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microRNA-7-5p inhibits melanoma cell proliferation and metastasis by suppressing RelA/NF-κB
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Keith M. Giles1,2,*, Rikki A.M. Brown1,*, Clarissa Ganda1, Melissa J. Podgorny1, Patrick A. Candy1, Larissa C. Wintle1, Kirsty L. Richardson1, Felicity C. Kalinowski1, Lisa M. Stuart1, Michael R. Epis1, Nikolas K. Haass3, Meenhard Herlyn4 and Peter J. Leedman1,5
1 Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and University of Western Australia Centre for Medical Research, Nedlands, WA, Australia
2 Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, United States of America
3 The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia
4 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, United States of America
5 School of Medicine and Pharmacology, The University of Western Australia, Nedlands, WA, Australia
* These authors have contributed equally to this work
Peter J. Leedman, email:
Keywords: microRNA, miR-7-5p, RelA, melanoma, metastasis
Received: February 05, 2016 Accepted: May 09, 2016 Published: May 17, 2016
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.
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