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J Invest Dermatol. 2014 Feb;134(2):441-51. doi: 10.1038/jid.2013.340. Epub 2013 Aug 9.

Transcription factor/microRNA axis blocks melanoma invasion program by miR-211 targeting NUAK1.

Author information

1
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
2
1] Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA [2] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
3
Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.
4
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

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.

PMID:
23934065
DOI:
10.1038/jid.2013.340
[Indexed for MEDLINE]
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