title: miR-214 coordinates melanoma progression by upregulating ALCAM through TFAP2 and miR-148b downmodulation.
abstract: Malignant melanoma is one of the most aggressive human cancers, but the mechanisms governing its metastatic dissemination are not fully understood. Upregulation of miR-214 and ALCAM and the loss of TFAP2 expression have been implicated in this process, with TFAP2 a direct target of miR-214. Here, we link miR-214 and ALCAM as well as identify a core role for miR-214 in organizing melanoma metastasis. miR-214 upregulated ALCAM, acting transcriptionally through TFAP2 and also posttranscriptionally through miR-148b (itself controlled by TFAP2), both negative regulators of ALCAM. We also identified several miR-214-mediated prometastatic functions directly promoted by ALCAM. Silencing ALCAM in miR-214-overexpressing melanoma cells reduced cell migration and invasion without affecting growth or anoikis in vitro, and it also impaired extravasation and metastasis formation in vivo. Conversely, cell migration and extravasation was reduced in miR-214-overexpressing cells by upregulation of either miR-148b or TFAP2. These findings were consistent with patterns of expression of miR-214, ALCAM, and miR-148b in human melanoma specimens. Overall, our results define a pathway involving miR-214, miR-148b, TFAP2, and ALCAM that is critical for establishing distant metastases in melanoma.
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Penna
authors.forename: Francesca
authors.initials: F
authors.lastname: Orso
authors.forename: Daniela
authors.initials: D
authors.lastname: Cimino
authors.forename: Irene
authors.initials: I
authors.lastname: Vercellino
authors.forename: Elena
authors.initials: E
authors.lastname: Grassi
authors.forename: Elena
authors.initials: E
authors.lastname: Quaglino
authors.forename: Emilia
authors.initials: E
authors.lastname: Turco
authors.forename: Daniela
authors.initials: D
authors.lastname: Taverna
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D005326:Fetal Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008545:Melanoma / Q000378:metabolism* / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D034622:RNA Interference; D050656:Transcription Factor AP-2 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D015703:Antigens, CD; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D035683:MicroRNAs; D050656:Transcription Factor AP-2; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C550570:MIRN148 microRNA, human; C547397:MIRN214 microRNA, human