title: Overexpression of miR-155 causes expansion, arrest in terminal differentiation and functional activation of mouse natural killer cells.
abstract: It is known that microRNAs (miRs) are involved in lymphocyte development, homeostasis, activation, and occasionally malignant transformation. In this study, a miR-155 transgene (tg) was driven to be overexpressed off of the lck promoter in order to assess its effects on natural killer (NK) cell biology in vivo. miR-155 tg mice have an increase in NK-cell number with an excess of the CD11b(low)CD27(high) NK subset, indicative of a halt in terminal NK-cell differentiation that proved to be intrinsic to the cell itself. The increase in NK cells results, in part, from improved survival in medium alone and enhanced expansion with endogenous or exogenous interleukin 15. Phenotypic and functional data from miR-155 tg NK cells showed constitutive activation and enhanced target cell conjugation, resulting in more potent antitumor activity in vitro and improved survival of lymphoma-bearing mice in vivo when compared with wild type NK cells. The enhanced NK-cell survival, expansion, activation, and tumor control that result from overexpression of miR-155 in NK cells could be explained, in part, via diminished expression of the inositol phosphatase SHIP1 and increased activation of ERK and AKT kinases. Thus, the regulation of miR-155 is important for NK-cell development, homeostasis, and activation.
authors: The Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. rossana.trotta@osumc.edu
authors: Rossana
authors: R
authors: Trotta
authors: Li
authors: L
authors: Chen
authors: Stefan
authors: S
authors: Costinean
authors: Srirama
authors: S
authors: Josyula
authors: Bethany L
authors: BL
authors: Mundy-Bosse
authors: David
authors: D
authors: Ciarlariello
authors: Charlene
authors: C
authors: Mao
authors: Edward L
authors: EL
authors: Briercheck
authors: Kathleen K
authors: KK
authors: McConnell
authors: Anjali
authors: A
authors: Mishra
authors: Lianbo
authors: L
authors: Yu
authors: Carlo M
authors: CM
authors: Croce
authors: Michael A
authors: MA
authors: Caligiuri
mesh_terms: D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D015536:Down-Regulation; D000072181:Inositol Polyphosphate 5-Phosphatases; D007371:Interferon-gamma / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D019076:Transgenes; D015854:Up-Regulation
chemical_list: D019409:Interleukin-15; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases