MiR-17-92 represses PTPROt and PP2A phosphatases and amplifies tonic BCR signaling in DLBCL cells.
Experimental Hematology(2017)
摘要
B-cell receptor (BCR) signaling plays pivotal role in the pathogenesis of diffuse large B-cell lymphomas (DLBCL), and targeting the BCR pathway is a highly promising therapeutic strategy in this malignancy. Oncogenic microRNA miR-17-92 modulates multiple cellular processes such as survival, proliferation, apoptosis, angiogenesis and BCR signaling. In the present study, we identified new targets of miR-17-92, PTPROt and PP2A phosphatases, which regulate SYK and AKT activity- critical components of BCR signal transduction in DLBCL cells. Introduction of miR-17-92 into DLBCL cells dampened the expression of PTPROt and PP2A regulatory subunits PPP2R2A and PPP2R5E and increased magnitude of SYK and AKT phosphorylations upon BCR ligation. Finally, we found that miR-17-92 expression modulates response to inhibitors of BCR signaling since downregulation of miR-17-92 increased SYK inhibitor-mediated toxicity in DLBCL cells. Taken together, our study reveals novel posttranscriptional regulatory pathways that contribute to the deregulation of BCR signaling, and modulate SYK inhibitor activity in DLBCL.
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关键词
AKT,BCR,DLBCL,PP2A,PTPROt,miR-17-92,microRNA
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