title: Oncogenic B-Raf signaling in melanoma cells controls a network of microRNAs with combinatorial functions.
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.
authors: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA.
authors: K L
authors: KL
authors: Couts
authors: E M
authors: EM
authors: Anderson
authors: M M
authors: MM
authors: Gross
authors: K
authors: K
authors: Sullivan
authors: N G
authors: NG
authors: Ahn
mesh_terms: D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D008544:Melanocytes / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014407:Tumor Cells, Cultured
chemical_list: D035683:MicroRNAs; D034741:RNA, Small Interfering; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human