Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor
Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor
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DOI：
10.1073/pnas.0808263106
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发表时间：
2009-02-10
影响因子：
11.1
通讯作者：
Hernando, Eva
中科院分区：
文献类型：
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作者：
Segura, Miguel F.;Hanniford, Douglas;Hernando, Eva
黑色素瘤的高度侵袭性使其成为探索转移机制的极佳模型，转移机制仍然是癌症治疗中最困难的挑战之一。我们发现，miR-182是在黑色素瘤中频繁扩增的染色体座位(7q31-34)上的miRNA簇的成员，在人类黑色素瘤细胞系和组织样本中普遍上调；这种上调与黑色素瘤细胞亚群中的基因拷贝数有关。此外，miR-182的异位表达促进了黑色素瘤细胞在体外的迁移和体内的转移潜能，而miR-182的下调则阻碍了黑色素瘤细胞的侵袭并触发了细胞凋亡。我们进一步表明，miR-182过表达通过直接抑制小眼球相关转录因子-M和FOXO_3来促进迁移和生存，而小眼球相关转录因子-M或FOXO_3的增强表达阻断了miR-182‘S的侵袭效应。在人类组织中，miR-182的表达随着黑色素瘤从原发到转移的进展而增加，并与FOXO_3和小眼球相关转录因子水平呈负相关。我们的数据为黑色素瘤的侵袭和存活提供了一种机制，该机制可能被证明适用于其他癌症的转移，并表明miRNA沉默可能是一种有价值的治疗策略。
The highly aggressive character of melanoma makes it an excellent model for probing the mechanisms underlying metastasis, which remains one of the most difficult challenges in treating cancer. We find that miR-182, member of a miRNA cluster in a chromosomal locus (7q31-34) frequently amplified in melanoma, is commonly up-regulated in human melanoma cell lines and tissue samples; this up-regulation correlates with gene copy number in a subset of melanoma cell lines. Moreover, miR-182 ectopic expression stimulates migration of melanoma cells in vitro and their metastatic potential in vivo, whereas miR-182 down-regulation impedes invasion and triggers apoptosis. We further show that miR-182 over-expression promotes migration and survival by directly repressing microphthalmia-associated transcription factor-M and FOXO3, whereas enhanced expression of either microphthalmia-associated transcription factor-M or FOXO3 blocks miR-182's proinvasive effects. In human tissues, expression of miR-182 increases with progression from primary to metastatic melanoma and inversely correlates with FOXO3 and microphthalmia-associated transcription factor levels. Our data provide a mechanism for invasion and survival in melanoma that could prove applicable to metastasis of other cancers and suggest that miRNA silencing may be a worthwhile therapeutic strategy.