Zhao Luqing, Zhao Yuelong, He Yanong, Mao Yitao
Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Pathology, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China.
Oncotarget. 2017 Jul 17;8(38):64330-64343. doi: 10.18632/oncotarget.19278. eCollection 2017 Sep 8.
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 and . 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.
miR-19b 是癌症发展的关键分子，然而目前其在乳腺癌转移中的关键作用鲜少被研究。在本研究中，我们利用多个生物信息学数据库预测 miR-19b 的下游靶点，证实了一个新的靶基因——肌球蛋白调节轻链相互作用蛋白（MYLIP），可被 miR-19b 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。我们进一步探究发现，在来自 TCGA 数据库的乳腺癌患者样本中，miR-19b 高表达且与 MYLIP 表达呈负相关。通过进行伤口愈合试验和 Transwell 侵袭试验，miR-19b 的过表达或 MYLIP 的抑制促进了乳腺癌细胞的迁移和转移。此外，miR-19b 可明显促进小鼠模型中的乳腺肿瘤生长，并通过下调 E-钙黏蛋白表达、上调 ICAM-1 和整合素β1 表达来影响细胞黏附分子（包括 E-钙黏蛋白、ICAM-1 和整合素β1）的表达。同时，miR-19b 有效激活了整合素β下游信号通路（如 Ras-MAPK 通路和 PI3K-AKT 通路），并提高了这两条通路中关键基因的表达水平。综上所述，这些发现全面阐明了 miR-19b 在乳腺癌转移中的调控机制，并为我们探索将 MYLIP 及其相关细胞黏附分子作为干预乳腺癌发展的有前景的治疗靶点提供了新的见解。
