是一种高度保守的分泌型细胞外基质（ECM）蛋白，对先天性免疫系统具有广泛的作用。然而，其在结直肠癌（CRC）进展中的功能尚未完全确定，其上游调控机制仍不清楚。与以前的报道相反，这项研究使用了两种不同的酶联免疫吸附测定（ELISA）试剂盒，以显示CRC患者的血清mindin水平显着降低，并且这种降低的水平与疾病的早期阶段更显着相关。为了探索mindin的调控，我们使用生物信息学方法来预测潜在的转录因子，并确定早期生长反应因子（Egr）-1直接调节mindin的表达在转录水平上使用双荧光素酶，染色质免疫沉淀（ChIP）DNA和电泳迁移率变动分析（EMSA）方法。Egr-1调节结直肠癌细胞中mindin mRNA和蛋白的表达，与癌旁对照组织相比，结直肠癌患者肿瘤组织中Egr-1和mindin的蛋白表达均显著降低。Mindin是Egr-1介导的抑制内皮细胞管形成所必需的，并且Mindin在体外抑制内皮细胞增殖、迁移和血管生成芽。mindin的过表达通过阻断血管生成而不是直接抑制CRC细胞增殖来抑制异种移植肿瘤的生长。mindin在机制上抑制CRC细胞中缺氧诱导的HIF-1a和VEGFA蛋白表达以及内皮细胞中VEGFR-2的磷酸化。结果表明，血清mindin水平可用作早期检测CRC的新生物标志物，Egr-1/mindin轴是抑制CRC发展中血管生成的潜在治疗靶点。
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.