title: microRNA-7-5p inhibits melanoma cell proliferation and metastasis by suppressing RelA/NF-κB.
abstract: microRNA-7-5p (miR-7-5p) is a tumor suppressor in multiple cancer types and inhibits growth and invasion by suppressing expression and activity of the epidermal growth factor receptor (EGFR) signaling pathway. While melanoma is not typically EGFR-driven, expression of miR-7-5p is reduced in metastatic tumors compared to primary melanoma. Here, we investigated the biological and clinical significance of miR-7-5p in melanoma. We found that augmenting miR-7-5p expression in vitro markedly reduced tumor cell viability, colony formation and induced cell cycle arrest. Furthermore, ectopic expression of miR-7-5p reduced migration and invasion of melanoma cells in vitro and reduced metastasis in vivo. We used cDNA microarray analysis to identify a subset of putative miR-7-5p target genes associated with melanoma and metastasis. Of these, we confirmed nuclear factor kappa B (NF-κB) subunit RelA, as a novel direct target of miR-7-5p in melanoma cells, such that miR-7-5p suppresses NF-κB activity to decrease expression of canonical NF-κB target genes, including IL-1β, IL-6 and IL-8. Importantly, the effects of miR-7-5p on melanoma cell growth, cell cycle, migration and invasion were recapitulated by RelA knockdown. Finally, analysis of gene array datasets from multiple melanoma patient cohorts revealed an association between elevated RelA expression and poor survival, further emphasizing the clinical significance of RelA and its downstream signaling effectors. Taken together, our data show that miR-7-5p is a potent inhibitor of melanoma growth and metastasis, in part through its inactivation of RelA/NF-κB signaling. Furthermore, miR-7-5p replacement therapy could have a role in the treatment of this disease.
authors.affiliation: Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, Australia.|Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, United States of America.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Giles
authors.affiliation: Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, Australia.
authors.forename: Rikki A M
authors.initials: RA
authors.lastname: Brown
authors.affiliation: Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, Australia.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Ganda
authors.affiliation: Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, Australia.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Podgorny
authors.affiliation: Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, Australia.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Candy
authors.affiliation: Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, Australia.
authors.forename: Larissa C
authors.initials: LC
authors.lastname: Wintle
authors.affiliation: Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, Australia.
authors.forename: Kirsty L
authors.initials: KL
authors.lastname: Richardson
authors.affiliation: Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, Australia.
authors.forename: Felicity C
authors.initials: FC
authors.lastname: Kalinowski
authors.affiliation: Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, Australia.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Stuart
authors.affiliation: Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, Australia.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Epis
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Nikolas K
authors.initials: NK
authors.lastname: Haass
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, United States of America.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, Australia.|School of Medicine and Pharmacology, The University of Western Australia, Nedlands, WA, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Leedman
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001665:Binding Sites; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011379:Prognosis; D034622:RNA Interference; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D007378:Interleukins; D035683:MicroRNAs; D051996:Transcription Factor RelA; C549242:MIRN7-1 microRNA, human; C498143:RELA protein, human
keywords: RelA; melanoma; metastasis; miR-7-5p; microRNA