Coordinated loss of microRNA group causes defenseless signaling in malignant lymphoma

作者：Yamagishi Makoto^*; Katano Harutaka; Hishima Tsunekazu; Shimoyama Tatsu; Ota Yasunori; Nakano Kazumi; Ishida Takaomi; Okada Seiji; Watanabe Toshiki

来源：Scientific Reports, 2015, 5(1): 17868.

DOI：10.1038/srep17868

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, PKC beta II, PLC gamma 1, IKK beta, NIK, MYD88, PI3K class I (alpha/beta/delta/gamma), 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-kappa B, 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.

• 出版日期2015-12-7
• 单位河北医科大学