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International Journal Of Bilogical Sciences

.: Home > International Journal Of Bilogical Sciences > 2015 > Volume 11 Number 1 > Fu Gao1, Song Chen2, Mingjuan Sun3, Ronald E.J. Mitchel4, Bailong Li1, Zhiyong Chu2, Jianming Cai1, Cong Liu1

MiR-467a is Upregulated in Radiation-Induced Mouse Thymic Lymphomas and Regulates Apoptosis by Targeting Fas and Bax

Fu Gao1, Song Chen2, Mingjuan Sun3, Ronald E.J. Mitchel4, Bailong Li1, Zhiyong Chu2, Jianming Cai1, Cong Liu1
1. Department of Radiation Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, PR China; 2. Department of Radiological Protection, Naval Medical Research Institute, Shanghai 200433, PR China; 3. Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai 200433, PR China; 4. Radiological Protection Research and Instrumentation Branch, Atomic Energy of Canada Limited, Chalk River Laboratories, Chalk River, ON, K0J1J0, Canada. These authors contributed equally to this work. Corresponding authors: Jianming Cai & Cong Liu. Address: Department of Radiation Medicine, Second Military Medical University; 800, Xiangyin Road 200433, Shanghai; P.R. China Fax: +86-21-81871149. E-mail: caijianming882003@163.com, victorliu20102020@163.com.
Abstract :

It has been reported dysregulation of certain microRNAs (miRNAs / miRs) is involved in tumorigenesis. However, the miRNAs associated with radiocarcinogenesis remain undefined. In this study, we validated the upregulation of miR-467a in radiation-induced mouse thymic lymphoma tissues. Then, we investigated whether miR-467a functions as an oncogenic miRNA in thymic lymphoma cells. For this purpose, we assessed the biological effect of miR-467a on thymic lymphoma cells. Using miRNA microarray, we found four miRNAs (miR-467a, miR-762, miR-455 and miR-714) were among the most upregulated (>4-fold) miRNAs in tumor tissues. Bioinformatics prediction suggests miR-467a may potentially regulate apoptosis pathway via targeting Fas and Bax. Consistently, in miR-467a-transfected cells, both proliferation and colony formation ability were significantly increased with decrease of apoptosis rate, while, in miR-467a-knockdown cells, proliferation was suppressed with increase of apoptosis rate, indicating that miR-467a may be involved in the regulation of apoptosis. Furthermore, miR-467a-knockdown resulted in smaller tumors and better prognosis in an in vivo tumor-transplanted model. To explain the mechanism of apoptosis suppression by miR-467a, we explore the expression of candidate target genes (Fas and Bax) in miR-467a-transfected relative to negative control transfected cells using flow cytometry and immunoblotting. Fas and Bax were commonly downregulated in miR-467a-transfected EL4 and NIH3T3 cells, and all of the genes harbored miR-467a target sequences in the 3’UTR of their mRNA. Fas and Bax were actually downregulated in radiation-induced thymic lymphoma tissues, and therefore both were identified as possible targets of miR-467a in thymic lymphoma. To ascertain whether downregulation of Fas and / or Bax is involved in apoptosis suppression by miR-467a, we transfected vectors expressing Fas and Bax into miR-467a-upregulated EL4 cells. Then we found that both Fas- and Bax-overexpression decreased cell viability with increase of apoptosis rate, indicating that downregulation of Fas and Bax may be at least partly responsible for apoptosis suppression by miR-467a. These data suggest that miR-467a may have oncogenic functions in radiation-induced thymic lymphoma cells and that its increased expression may confer a growth advantage on tumor cells via aberrant expression of Fas and Bax.

Keywords :
radiocarcinogenesis, thymic lymphoma, miR-467a, Fas, Bax, apoptosis

Date Deposited : 15 Feb 2016 12:08

Last Modified : 15 Feb 2016 12:08

Official URL: http://www.ijbs.com/v11i1

Volume 11, Number 1, - 2015 , ISSN 1449-2288

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