Abstract
Biological robustness is exposed to stochastic perturbations, which should be controlled by intrinsic mechanisms; the promiscuous signaling network without appropriate alleviation is the true nature of cancer cells. B cell receptor (BCR) signaling is a major source of gene expression signature important for B cell. It is still unclear the mechanism by which the expression of functionally important genes is continuously deregulated in malignant lymphomas. Using RISC-capture assay, we reveal that multiple BCR signaling factors are persistently regulated by microRNA (miRNA) in human B cells. Clinical samples from patients with diffuse large B-cell lymphoma (DLBCL, n = 83) show loss of an essential miRNA set (miR-200c, miR-203, miR-31). Conventional screening and RISC profiling identify multiple targets (CD79B, SYK, PKCβII, PLCγ1, IKKβ, NIK, MYD88, PI3K class I (α/β/δ/γ), RasGRP3); signaling network habitually faces interference composed by miRNA group in normal B cells. We demonstrate that simultaneous depletion of the key miRNAs enhances translation of the multiple targets and causes chronic activation of NF-κB, PI3K-Akt, and Ras-Erk cascades, leading to B cell transformation. This study suggests that compensatory actions by multiple miRNAs rather than by a single miRNA ensure robustness of biological processes.
Highlights
For an effective humoral immune response, mature B cells must recognize foreign antigens and generate antigen-specific effectors
The integrated signaling amplitude should be equilibrated; when chronically activated by genetic perturbations or other mechanisms, B cell receptor (BCR) signaling has been accepted as a stem in the pathogenesis of malignant lymphoma/leukemia[2]
Gene expression is tightly and spatiotemporally regulated by transcription factors, whose activities are provided from the momentary fluctuations and magnitude and spread are effectively amplified by signaling pathways. microRNAs, an emerging class of intrinsic buffering molecules that have diverse functions in mainly post-transcriptional regulation[5], have been suggested to play pivotal roles in regulation of signaling components[6]
Summary
For an effective humoral immune response, mature B cells must recognize foreign antigens and generate antigen-specific effectors. DLBCL with more aggressive phenotypes often associates with BCR signaling activation due to upregulation of key signaling factors. It is still unclear the mechanism by which the expression of functionally important genes is continuously deregulated. Each knockdown decreased endogenous miRNA function and increased Luciferase activity in 293T cells. (b,c) Inhibition of miRNA biogenesis affects proliferation of human primary B cells induced by anti-IgM (5 μ g/ml). Dynamic proliferation was examined for 3 days in CD19 + B cells with shRNA targeting RISC components. (e) Inhibition of miRNA biogenesis affects B cell proliferation induced by various stimuli (anti-IgM, 5 μ g/ml; BAFF, 0.2 μ g/ml; anti-CD40, 2 μ g/ml, IL-4, 20 ng/ml). A corresponding set of experiments of the physiologically active miRNA group is required to clarify the integrated contribution of miRNA to biological processes of interest
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