Oncogenic B-Raf signaling in melanoma cells controls a network of microRNAs with combinatorial functions
Open Access
- 2 July 2012
- journal article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 32 (15), 1959-1970
- https://doi.org/10.1038/onc.2012.209
Abstract
Over two-thirds of melanomas have activating mutations in B-Raf, leading to constitutive activation of the B-Raf/MKK/ERK signaling pathway. The most prevalent mutation, B-RafV600E, promotes cancer cell behavior through mechanisms that are still incompletely defined. Here, we used a sensitive microarray profiling platform to compare microRNA (miRNA) expression levels between primary melanocytes and B-RafV600E-positive melanoma cell lines, and between melanoma cells treated in the presence and absence of an MKK1/2 inhibitor. We identified a network of >20 miRNAs deregulated by B-Raf/MKK/ERK in melanoma cells, the majority of which modulate the expression of key cancer regulatory genes and functions. Importantly, miRNAs within the network converge on protein regulation and cancer phenotypes, suggesting that these miRNAs might function combinatorially. We show that miRNAs augment effects on protein repression and cell invasion when co-expressed, and gene-specific latency and interference effects between miRNAs were also observed. Thus, B-Raf/MKK/ERK controls key aspects of cancer cell behavior and gene expression by modulating a network of miRNAs with cross-regulatory functions. The findings highlight the potential for complex interactions between coordinately regulated miRNAs within a network.Keywords
This publication has 42 references indexed in Scilit:
- Phosphorylation of the Human MicroRNA-Generating Complex Mediates MAPK/Erk SignalingCell, 2009
- The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivoGenes & Development, 2009
- Plexin B1 is repressed by oncogenic B-Raf signaling and functions as a tumor suppressor in melanoma cellsOncogene, 2009
- The database of experimentally supported targets: a functional update of TarBaseNucleic Acids Research, 2008
- miRiad Roles for the miR-17-92 Cluster in Development and DiseaseCell, 2008
- Widespread microRNA repression by Myc contributes to tumorigenesisNature Genetics, 2007
- MicroRNA Targeting Specificity in Mammals: Determinants beyond Seed PairingMolecular Cell, 2007
- Distance constraints between microRNA target sites dictate efficacy and cooperativityNucleic Acids Research, 2007
- Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA TargetsCell, 2005
- Mutations of the BRAF gene in human cancerNature, 2002