miR-19b promotes breast cancer metastasis through targeting MYLIP and its related cell adhesion molecules.
miR-19b promotes breast cancer metastasis through targeting MYLIP and its related cell adhesion molecules.
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miR-19b通过靶向MYLIP及其相关细胞粘附分子促进乳腺癌转移
DOI：
10.18632/oncotarget.19278
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发表时间：
2017-09-08
期刊：
影响因子：
--
通讯作者：
Mao Y
中科院分区：
文献类型：
--
作者：
Zhao L;Zhao Y;He Y;Mao Y
miR-19 b是肿瘤发生发展的关键分子，但其在乳腺癌转移中的关键作用目前很少研究。本研究利用多种生物信息学数据库预测miR-19 b的下游靶基因，验证了一个新的靶基因--肌球蛋白调节轻链相互作用蛋白（myosin regulatory light chain interacting protein，MYLIP）可被miR-19 b通过其3′-UTR区域直接下调。MYLIP属于细胞骨架蛋白簇，参与细胞运动和迁移的调节。我们进一步探索了miR-19 b在TCGA数据库中乳腺癌患者样本中的高表达，并与MYLIP表达呈负相关。通过创伤愈合实验和transwell侵袭实验，发现过表达miR-19 b或抑制MYLIP均有利于乳腺癌细胞的迁移和转移。此外，miR-19 b在体内外均能明显促进小鼠乳腺肿瘤的生长，并通过下调E-Cadherin的表达，上调ICAM-1和Integrin β1的表达，影响E-Cadherin、ICAM-1和Integrin β 1等细胞粘附分子的表达。同时，miR-19 b有效激活了整合素β下游信号通路（如Ras-MAPK通路和PI 3 K-AKT通路），并提高了这两条通路中必需基因的表达水平。综上所述，这些研究结果全面阐明了miR-19 b在乳腺癌转移中的调控机制，并为我们探索MYLIP及其相关细胞粘附分子作为干预乳腺癌发展的有前途的治疗靶点提供了新的见解。
miR-19b is a key molecule for cancer development, however its crucial roles in breast cancer metastasis are rarely studied right now. In this study, using several bioinformatics databases to predict the downstream targets for miR-19b, we verified that a novel target gene, myosin regulatory light chain interacting protein (MYLIP), could be directly down-regulated by miR-19b through its 3′-UTR region. MYLIP belongs to the cytoskeletal protein clusters and is involved in the regulation of cell movement and migration. We further explored that miR-19b was highly expressed and negatively correlated with MYLIP expression in breast cancer patient samples from the TCGA database. And the over-expression of miR-19b or inhibition of MYLIP facilitated the migration and metastasis of breast cancer cells, through conducting the wound healing assay and transwell invasion assay. Additionally, miR-19b could obviously promote breast tumor growth in mouse models and affect the expressions of cell adhesion molecules (including E-Cadherin, ICAM-1 and Integrin β1) by down-regulating E-Cadherin expression and up-regulating ICAM-1 and Integrin β1 expressions in vitro and in vivo. Meanwhile, miR-19b effectively activated the Integrin β downstream signaling pathways (such as the Ras-MAPK pathway and the PI3K-AKT pathway) and elevated the expression levels of essential genes in these two pathways. Taken together, these findings comprehensively illustrate the regulatory mechanisms ofmiR-19b in breast cancer metastasis, and provide us new insights for exploring MYLIP and its related cell adhesion molecules as promising therapeutic targets to interfere breast cancer development.
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