title: MicroRNA-26a is strongly downregulated in melanoma and induces cell death through repression of silencer of death domains (SODD).
abstract: Melanoma is an aggressive cancer that metastasizes rapidly and is refractory to conventional chemotherapies. Identifying microRNAs (miRNAs) that are responsible for this pathogenesis is therefore a promising means of developing new therapies. We identified miR-26a through microarray and quantitative reverse-transcription-PCR (qRT-PCR) experiments as an miRNA that is strongly downregulated in melanoma cell lines as compared with primary melanocytes. Treatment of cell lines with miR-26a mimic caused significant and rapid cell death compared with a negative control in most melanoma cell lines tested. In surveying targets of miR-26a, we found that protein levels of SMAD1 (mothers against decapentaplegic homolog 1) and BAG-4/SODD were strongly decreased in sensitive cells treated with miR-26a mimic as compared with the control. The luciferase reporter assays further demonstrated that miR-26a can repress gene expression through the binding site in the 3' untranslated region (3'UTR) of SODD (silencer of death domains). Knockdown of these proteins with small interfering RNA (siRNA) showed that SODD has an important role in protecting melanoma cells from apoptosis in most cell lines sensitive to miR-26a, whereas SMAD1 may have a minor role. Furthermore, transfecting cells with a miR-26a inhibitor increased SODD expression. Our findings indicate that miR-26a replacement is a potential therapeutic strategy for metastatic melanoma, and that SODD, in particular, is a potentially useful therapeutic target.
authors.affiliation: Department of Dermatology, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Reuland
authors.forename: Shilo M
authors.initials: SM
authors.lastname: Smith
authors.forename: Lynne T
authors.initials: LT
authors.lastname: Bemis
authors.forename: Nathaniel B
authors.initials: NB
authors.lastname: Goldstein
authors.forename: Adam R
authors.initials: AR
authors.lastname: Almeida
authors.forename: Katie A
authors.initials: KA
authors.lastname: Partyka
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Zhang
authors.forename: David A
authors.initials: DA
authors.lastname: Norris
authors.forename: Yiqun G
authors.initials: YG
authors.lastname: Shellman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D046228:Microarray Analysis; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D051898:Smad1 Protein / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D035683:MicroRNAs; D051898:Smad1 Protein; C116906:BAG4 protein, human; C528163:MIRN26 microRNA, human; C497399:SMAD1 protein, human