MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers
MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers
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DOI：
10.1038/onc.2010.233
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发表时间：
2010-09-01
期刊：
影响因子：
8
通讯作者：
Rao, M. K.
中科院分区：
文献类型：
--
作者：
Imam, J. S.;Buddavarapu, K.;Rao, M. K.
同源盒基因编码的转录因子是正常发育所必需的，在癌症中经常失调。导致它们在癌症中失调的分子机制在很大程度上是未知的。在这项研究中，我们研究了Six1同源盒蛋白的机制，它在发育过程中起着至关重要的作用，在几种预后不良、侵袭性、转移性的成人癌症中，包括乳腺癌、卵巢癌、肝细胞癌和儿童恶性肿瘤，如横纹肌肉瘤和威尔姆斯瘤，经常被解除调控。我们的研究结果表明，miRNA-185通过结合Six1的3'-非翻译区来抑制Six1的翻译。卵巢癌、儿童肾肿瘤和多种乳腺癌细胞系的分析显示miR-185表达降低，与Six1水平升高平行。进一步的研究表明，miR-185除了在体内抑制肿瘤生长外，还能抑制锚定不依赖的生长和细胞迁移，这表明它是一种有效的肿瘤抑制因子。我们的研究结果表明，miR-185通过调节细胞周期蛋白和Six1转录靶点c-myc和cyclin A1来调节其肿瘤抑制功能。此外，我们发现miR-185一般会使six1过表达的耐药癌细胞对凋亡敏感，特别是肿瘤坏死因子相关的凋亡诱导配体（TRAIL）介导的凋亡。总之，我们的研究结果表明，新型肿瘤抑制因子miR-185的表达改变可能是导致人类癌症中致癌蛋白Six1失调的中心事件之一。中华肿瘤杂志（2010）29 (4):471 - 479；doi: 10.1038 / onc.2010.233;2010年7月5日在线发布
Homeobox genes encode transcription factors that are essential for normal development and are often dysregulated in cancers. The molecular mechanisms that cause their misregulation in cancers are largely unknown. In this study, we investigate the mechanism by which the Six1 homeobox protein, which has a crucial role during development, is frequently deregulated in several poor outcome, aggressive, metastatic adult human cancers, including breast cancer, ovarian cancer, hepatocellular carcinoma and pediatric malignancies such as rhabdomyosarcoma and Wilms' tumor. Our results reveal that miRNA-185 translationally represses Six1 by binding to its 3'-untranslated region. Analyses of ovarian cancers, pediatric renal tumors and multiple breast cancer cell lines showed decreased miR-185 expression, paralleling an increase in Six1 levels. Further investigation revealed that miR-185 impedes anchorage-independent growth and cell migration, in addition to suppressing tumor growth in vivo, implicating it to be a potent tumor suppressor. Our results indicate that miR-185 mediates its tumor suppressor function by regulating cell-cycle proteins and Six1 transcriptional targets c-myc and cyclin A1. Furthermore, we show that miR-185 sensitizes Six1-overexpressing resistant cancer cells to apoptosis in general and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in particular. Together, our findings suggest that the altered expression of the novel tumor suppressor miR-185 may be one of the central events that leads to dysregulation of oncogenic protein Six1 in human cancers. Oncogene (2010) 29, 4971-4979; doi: 10.1038/onc.2010.233; published online 5 July 2010