title: MiR-495 functions as an adjuvant to radiation therapy by reducing the radiation-induced bystander effect.
abstract: The radiation-induced bystander effect (RIBE) is an important factor in tumor radiation therapy because it may increase the probability of normal cellular injury and the likelihood of secondary cancers after radiotherapy. Here, we identified the role of miR-495 in alleviating RIBEs during radiotherapy. Luciferase reporter assay results confirmed that miR-495 regulated endothelial nitric oxide synthase (eNOS) by targeting the Sp1 3'-untranslated region. Consequently, after radiation, tumor cells expressed less eNOS and Sp1 than controls. In vitro cell irradiation data based on flow-cytometric analysis and enzymed linked immunosorbent assay confirmed that nitric oxide (NO) and its downstream product transforming growth factor β1 (TGF-β1) were critical signaling factors contributing to RIBEs. Fewer normal LO2liver cells were injured and fewer micronuclei were observed when treated with the medium of the miR-495 overexpressing HepG2 and ZR75-1 tumor cells. Accordingly, treatment with the miR-495 antagomir led to higher NO and TGF-β1 levels and more injured LO2cells. In vivo experiments indicated that local irradiation of tumors overexpressing miR-495 produced fewer necrotic foci in non-irradiated liver tissue compared with controls. miR-495 was upregulated in clinical cancer tissues compared with adjacent non-cancerous tissues, and radiation significantly reduced the expression level of miR-495 in carcinoma cell lines. In summary, miR-495 may have promise as an adjuvant for tumor radiation therapy to decrease RIBEs involving the Sp1/eNOS pathway.
authors.affiliation: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.|Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Shensi
authors.initials: S
authors.lastname: Xiang
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China bapklab@yahoo.com yeqn66@yahoo.com.
authors.forename: Qinong
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China bapklab@yahoo.com yeqn66@yahoo.com.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Song
mesh_terms: D024201:Bystander Effect; D002460:Cell Line; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011878:Radiotherapy / Q000009:adverse effects*; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: C577768:MIRN495 microRNA, human; D035683:MicroRNAs; D016329:Sp1 Transcription Factor; D052250:Nitric Oxide Synthase Type III
keywords: Sp1; endothelial nitric oxide synthase (eNOS); miR-495; radiation-induced injury; transforming growth factor β1 (TGF-β1)