Transcription Factor/microRNA Axis Blocks Melanoma Invasion Program by miR-211 Targeting NUAK1
Transcription Factor/microRNA Axis Blocks Melanoma Invasion Program by miR-211 Targeting NUAK1
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DOI：
10.1038/jid.2013.340
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发表时间：
2014-02-01
影响因子：
6.5
通讯作者：
Levy, Carmit
中科院分区：
文献类型：
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作者：
Bell, Rachel E.;Khaled, Mehdi;Levy, Carmit
黑色素瘤是最致命的人类癌症之一，约占皮肤癌死亡率的80%。黑色素瘤的侵袭性是由于其增殖和快速侵入周围组织的能力，导致转移。最近的模型表明黑色素瘤通过在增殖和侵袭转录特征之间可逆地转换而进展。最近的研究表明，癌细胞比非癌细胞对microRNA（miRNA）干扰更敏感;然而，miRNA在黑色素瘤可塑性中的作用仍未被探索。在这里，我们使用黑色素瘤和正常黑色素细胞的基因表达谱来表征调节黑色素瘤增殖和侵袭程序的转录因子miRNA的关系。我们鉴定了两组可能调节这些程序的miRNAs。有趣的是，参与黑色素瘤侵袭的miRNAs之一是miR-211，它是主调节因子小眼症相关转录因子（MITF）的已知靶点。我们证明了miR-211通过直接靶向基因NUAK 1促进黑色素瘤粘附。抑制miR-211可增加NUAK 1表达并降低黑色素瘤粘附，而上调miR-211可通过NUAK 1抑制恢复粘附。本研究定义了MITF/miR-211轴，其通过阻断粘附来抑制侵入性程序。此外，我们已经确定NUAK 1作为治疗转移性黑色素瘤的潜在靶点。
Melanoma is one of the deadliest human cancers, responsible for approximately 80% of skin cancer mortalities. The aggressiveness of melanoma is due to its capacity to proliferate and rapidly invade surrounding tissues, leading to metastases. A recent model suggests melanoma progresses by reversibly switching between proliferation and invasion transcriptional signatures. Recent studies show that cancer cells are more sensitive to microRNA (miRNA) perturbation than are non-cancer cells; however, the roles of miRNAs in melanoma plasticity remain unexplored. Here, we use the gene expression profiles of melanoma and normal melanocytes to characterize the transcription factor miRNA relationship that modulates the proliferative and invasive programs of melanoma. We identified two sets of miRNAs that likely regulate these programs. Interestingly, one of the miRNAs involved in melanoma invasion is miR-211, a known target of the master regulator microphthalmia-associated transcription factor (MITF). We demonstrate that miR-211 contributes to melanoma adhesion by directly targeting a gene, NUAK1. Inhibition of miR-211 increases NUAK1 expression and decreases melanoma adhesion, whereas upregulation of miR-211 restores adhesion through NUAK1 repression. This study defines the MITF/miR-211 axis that inhibits the invasive program by blocking adhesion. Furthermore, we have identified NUAK1 as a potential target for the treatment of metastatic melanoma.