MicroRNA miR-196a is a central regulator of HOX-B7 and BMP4 expression in malignant melanoma.
Since bone morphogenetic proteins (BMPs) play an important role in melanoma progression, we aimed to determine the molecular mechanisms leading to overexpression of BMP4 in melanoma cells compared to normal melanocytes. With our experimental approach we revealed that loss of expression of a microRNA represents the starting point for a signaling cascade finally resulting in overexpression of BMP4 in melanoma cells. In detail, strongly reduced expression of the microRNA miR-196a in melanoma cells compared to healthy melanocytes leads to enhanced HOX-B7 mRNA and protein levels, which subsequently raise Ets-1 activity by inducing basic fibroblast growth factor (bFGF). Ets-1 finally accounts for induction of BMP4 expression. We were furthermore able to demonstrate that bFGF-mediated induction of migration is achieved via activation of BMP4, thus determining BMP4 as major modulator of migration in melanoma. In summary, our study provides insights into the early steps of melanoma progression and might thereby harbor therapeutic relevance.
Braig
Simone
S
Institute of Pathology, University of Regensburg Medical School, Franz-Josef-Strauss-Allee 11, Regensburg, Germany.
Mueller
Daniel W
DW
Rothhammer
Tanja
T
Bosserhoff
Anja-Katrin
AK
D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; C494041:ETS1 protein, human; C490538:HOXB7 protein, human; D018398:Homeodomain Proteins; C542543:MIRN196 microRNA, human; D035683:MicroRNAs; D050784:Proto-Oncogene Protein c-ets-1; D016222:Fibroblast Growth Factor 2