Distinct microRNA expression signatures are associated with melanoma subtypes and are regulated by HIF1A.
The complex genetic changes underlying metastatic melanoma need to be deciphered to develop new and effective therapeutics. Previously, genome-wide microarray analyses of human melanoma identified two reciprocal gene expression programs, including transcripts regulated by either transforming growth factor, beta 1 (TGFβ1) pathways, or microphthalmia-associated transcription factor (MITF)/SRY-box containing gene 10 (SOX10) pathways. We extended this knowledge by discovering that melanoma cell lines with these two expression programs exhibit distinctive microRNA (miRNA) expression patterns. We also demonstrated that hypoxia-inducible factor 1 alpha (HIF1A) is increased in TGFβ1 pathway-expressing melanoma cells and that HIF1A upregulates miR-210, miR-218, miR-224, and miR-452. Reduced expression of these four miRNAs in TGFβ1 pathway-expressing melanoma cells arrests the cell cycle, while their overexpression in mouse melanoma cells increases the expression of the hypoxic response gene Bnip3. Taken together, these data suggest that HIF1A may regulate some of the gene expression and biological behavior of TGFβ1 pathway-expressing melanoma cells, in part via alterations in these four miRNAs.
Genetic Disease Research Branch, Department of Health and Human Services, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Hun-Way
HW
Hwang
Laura L
LL
Baxter
Stacie K
SK
Loftus
Julia C
JC
Cronin
Niraj S
NS
Trivedi
Bhavesh
B
Borate
William J
WJ
Pavan
D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
C508686:BNip3 protein, mouse; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C543800:MIRN210 microRNA, human; C547471:MIRN218 microRNA, human; C546140:MIRN224 microRNA, human; C574051:MIRN452 microRNA, human; C497234:MITF protein, human; D008565:Membrane Proteins; D035683:MicroRNAs; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D024101:Mitochondrial Proteins; D053773:Transforming Growth Factor beta1
Bnip3; HIF1; hypoxia; melanoma; miRNA