BMP4 depletion by miR-200 inhibits tumorigenesis and metastasis of lung adenocarcinoma cells.
BMP4 depletion by miR-200 inhibits tumorigenesis and metastasis of lung adenocarcinoma cells.
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DOI：
10.1186/s12943-015-0441-y
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发表时间：
2015-09-22
期刊：
影响因子：
37.3
通讯作者：
Ahn YH
中科院分区：
文献类型：
--
作者：
Kim JS;Kurie JM;Ahn YH
microRNA-200（miR-200）抑制各种癌细胞（包括肺腺癌细胞）的上皮-间质转化。我们发现骨形态发生蛋白4（BMP 4）在miR-200过表达细胞和上皮样肺癌细胞中减少。在这项研究中，我们研究了miR-200在小鼠肺腺癌细胞中对BMP 4消耗的机制和作用。通过定量逆转录-PCR（qRT-PCR）和蛋白质印迹法测量小鼠肺癌细胞中的BMP 4表达水平。通过启动子和3′-非翻译区（UTR）荧光素酶报告基因分析，探讨miR-200对BMP 4的调控机制。将BMP 4 shRNA转染小鼠肺癌细胞，然后将其注射到同基因小鼠中以测量其致瘤性和转移潜力，并在Matrigel上培养以研究BMP 4对三维腺泡形成的影响。miR-200通过直接靶向刺激Bmp 4转录的GATA 4和GATA 6转录因子下调BMP 4。BMP 4上调miR-200的上游因子JAG 2;因此，JAG 2、miR-200和BMP 4形成调控环。bmp 4基因敲减抑制了肺癌细胞的生长、迁移和侵袭，并抑制了肺癌细胞的肿瘤发生和转移。此外，BMP 4是小鼠肺癌细胞的Matrigel 3-D培养中正常腺泡形成所必需的，这可能是由BMP 4的下游靶标MYH 10介导的。BMP 4在小鼠肺癌模型中作为促肿瘤发生因子发挥作用，其转录受miR-200和GATA 4/6调控。因此，我们建议BMP 4及其拮抗剂可能是治疗肺癌的合适的治疗靶点。本文的在线版本（doi：10.1186/s12943-015-0441-y）包含补充材料，可供授权用户使用。
MicroRNA-200 (miR-200) suppresses the epithelial-mesenchymal transition of various cancer cells, including lung adenocarcinoma cells. We found that bone morphogenetic protein 4 (BMP4) was decreased in miR-200-overexpressing cells and epithelial-like lung cancer cells. In this study, we investigated the mechanism and role of BMP4 depletion by miR-200 in murine lung adenocarcinoma cells. BMP4 expression levels in murine lung cancer cells were measured by quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. Promoter and 3′-untranslated region (UTR) luciferase reporter assays were performed to discover the mechanism of regulation of BMP4 by miR-200. Murine lung cancer cells were transfected with Bmp4 shRNAs, which were then injected into syngeneic mice to measure their tumorigenic and metastatic potential and cultured on Matrigel to study the influence of BMP4 on 3-D acinus formation. miR-200 down-regulated BMP4 via direct targeting of the GATA4 and GATA6 transcription factors that stimulate Bmp4 transcription. BMP4 up-regulated JAG2, an upstream factor of miR-200; therefore, JAG2, miR-200, and BMP4 form a regulatory loop. Bmp4 knockdown suppressed cancer cell growth, migration, and invasion and inhibited tumorigenesis and metastasis of lung cancer cells when injected into syngeneic mice. In addition, BMP4 was required for normal acinus formation in Matrigel 3-D culture of murine lung cancer cells, which may be mediated by MYH10, a downstream target of BMP4. BMP4 functions as a pro-tumorigenic factor in a murine lung cancer model, and its transcription is regulated by miR-200 and GATA4/6. Thus, we propose that BMP4 and its antagonists may be suitable therapeutic targets for the treatment of lung cancer. The online version of this article (doi:10.1186/s12943-015-0441-y) contains supplementary material, which is available to authorized users.