title: Regulation of cancer aggressive features in melanoma cells by microRNAs.
abstract: MicroRNAs (miRNAs) are small non-coding RNAs with regulatory roles, which are involved in a broad spectrum of physiological and pathological processes, including cancer. A common strategy for identification of miRNAs involved in cell transformation is to compare malignant cells to normal cells. Here we focus on identification of miRNAs that regulate the aggressive phenotype of melanoma cells. To avoid differences due to genetic background, a comparative high-throughput miRNA profiling was performed on two isogenic human melanoma cell lines that display major differences in their net proliferation, invasion and tube formation activities. This screening revealed two major cohorts of differentially expressed miRNAs. We speculated that miRNAs up-regulated in the more-aggressive cell line contribute oncogenic features, while the down-regulated miRNAs are tumor suppressive. This assumption was further tested experimentally on five candidate tumor suppressive miRNAs (miR-31, -34a, -184, -185 and -204) and on one candidate oncogenic miRNA (miR-17-5p), all of which have never been reported before in cutaneous melanoma. Remarkably, all candidate Suppressive-miRNAs inhibited net proliferation, invasion or tube formation, while miR-17-5p enhanced cell proliferation. miR-34a and miR-185 were further shown to inhibit the growth of melanoma xenografts when implanted in SCID-NOD mice. Finally, all six candidate miRNAs were detected in 15 different metastatic melanoma specimens, attesting for the physiological relevance of our findings. Collectively, these findings may prove instrumental for understanding mechanisms of disease and for development of novel therapeutic and staging technologies for melanoma.
authors.affiliation: Ella Institute of Melanoma, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Greenberg
authors.forename: Liat
authors.initials: L
authors.lastname: Hershkovitz
authors.forename: Orit
authors.initials: O
authors.lastname: Itzhaki
authors.forename: Steven
authors.initials: S
authors.lastname: Hajdu
authors.forename: Yael
authors.initials: Y
authors.lastname: Nemlich
authors.forename: Rona
authors.initials: R
authors.lastname: Ortenberg
authors.forename: Nir
authors.initials: N
authors.lastname: Gefen
authors.forename: Liat
authors.initials: L
authors.lastname: Edry
authors.forename: Shira
authors.initials: S
authors.lastname: Modai
authors.forename: Yona
authors.initials: Y
authors.lastname: Keisari
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Besser
authors.forename: Jacob
authors.initials: J
authors.lastname: Schachter
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
authors.forename: Gal
authors.initials: G
authors.lastname: Markel
mesh_terms: D000818:Animals; D001681:Biological Assay; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010641:Phenotype
chemical_list: D035683:MicroRNAs