Abstract
Human health risks of exposure to low dose ionizing radiation remain ambiguous and are the subject of intense debate. A wide variety of biological effects are induced after cellular exposure to ionizing radiation, but the underlying molecular mechanism(s) remain to be completely understood. We hypothesized that low dose γ-radiation-induced effects are controlled by the modulation of micro RNA (miRNA) that participate in the control of gene expression at the posttranscriptional level and are involved in many cellular processes. We monitored the expression of several miRNA in human cells exposed to acute or chronic low doses of 10 cGy or a moderate dose of 400 cGy of 137Cs γ-rays. Dose, dose rate and time dependent differences in the relative expression of several miRNA were investigated. The expression patterns of many miRNA differed after exposure to either chronic or acute 10 cGy. The expression of miRNA let-7e, a negative regulator of RAS oncogene, and the c-MYC miRNA cluster were upregulated after 10 cGy chronic dose but were downregulated after 3 h of acute 10 cGy. The miR-21 was upregulated in chronic or acute low dose and moderate dose treated cells and its target genes hPDCD4, hPTEN, hSPRY2, and hTPM1 were found to be downregulated. These findings provide evidence that low dose and dose rate γ-irradiation dictate the modulation of miRNA, which can result in a differential cellular response than occurs at high doses. This information will contribute to understanding the risks to human health after exposure to low dose radiation.
Similar content being viewed by others
References
Preston RJ (2003) The LNT model is the best we can do—today. J Radiol Prot 23(3):263–268
Little MP, Muirhead CR (2000) Derivation of low-dose extrapolation factors from analysis of curvature in the cancer incidence dose response in Japanese atomic bomb survivors. Int J Radiat Biol 76(7):939–953
Chaudhry MA, Kreger B, Omaruddin RA (2010) Transcriptional modulation of micro-RNA in human cells differing in radiation sensitivity. Int J Radiat Biol 86(7):569–583
Tubiana M, Aurengo A, Averbeck D, Masse R (2006) Recent reports on the effect of low doses of ionizing radiation and its dose-effect relationship. Radiat Environ Biophys 44(4):245–251
Averbeck D (2010) Non-targeted effects as a paradigm breaking evidence. Mutat Res 687(1–2):7–12
Huang L, Kim PM, Nickoloff JA, Morgan WF (2007) Targeted and nontargeted effects of low-dose ionizing radiation on delayed genomic instability in human cells. Cancer Res 67(3):1099–1104
Murnane JP, Sabatier L (2004) Chromosome rearrangements resulting from telomere dysfunction and their role in cancer. Bioessays 26(11):1164–1174
Wolff S (1998) The adaptive response in radiobiology: evolving insights and implications. Environ Health Perspect 106(Suppl 1):277–283
Azzam EI, Little JB (2004) The radiation-induced bystander effect: evidence and significance. Hum Exp Toxicol 23(2):61–65
Rigaud O, Moustacchi E (1996) Radioadaptation for gene mutation and the possible molecular mechanisms of the adaptive response. Mutat Res 358(2):127–134
de Toledo SM, Azzam EI (2006) Adaptive and bystander responses in human and rodent cell cultures exposed to low level ionizing radiation: the impact of linear energy transfer. Dose Response 4(4):291–301
de Toledo SM, Asaad N, Venkatachalam P, Li L, Howell RW, Spitz DR, Azzam EI (2006) Adaptive responses to low-dose/low-dose-rate gamma rays in normal human fibroblasts: the role of growth architecture and oxidative metabolism. Radiat Res 166(6):849–857
Gaillard S, Pusset D, de Toledo SM, Fromm M, Azzam EI (2009) Propagation distance of the alpha-particle-induced bystander effect: the role of nuclear traversal and gap junction communication. Radiat Res 171(5):513–520
Spitz DR, Azzam EI, Li JJ, Gius D (2004) Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: a unifying concept in stress response biology. Cancer Metastasis Rev 23(3–4):311–322
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297
Yekta S, Shih IH, Bartel DP (2004) MicroRNA-directed cleavage of HOXB8 mRNA. Science 304(5670):594–596
Pillai RS, Bhattacharyya SN, Artus CG, Zoller T, Cougot N, Basyuk E, Bertrand E, Filipowicz W (2005) Inhibition of translational initiation by Let-7 MicroRNA in human cells. Science 309(5740):1573–1576
Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433(7027):769–773
John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS (2004) Human MicroRNA targets. PLoS Biol 2(11):e363
Chaudhry MA (2009) Real-time PCR analysis of micro-RNA expression in ionizing radiation-treated cells. Cancer Biother Radiopharm 24(1):49–56
Chaudhry MA, Kreger B, Omaruddin RA (2010) Transcriptional modulation of micro-RNA in human cells differing in radiation sensitivity. Int J Radiat Biol 86:569–583
Chaudhry MA, Sachdeva H, Omaruddin RA (2010) Radiation-induced Micro-RNA modulation in glioblastoma cells differing in DNA-repair pathways. DNA Cell Biol 29(9):553–561
Goddu SM, Howell RW, Rao DV (2001) Method and means for variably attenuating radiation. United States Patent US 6,201,852 B1
Howell RW, Goddu SM, Rao DV (1997) Design and performance characteristics of an experimental Cs-137 irradiator to simulate internal radionuclide dose rate patterns. J Nucl Med 38:727–731
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408
Bagley J, Rosenzweig M, Marks DF, Pykett MJ (1999) Extended culture of multipotent hematopoietic progenitors without cytokine augmentation in a novel three-dimensional device. Exp Hematol 27(3):496–504
Poznansky MC, Evans RH, Foxall RB, Olszak IT, Piascik AH, Hartman KE, Brander C, Meyer TH, Pykett MJ, Chabner KT, Kalams SA, Rosenzweig M, Scadden DT (2000) Efficient generation of human T cells from a tissue-engineered thymic organoid. Nat Biotechnol 18(7):729–734
Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ (2005) RAS is regulated by the let-7 microRNA family. Cell 120(5):635–647
Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64(11):3753–3756
Goodsell DS (1999) The molecular perspective: the ras oncogene. Oncologist 4(3):263–264
Yaguang Xi JRE, Jingfang Ju (2007) Investigation of miRNA Biology by bioinformatic tools and impact of miRNAs in colorectal cancer—regulatory relationship of c-Myc and p53 with miRNAs. Cancer Inform 3:245–253
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM (2005) A microRNA polycistron as a potential human oncogene. Nature 435(7043):828–833
Pelengaris S, Khan M, Evan GI (2002) Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109(3):321–334
Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102(39):13944–13949
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM (2002) Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99(24):15524–15529
Akerman GS, Rosenzweig BA, Domon OE, Tsai CA, Bishop ME, McGarrity LJ, Macgregor JT, Sistare FD, Chen JJ, Morris SM (2005) Alterations in gene expression profiles and the DNA-damage response in ionizing radiation-exposed TK6 cells. Environ Mol Mutagen 45(2–3):188–205
Chung EY, Dews M, Cozma D, Yu D, Wentzel EA, Chang TC, Schelter JM, Cleary MA, Mendell JT, Thomas-Tikhonenko A (2008) c-Myb oncoprotein is an essential target of the dleu2 tumor suppressor microRNA cluster. Cancer Biol Ther 7(11):1758–1764
Eis PS, Tam W, Sun L, Chadburn A, Li Z, Gomez MF, Lund E, Dahlberg JE (2005) Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci USA 102(10):3627–3632
Shahi P, Loukianiouk S, Bohne-Lang A, Kenzelmann M, Kuffer S, Maertens S, Eils R, Grone HJ, Gretz N, Brors B (2006) Argonaute—a database for gene regulation by mammalian microRNAs. Nucleic Acids Res 34(Database issue):D115–D118
Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, Calin GA, Liu CG, Croce CM, Harris CC (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9(3):189–198
Michael MZ, O’Connor SM, van Holst Pellekaan NG, Young GP, James RJ (2003) Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 1(12):882–891
Chan JA, Krichevsky AM, Kosik KS (2005) MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65(14):6029–6033
Cha HJ, Seong KM, Bae S, Jung JH, Kim CS, Yang KH, Jin YW, An S (2009) Identification of specific microRNAs responding to low and high dose gamma-irradiation in the human lymphoblast line IM9. Oncol Rep 22(4):863–868
Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H (2008) MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27(15):2128–2136
Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH (2008) Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 283(2):1026–1033
Lu Z, Liu M, Stribinskis V, Klinge CM, Ramos KS, Colburn NH, Li Y (2008) MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene 27:4373–4379
Zhu S, Si ML, Wu H, Mo YY (2007) MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem 282(19):14328–14336
Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133(2):647–658
Sayed D, Rane S, Lypowy J, He M, Chen IY, Vashistha H, Yan L, Malhotra A, Vatner D, Abdellatif M (2008) MicroRNA-21 targets sprouty2 and promotes cellular outgrowths. Mol Biol Cell
Ding LH, Shingyoji M, Chen F, Hwang JJ, Burma S, Lee C, Cheng JF, Chen DJ (2005) Gene expression profiles of normal human fibroblasts after exposure to ionizing radiation: a comparative study of low and high doses. Radiat Res 164(1):17–26
Long XH, Zhao ZQ, He XP, Wang HP, Xu QZ, An J, Bai B, Sui JL, Zhou PK (2007) Dose-dependent expression changes of early response genes to ionizing radiation in human lymphoblastoid cells. Int J Mol Med 19(4):607–615
Fujimori A, Okayasu R, Ishihara H, Yoshida S, Eguchi-Kasai K, Nojima K, Ebisawa S, Takahashi S (2005) Extremely low dose ionizing radiation up-regulates CXC chemokines in normal human fibroblasts. Cancer Res 65(22):10159–10163
Fachin AL, Mello SS, Sandrin-Garcia P, Junta CM, Donadi EA, Passos GA, Sakamoto-Hojo ET (2007) Gene expression profiles in human lymphocytes irradiated in vitro with low doses of gamma rays. Radiat Res 168(6):650–665
Amundson SA, Lee RA, Koch-Paiz CA, Bittner ML, Meltzer P, Trent JM, Fornace AJ Jr (2003) Differential responses of stress genes to low dose-rate gamma irradiation. Mol Cancer Res 1(6):445–452
Sugihara T, Magae J, Wadhwa R, Kaul SC, Kawakami Y, Matsumoto T, Tanaka K (2004) Dose and dose-rate effects of low-dose ionizing radiation on activation of Trp53 in immortalized murine cells. Radiat Res 162(3):296–307
Gridley DS, Pecaut MJ, Rizvi A, Coutrakon GB, Luo-Owen X, Makinde AY, Slater JM (2009) Low-dose, low-dose-rate proton radiation modulates CD4(+) T cell gene expression. Int J Radiat Biol 85(3):250–261
Acknowledgments
The authors are grateful to the DNA Analysis Facility, University of Vermont for assistance with the real-time PCR experiments. This work was funded by a grant to MAC from College of Nursing and Health Sciences, University of Vermont. Grants from the US Department of Energy Low Dose Radiation Research Program, NASA and the NIH supported research in EIA laboratory.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chaudhry, M.A., Omaruddin, R.A., Kreger, B. et al. Micro RNA responses to chronic or acute exposures to low dose ionizing radiation. Mol Biol Rep 39, 7549–7558 (2012). https://doi.org/10.1007/s11033-012-1589-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-012-1589-9