miR-514a regulates the tumour suppressor NF1 and modulates BRAFi sensitivity in melanoma

Stark, Mitchell S., Bonazzi, Vanessa F., Boyle, Glen M., Palmer, Jane M., Symmons, Judith, Lanagan, Catherine M., Schmidt, Christopher W., Herington, Adrian C., Ballotti, Robert, Pollock, Pamela M., & Hayward, Nicholas K. (2015) miR-514a regulates the tumour suppressor NF1 and modulates BRAFi sensitivity in melanoma. Oncotarget, 6(19), pp. 17753-17763.

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Abstract

To identify ‘melanoma-specific’ microRNAs (miRNAs) we used an unbiased microRNA profiling approach to comprehensively study cutaneous melanoma in relation to other solid malignancies, which revealed 233 differentially expressed (≥ 2 fold, p < 0.05) miRNAs. Among the top 20 most significantly different miRNAs was hsa-miR-514a-3p. miR-514a is a member of a cluster of miRNAs (miR-506-514) involved in initiating melanocyte transformation and promotion of melanoma growth. We found miR-514a was expressed in 38/55 (69%) melanoma cell lines but in only 1/34 (3%) other solid cancers. To identify miR-514a regulated targets we conducted a miR-514a-mRNA ‘pull-down’ experiment, which revealed hundreds of genes, including: CTNNB1, CDK2, MC1R, and NF1, previously associated with melanoma. NF1 was selected for functional validation because of its recent implication inacquired resistance to BRAFV600E-targeted therapy. Luciferase-reporter assays confirmed NF1 as a direct target of miR-514a and over-expression of miR-514a in melanoma cell lines inhibited NF1 expression, which correlated with increased survival of BRAFV600E cells treated with PLX4032. These data provide another mechanism for the dysregulation of the MAPK pathway which may contribute to the profound resistance associated with current RAF-targeted therapies.

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ID Code: 90803
Item Type: Journal Article
Refereed: Yes
Keywords: miRNA, microRNA, miR-514a, BRAFi, NF1
DOI: 10.18632/oncotarget.3924
ISSN: 1949-2553
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Funding:
Copyright Owner: Copyright 2015 Impact Journals LLC
Copyright Statement: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Deposited On: 26 Nov 2015 22:41
Last Modified: 29 Nov 2015 21:48

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