miR-27a induced by colon cancer cells in HLECs promotes lymphangiogenesis by targeting SMAD4.
miR-27a induced by colon cancer cells in HLECs promotes lymphangiogenesis by targeting SMAD4.
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HLEC 中结肠癌细胞诱导的 miR-27a 通过靶向 SMAD4 促进淋巴管生成
DOI：
10.1371/journal.pone.0186718
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Xiao XY
中科院分区：
文献类型：
--
作者：
Xu Q;Tong JL;Zhang CP;Xiao Q;Lin XL;Xiao XY
目的肿瘤细胞通过淋巴管、血管和跨体腔扩散发生转移。越来越多的体内和体外研究表明，肿瘤淋巴管生成促进转移。然而，结肠癌中淋巴管生成的调节仍不清楚。本研究的目的是鉴定结肠癌淋巴管生成中的关键miRNAs，并探讨其作用靶点和机制。方法应用微RNA芯片技术检测结肠癌细胞对人淋巴管内皮细胞（HLECs）中miRNA表达的影响。进行功能获得和功能丧失研究以确定miR-27 a（一个重要提示）对HLEC中淋巴管生成和迁移的功能。进一步进行生物信息学预测和实验验证，筛选出与淋巴管生成相关的miR-27 a靶基因。结果与结肠癌细胞共培养可诱导HLECs表达miR-27 a。HLEC中miR-27 a的过表达增强了淋巴管的形成和迁移，而miR-27 a的抑制则减少了淋巴管的形成和迁移。荧光素酶报告基因分析显示，miR-27 a直接靶向SMAD 4，SMAD 4是TGF-β途径的关键组分。此外，功能获得和功能丧失实验表明，SMAD 4负调控HLEC形成的淋巴管长度和迁移。结论结肠癌细胞诱导HLECs表达miR-27 a，并通过靶向SMAD 4促进淋巴管生成。我们的发现暗示miR-27 a是结肠癌新抗癌疗法的潜在靶点。
Aim Metastasis of tumor cells occurs through lymphatic vessels, blood vessels and transcoelomic spreading. Growing evidence from in vivo and in vitro studies has indicated that tumor lymphangiogenesis facilitates metastasis. However, the regulation of lymphangiogenesis in colon cancer remains unclear. The aims of this study were to identify key miRNAs in colon cancer lymphangiogenesis and to investigate its target and mechanism. Methods miRNA microarray analysis was conducted to identify miRNAs in human lymphatic endothelial cells (HLECs) that were regulated by co-cultured human colon cancer cells. Gain- and loss-of-function studies were performed to determine the function of miR-27a, a top hint, on lymphangiogenesis and migration in HLECs. Furthermore, bioinformatics prediction and experimental validation were performed to identify miR-27a target genes in lymphangiogenesis. Results We found that expression of miR-27a in HLECs was induced by co-culturing with colon cancer cells. Over-expression of miR-27a in HLECs enhanced lymphatic tube formation and migration, whereas inhibition of miR-27a reduced lymphatic tube formation and migration. Luciferase reporter assays showed that miR-27a directly targeted SMAD4, a pivotal component of the TGF-β pathway. In addition, gain-of-function and loss-of-function experiments showed that SMAD4 negatively regulated the length of lymphatic vessels formed by HLECs and migration. Conclusions Our data indicated that colon cancer cell induced the expression of miR-27a in HLECs, which promoted lymphangiogenesis by targeting SMAD4. Our finding implicated miR-27a as a potential target for new anticancer therapies in colon cancer.
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影响因子：
3.7
作者：
Guo, Chunguang;Sah, Jerome F.;Beard, Lydia;Willson, James K. V.;Markowitz, Sanford D.;Guda, Kishore
通讯作者：
Guda, Kishore
影响因子：
6.4
作者：
Huang, Shenglin;He, Xianghuo;Gu, Jianren
通讯作者：
Gu, Jianren
影响因子：
--
作者：
Gale M;Sayegh J;Cao J;Norcia M;Gareiss P;Hoyer D;Merkel JS;Yan Q
通讯作者：
Yan Q
影响因子：
8
作者：
Chen, X.;Guo, X.;Zhang, C-Y
通讯作者：
Zhang, C-Y
影响因子：
11.8
作者：
Fish, Jason E.;Santoro, Massimo M.;Morton, Sarah U.;Yu, Sangho;Yeh, Ru-Fang;Wythe, Joshua D.;Lvey, Kathryn N.;Bruneau, Benoit G.;Stainier, Didier Y. R.;Srivastava, Deepak
通讯作者：
Srivastava, Deepak