Abstract
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.
Highlights
MiR-155 is an oncogenic pro-inflammatory microRNA that is up-regulated in a number of solid tumors and liquid malignancies [1,2,3]
We show that (i) QKI is a target of miR-155 in B cells; (ii) the expression of QKI is lower in B-cells from chronic lymphocytic leukemia (CLL) patients compare to B cells from healthy donors, and acts as tumor suppressor gene (TSG) in CLL; (iii) Qki is a target of LPS signaling, and its expression is downregulated following LPS challenge of macrophages; (iv) Qki modulates downstream LPS signaling in return; p38 MAPK activation and IL-10 production, presenting with anti-inflammatory properties
As Qki is a potential www.impactjournals.com/oncotarget target of miR-155, we monitored the expression of Qki, using a probe spanning exons 4 and 5 that recognizes all Qki isoforms, as well as of miR-155 and Tnf in mouse RAW-264.7 macrophages following LPS stimulation
Summary
MiR-155 is an oncogenic pro-inflammatory microRNA (miRNA) that is up-regulated in a number of solid tumors and liquid malignancies [1,2,3]. High levels of miR-155 often correlate with a poor prognosis [4,5]. Targeted expression of miR-155 in B cells results in pre-B cell acute leukemia/high-grade lymphoma [6]. The expression of miR-155 is controlled by several immune signals [1,2,3]. The oncogenic and pro-inflammatory effects of miR-155 have been attributed at least in part to its targeting of many transcripts encoding tumor suppressors and/or antiinflammatory factors, especially Ship1 [10,11,12], Socs1 [13]
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