Knockdown of MALAT1 expression inhibits HUVEC proliferation by upregulation of miR-320a and downregulation of FOXM1 expression.
Knockdown of MALAT1 expression inhibits HUVEC proliferation by upregulation of miR-320a and downregulation of FOXM1 expression.
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DOI：
10.18632/oncotarget.18507
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发表时间：
2017-09-22
期刊：
影响因子：
--
通讯作者：
Li XF
中科院分区：
文献类型：
--
作者：
Sun JY;Zhao ZW;Li WM;Yang G;Jing PY;Li P;Dang HZ;Chen Z;Zhou YA;Li XF
调节肿瘤血管生成可能是肿瘤治疗的一个有用的策略。转移相关肺腺癌转录本1（MALAT 1）是一种长链非编码RNA（lncRNA），可诱导癌细胞增殖，而lncRNA通常可作为microRNA（miRNA）海绵。后者是一种竞争性内源性RNA（ceRNA），其调节靶向miRNA和蛋白质编码基因的表达。本研究探讨了MALAT 1在人脐静脉内皮细胞（HUVECs）中的增殖作用及其潜在的分子事件。数据显示，使用MALAT 1 siRNA敲低MALAT 1表达抑制HUVEC增殖，并且还显著降低体外FOXM 1 mRNA和蛋白水平，而敲低FOXM 1表达降低HUVEC增殖。HUVEC微阵列数据的注释显示，包括miR-320 a在内的7种miRNA在HUVEC中MALAT 1表达被敲低后上调。MALAT 1显示与miR-320 a不相互作用，即，其中一种的表达负调节另一种的水平，而MALAT 1表达的敲低促进miR-320 a水平。此外，miR-320 a可直接靶向并抑制HUVECs中FOXM 1的表达。MALAT 1表达的敲低增强了miR-320 a的表达，但降低了FOXM 1的表达，导致HUVEC增殖的下调。然而，这种作用被miR-320 a耗尽所抑制。总之，本研究表明miR-320 a通过抑制FOXM 1表达在介导MALAT 1对HUVEC增殖的影响中起重要作用。因此，靶向该基因通路可能是癌症治疗的新策略。
Regulation of cancer angiogenesis could be a useful strategy in cancer therapy. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA), and can induce cancer cell proliferation, while lncRNAs, generally are able to act as microRNA (miRNA) sponges. The latter is a type of competitive endogenous RNA (ceRNA) that regulates expression of the targeting miRNAs and protein-coding genes. This study investigated the proliferative role of MALAT1 in human umbilical vein endothelial cells (HUVECs) and the underlying molecular events. The data showed that knockdown of MALAT1 expression using MALAT1 siRNA inhibited HUVEC proliferation and also significantly decreased levels of FOXM1 mRNA and protein in vitro, while knockdown of FOXM1 expression reduced HUVEC proliferation. Annotation of HUVEC microarray data revealed that seven miRNAs, including miR-320a, were upregulated after knockdown of MALAT1 expression in HUVECs. MALAT1 was shown to reciprocally interact with miR-320a, i.e., expression of one negatively regulated levels of the other, whereas knockdown of MALAT1 expression promoted miR-320a levels. Furthermore, miR-320a could directly target and inhibit FOXM1 expression in HUVECs. Knockdown of MALAT1 expression enhanced miR-320a expression but reduced FOXM1 expression resulting in downregulation of HUVEC proliferation. However, such an effect was inhibited by miR-320a depletion. In conclusion, this study demonstrates that miR-320a plays an important role in mediating the effects of MALAT1 on HUVEC proliferation by suppression of FOXM1 expression. Thus, targeting of this gene pathway could be a novel strategy in cancer therapy.
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