LncRNA-MALAT1 promotes tumorogenesis of infantile hemangioma by competitively binding miR-424 to stimulate MEKK3/NF-κB pathway
LncRNA-MALAT1 promotes tumorogenesis of infantile hemangioma by competitively binding miR-424 to stimulate MEKK3/NF-κB pathway
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DOI：
10.1016/j.lfs.2019.116946
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发表时间：
2019-12-15
期刊：
影响因子：
6.1
通讯作者：
Sun, Zheng-Wei
中科院分区：
文献类型：
--
作者：
Li, Miao-Miao;Dong, Chang-Xian;Sun, Zheng-Wei
目的：婴儿血管瘤（IH）是婴幼儿最常见的血管肿瘤。已知长链非编码RNA（lncRNA）与IH相关。本研究旨在探讨lncRNA-MALAT 1在IH中的作用及其机制。主要方法：采用qRT-PCR方法检测IH组织中MALAT 1、miR-424和MEKK 3的表达。采用MTT法、集落形成法、流式细胞仪、transwell法和微管形成法检测细胞增殖、凋亡、迁移、侵袭和微管形成能力。采用荧光素酶报告基因分析法检测MALAT 1、miR-424和MEKK 3之间的相互作用。免疫组化和Western blotting检测MEKK 3、Ki-67和NF-κ B B通路相关蛋白的表达水平。沉默MALAT 1或过表达miR-424可显著抑制IH细胞增殖、迁移和管腔形成，但促进细胞凋亡。MALAT 1的敲除抑制MEKK 3的表达，并通过海绵状miR-424使IKK/NF-κ B通路失活。MEKK 3在HemEcs中的过表达逆转了MALAT 1敲低和miR-424过表达对细胞增殖、凋亡、迁移、侵袭和管形成率的影响。意义：MALAT 1通过抑制miR-424激活MEKK 3介导的IKK/NF-κ B通路，促进IH进展，提示MALAT 1、miR-424和MEKK 3可作为潜在的靶点，提高IH治疗效率。
Aims: Infantile hemangioma (IH) is the most common vascular neoplasm in infant and young children. Long non-coding RNAs (lncRNAs) are known to be associated with IH. This study aims to investigate the role and underlying mechanism of lncRNA-MALAT1 in IH.Main methods: qRT-PCR was used to quantify the expressions of MALAT1, miR-424, and MEKK3 in IH tissues. The cell proliferation, apoptosis, migration, invasion, and tube formation ability were assessed by MTT assay, colony formation assay, flow cytometric analysis, transwell assay and tube formation assay, respectively. The interaction among MALAT1, miR-424 and MEKK3 was evaluated by luciferase reporter assay. Immunohistochemistry (IHC) and Western blotting were utilized to evaluate the expression levels of MEKK3, Ki-67 and NF-kappa B pathway-related proteins both in vitro and in vivo.Key findings: In IH tissues, MALAT1 and MEKK3 were overexpressed while miR-424 was down-regulated. Silencing MALAT1 or overexpression of miR-424 significantly inhibited the IH cell proliferation, migration and tube formation, but promoted the cell apoptosis. Knockdown of MALAT1 suppressed the expression of MEKK3 and inactivated the IKK/NF-kappa B pathway by sponging miR-424. Overexpression of MEKK3 in HemEcs reversed the impact of knockdown of MALAT1 and overexpression of miR-424 on the cell proliferation, apoptosis, migration, invasion and tube formation rate. The tumor xenografts experiments demonstrated that silencing MALAT1 significantly inhibited the tumor growth in vivo and Ki-67 in the tumor tissues was also significantly suppressed.Significance: MALAT1 promoted the IH progression through inhibiting miR-424 to activate MEKK3-mediated IKK/NF-kappa B pathway, suggesting that MALAT1, miR-424 and MEKK3 could be used as potential targets to improve IH treatment efficiency.