title: MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia.
abstract: Despite their potential to regulate approximately one-third of the whole genome, relatively few microRNA (miRNA) targets have been experimentally validated, particularly in stratified squamous epithelia. Here we demonstrate not only that the lipid phosphatase SHIP2 is a target of miRNA-205 (miR-205) in epithelial cells, but, more importantly, that the corneal epithelial-specific miR-184 can interfere with the ability of miR-205 to suppress SHIP2 levels. This is the first example of a miRNA negatively regulating another to maintain levels of a target protein. Interfering with miR-205 function by using a synthetic antagomir, or by the ectopic expression of miR-184, leads to a coordinated damping of the Akt signaling pathway via SHIP2 induction. This was associated with a marked increase in keratinocyte apoptosis and cell death. Aggressive squamous cell carcinoma (SCC) cells exhibited elevated levels of miR-205. This was associated with a concomitant reduction in SHIP2 levels. Partial knockdown of endogenous miR-205 in SCCs markedly decreased phosphorylated Akt and phosphorylated BAD levels and increased apoptosis. We were able to increase SHIP2 levels in SCC cells after inhibition of miR-205. Therefore, miR-205 might have diagnostic value in determining the aggressivity of SCCs. Blockage of miR-205 activity with an antagomir or via ectopic expression of miR-184 could be novel therapeutic approaches for treating aggressive SCCs.
authors.affiliation: Department of Dermatology, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.forename: David G
authors.initials: DG
authors.lastname: Ryan
authors.forename: Spiro
authors.initials: S
authors.lastname: Getsios
authors.forename: Michelle
authors.initials: M
authors.lastname: Oliveira-Fernandes
authors.forename: Anees
authors.initials: A
authors.lastname: Fatima
authors.forename: Robert M
authors.initials: RM
authors.lastname: Lavker
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000503:physiopathology; D002470:Cell Survival / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics; D019573:Epithelium, Corneal / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D007668:Kidney / Q000166:cytology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor / Q000235:genetics; D012878:Skin Neoplasms / Q000503:physiopathology; D014162:Transfection
chemical_list: D035683:MicroRNAs; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C534424:MIRN184 microRNA, human; C534425:MIR205, human; C098706:INPPL1 protein, human