title: MiR-663 inhibits radiation-induced bystander effects by targeting TGFB1 in a feedback mode.
abstract: The mechanisms of radiation-induced bystander effects (RIBE) have been investigated intensively over the past two decades. Although quite a few reports demonstrated that cytokines such as TGF-β1 are induced within the directly irradiated cells and play critical roles in mediating the bystander effects, little is known about the signaling pathways that occur in bystander cells. The crucial question as to why RIBE signals cannot be infinitely transmitted, therefore, remains unclear. In the present study, we showed that miR-663, a radiosensitive microRNA, participates in the regulation of biological effects in both directly irradiated and bystander cells via its targeting of TGF-β1. MiR-663 was downregulated, while TGFB1 was upregulated in directly irradiated cells. The regulation profile of miR-663 and TGFB1, on the other hand, was reversed in bystander cells, in which an elevated miR-663 expression was exhibited and led to downregulation of TGF-β1. Further studies revealed that miR-663 interacts with TGFB1 directly and that through its binding to the core regulation sequence, miR-663 suppresses the expression of TGFB1. Based on the results, we propose that miR-663 inhibits the propagation of RIBE in a feedback mode, in which the induction of TGF-β1 by reduced miR-663 in directly irradiated cells leads to increased level of miR-663 in bystander cells. The upregulation of miR-663 in turn suppresses the expression of TGF-β1 and limits further transmission of the bystander signals.
authors.affiliation: a Department of Space Radiobiology; Key Laboratory of Heavy Ion Radiation Biology and Medicine; Institute of Modern Physics; Chinese Academy of Sciences ; Lanzhou , China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Hu
authors.forename: Shuai
authors.initials: S
authors.lastname: Xu
authors.forename: Bin
authors.initials: B
authors.lastname: Yao
authors.forename: Mei
authors.initials: M
authors.lastname: Hong
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.forename: Hailong
authors.initials: H
authors.lastname: Pei
authors.forename: Lei
authors.initials: L
authors.lastname: Chang
authors.forename: Nan
authors.initials: N
authors.lastname: Ding
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Gao
authors.forename: Caiyong
authors.initials: C
authors.lastname: Ye
authors.forename: Jufang
authors.initials: J
authors.lastname: Wang
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
authors.forename: Guangming
authors.initials: G
authors.lastname: Zhou
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D024201:Bystander Effect / Q000235:genetics / Q000528:radiation effects*; D002450:Cell Communication / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000528:radiation effects; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000528:radiation effects*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011839:Radiation, Ionizing; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000528:radiation effects; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D014410:Tumor Stem Cell Assay
chemical_list: C552243:MIRN663 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1
keywords: TGF-β1; bystander effects; ionizing radiation; miR-663; microRNA