Down-Regulation of miR-183 Promotes Migration and Invasion of Osteosarcoma by Targeting Ezrin
Down-Regulation of miR-183 Promotes Migration and Invasion of Osteosarcoma by Targeting Ezrin
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miR-183的下调通过靶向Ezrin促进骨肉瘤的迁移和侵袭
DOI：
10.1016/j.ajpath.2012.02.023
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发表时间：
2012-06-01
影响因子：
6
通讯作者：
Wang, Liantang
中科院分区：
文献类型：
--
作者：
Zhu, Junfeng;Feng, Yupeng;Wang, Liantang
最近的研究强调了异常的 microRNA 表达模式与癌症进展之间的因果关系。 miR-183 在某些类型的人类癌症中失调。然而，miR-183 在骨肉瘤中的表达模式、临床意义和生物学作用在很大程度上仍不清楚。在这项配对分析中，我们使用 RT-qPCR 发现，与匹配的正常骨组织相比，骨肉瘤细胞和组织中 miR-183 显着下调。统计分析显示，miR-183的表达水平与骨肉瘤的肺转移以及局部复发显着相关。在骨肉瘤细胞以及原发性骨肉瘤的子集中，miR-183 表达与 Ezrin mRNA 和蛋白表达水平呈负相关。异位表达的 miR-183 抑制骨肉瘤细胞的迁移和侵袭能力，而内源性 miR-183 的敲低显着增强了这些能力。使用携带 Ezrin 3'-非翻译区 (3'-UTR) 的荧光素酶报告基因，我们确定 Ezrin 是 miR-183 的直接靶标。此外，Ezrin 的异位表达可以显着挽救 miR-183 抑制的迁移和侵袭。有趣的是，miR-183 对 Ezrin 的抑制导致磷酸化 p44/42 (p-p44/42) 的减少。最后，RNAi 对 Ezrin 的抑制模仿了 miR-183 在抑制迁移和侵袭方面的作用，这与 p-p44/42 的下调有关。综上所述，这些结果表明，作为一种肿瘤抑制 miRNA，miR-183 在骨肉瘤的侵袭性中发挥着重要作用。 （Am J Pathol 2012 180：2440-2451；http://dx.doi.org/10.1016/j.ajpath.2012.02.023）
Recent studies have emphasized causative links between aberrant microRNA expression patterns and cancer progression. miR-183 is dysregulated in certain types of human cancers. The expression pattern, clinical significance, and biological role of miR-183 in osteosarcoma, however, remain largely undefined. In this paired analysis, we found that miR-183 was markedly down-regulated in osteosarcoma cells and tissues compared with matching normal bone tissues using RT-qPCR. Statistical analyses revealed that the expression levels of miR-183 significantly correlated with lung metastasis as well as with local recurrence of osteosarcoma. miR-183 expression was inversely correlated with Ezrin mRNA and protein expression levels in osteosarcoma cells as well as in a subset of primary osteosarcoma. Ectopically expressed miR-183 inhibited migratory and invasive abilities of osteosarcoma cells, whereas knockdown of endogenous miR-183 significantly enhanced these abilities. Using a luciferase reporter carrying the 3'-untranslated region (3'-UTR) of Ezrin, we identified Ezrin as a direct target of miR-183. Moreover, ectopic expression of Ezrin could significantly rescue miR-183-suppressed migration and invasion. Of interest, suppression of Ezrin by miR-183 caused a reduction of phosphorylated p44/42 (p-p44/42). Finally, suppression of Ezrin by RNAi mimicked miR-183 action in the suppression of migration and invasion, which was associated with down-regulation of p-p44/42. Taken together, these results suggest that as a tumor suppressor miRNA, miR-183 plays an important role in the aggressiveness of osteosarcoma. (Am J Pathol 2012 180:2440-2451; http://dx.doi.org/10.1016/j.ajpath.2012.02.023)