Quaking and miR-155 interactions in inflammation and leukemogenesis.
Quaking (QKI) is a tumor-suppressor gene encoding a conserved RNA-binding protein, whose expression is downregulated in several solid tumors. Here we report that QKI plays an important role in the immune response and suppression of leukemogenesis. We show that the expression of Qki is reduced in lipopolysaccharide (LPS)-challenged macrophages, suggesting that Qki is a key regulator of LPS signaling pathway. Furthermore, LPS-induced downregulation of Qki expression is miR-155-dependent. Qki overexpression impairs LPS-induced phosphorylation of JNK and particularly p38 MAPKs, in addition to increasing the production of anti-inflammatory cytokine IL-10. In contrast, Qki ablation decreases Fas expression and the rate of Caspase3/7 activity, while increasing the levels of IL-1α, IL-1β and IL-6, and p38 phosphorylation. Similarly, the p38 pathway is also a target of QKI activity in chronic lymphocytic leukemia (CLL)-derived MEC2 cells. Finally, B-CLL patients show lower levels of QKI expression compared with B cells from healthy donor, and Qki is similarily downregulated with the progression of leukemia in Eµ-miR-155 transgenic mice. Altogether, these data implicate QKI in the pathophysiology of inflammation and oncogenesis where miR-155 is involved.
Department of Anesthesiology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.|Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, USA.
Esmerina
E
Tili
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, USA.
Marcela
M
Chiabai
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, USA.
Dario
D
Palmieri
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, USA.
Melissa
M
Brown
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, USA.
Ri
R
Cui
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, USA.
Cecilia
C
Fernandes
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, USA.
Tim
T
Richmond
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Taewan
T
Kim
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, USA.
Tyler
T
Sheetz
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, USA.
Hui-Lung
HL
Sun
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Alessandro
A
Lagana
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, USA.
Dario
D
Veneziano
University of Ferrara, Department of Morphology, Surgery and Experimental Medicine, Ferrara, Italy.
Stefano
S
Volinia
CLL Research Consortium, Moores UCSD Cancer Center, La Jolla, CA, USA.
Laura
L
Rassenti
CLL Research Consortium, Moores UCSD Cancer Center, La Jolla, CA, USA.
Thomas
T
Kipps
Department of Anesthesiology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
Hamdy
H
Awad
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, USA.|BioPerox-IL, UB-INSERM IFR #100, Université de Bourgogne, Faculté Gabriel, Gabriel, Dijon, France.
Jean-Jacques
JJ
Michaille
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, USA.
Carlo M
CM
Croce
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D000067996:RAW 264.7 Cells; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D020298:U937 Cells
D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D008070:Lipopolysaccharides; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; C490832:QKI protein, human; C098217:Qk protein, mouse; D016601:RNA-Binding Proteins; D020928:Mitogen-Activated Protein Kinases
CLL; QKI; glioblastoma; inflammation; miR-155