title: Coordinated loss of microRNA group causes defenseless signaling in malignant lymphoma.
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.
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, The University of Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamagishi
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Japan.
authors.forename: Harutaka
authors.initials: H
authors.lastname: Katano
authors.affiliation: Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan.
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Hishima
authors.affiliation: Department of Clinical Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan.
authors.forename: Tatsu
authors.initials: T
authors.lastname: Shimoyama
authors.affiliation: Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Ota
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, The University of Tokyo, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Center for AIDS Research, Kumamoto University, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.affiliation: Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, The University of Tokyo, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D001681:Biological Assay; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D011947:Receptors, Antigen, B-Cell