The Role of Epigenetic Modulation in the Cellular Response to Ionizing Radiation

 

 

Dong Pan, Yarong Du, Burong Hu

 

 

Dong Pan, Yarong Du, Burong Hu, Department of Space Radiobiology, Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China

Dong Pan, University of Chinese Academy of Sciences, Beijing, 100049, China

Correspondence to: Burong Hu PhD, Department of Space Radiobiology, Key Laboratory of Heavy Ion Radiation Biology and Medicine,Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Building 5-204, Lanzhou 730000, China.

Email: hubr@impcas.ac.cn

Telephone: +86-18509316339        Fax: +86-0931-4969169        

Received: March  13, 2015         Revised: April 6, 2015

Accepted: April 8, 2015

Published online: June 2, 2015

 

ABSTRACT

More and more evidence demonstrate that epigenetic modulation plays important roles in many cellular processes and carcinogenesis. It also showed that epigenetic changes are involved in the cellular response to ionizing radiation. In current review, we will discuss the radiation-induced epigenetic modifications including DNA methylation changes, chromatin remodelling and alterations in microRNA expression, and their roles in the cellular response to ionizing radiation. The aim is to help understand the mechanisms underlying the radiation induced biological effects in cells and to find the future research interests.

 

© 2015 ACT. All rights reserved.

 

Key words: Epigenetic modulation; DNA methylation; Chromatin remodelling; MicroRNA; Ionizing radiation

 

Pan D, Du YR, Hu BR. The Role of Epigenetic Modulation in the Cellular Response to Ionizing Radiation. International Journal of Radiology 2015; 2(1): 1-14 Available from: URL: http://www.ghrnet.org/index.php/ijr/article/view/1109

 

Introduction

Epigenetic alterations are heritable changes underlying gene expression by regulating the structure and function of the genome that are not caused by alterations in the DNA sequence itself. It includes an array of molecular modifications such as DNA methylation, chromatin remodelling, histone modifications, genetic imprinting, random chromosome(X) inactivation and noncoding RNA (microRNA, lincRNA and siRNA, etc) regulated gene expression[1]. The principal mechanisms of epigenetic changes are alterations in DNA methylation and alterations to the packaging of DNA around the core histones, both of which can result in gene activation or repression[2,3].

    Epigenetics plays important roles in many cellular processes from gene expression to cellular proliferation and an aberrant epigenetic state in cells can result in carcinogenesis[4]. Changes in genomic DNA methylation post-irradiation and its potential correlation with cellular response have been indicated[5-7], and changes in expression profiles of microRNA (miRNA) have been observed following irradiation in mouse and human cells. These evidences suggests that epigenetics may be the core mechanistic link between irradiation and cellular response. Here, we mainly review the DNA methylation changes, chromatin remodelling and alterations in miRNA expression, and their roles in the cellular response to ionizing radiation (IR).

 

DNA methylation

DNA methylation is one of the most important epigenetic modifications of the genome involving in the regulation of numerous cellular processes through gene silencing without altering DNA sequences. It is the most extensively studied epigenetic mechanism and refers to the addition of a methyl group (-CH3) to the carbon 5 position of cytosine ring in a CpG dinucleotide by DNA methyltransferase (DNMTs)[8,9]. The remaining CpG dinucleotides in the mammalian genome are often methylated. CpG dinucleotides are not uniformly distributed throughout the human genome. Rather, they are concentrated in specific regions (CpG islands) that are located in the upstream region from the transcriptional start site of many genes as well as at other regions. In human, approximately 60% of all genes have CpG islands in their promoter regions, and these promoter associated CpG islands are generally unmethylated in normal cells, with the exception of genomic imprinting, X-chromosome inactivation or tissue specific gene hypermethylation[10,11]. Cancer research in epigenetics in the 1990s was dominated by a focus on understanding and extending the discoveries of DNA methylation abnormalities[4]. DNA methylation plays a central role in the epigenetic control of genomic programs in both normal and cancer cells[12]. Of which the majority is unmethylated in all normal tissue types and throughout development, which was demonstrated by using computational analyses[13].

    In mammals, there are four types of DNMT: DNMT1, DNMT2, DNMT3a and DNMT3b. DNMT1 functions as the maintenance methyltransferase by copying the methylation pattern of the old DNA strand onto the newly synthesised strand during DNA replication[14]. In cancer and embryonic stem cells unmethylated CpG sites are targeted for de novo methylation by DNMT3a and DNMT3b[15]. Information about Dnmt2-dependent methylation patterns has been limited to a few isolated loci and the results have been discussed controversially. In mammals DNMT2 is not a DNA methyltransferase. It was shown that Dnmt2 has a robust methyltransferase activity toward cytosine 38 in the anticodon loop of tRNA-Asp and other tRNAs and that the enzyme uses the conserved DNA methyltransferase mechanism to methylate tRNA[16]. In agreement with this notion, several independent phylogenetic analyses have suggested that Dnmt2 is an ancient DNA methyltransferase that has switched its substrate specificity from DNA to tRNA[16-18]. The DNMT2 protein methylates C38 of tRNA-Asp and it has a role in cellular physiology and stress response and its expression levels are altered in cancer tissues[19].

    In cancer cells, the promoter-associated CpG islands of tumor suppressor genes (TSGs) may be aberrantly methylated (or hypermethylated), thereby promoting recruitment of methyl-binding domain proteins, and histone-modifying and chromatin-remodeling complexes to the methylated promoter-associated CpG sites[20]. This renders formation of a compact chromatin configuration, precluding access of transcription factors and hence transcriptional silencing of the corresponding TSGs[21]. Therefore, DNA methylation is an important mechanism leading to the inactivation of protein-coding or noncoding genes in human cancers. Promoter regions of TSGs are hypomethylated to allow their expression and maintain the normal state of the cell[12]. Cells that have mutations in DNMT lack the stabilise effect of DNA methylation and have prominent nuclear abnormalities[22].

 

DNA methylation and radiation

DNA methylation is one of the most common mechanisms of epigenetic regulation. Accumulating evidence suggests that changes in methylation patterns may help mediate the sensitivity or resistance of cancer cells to IR. The present studies provide evidence for the involvement of radioresistance-induced DNA methylation changes in tumor radioresistance. There are multiple reports of altered DNA methylation patterns following exposure to IR in plants, rodents, and rodent and human cell lines[5,6,23-28]. Plants when exposed to IR showed dose-dependent hypermethylation[29]. IR exposure has been found to have dose-dependent, sex, and tissue-specific effects on global hypomethylation using mouse model system[30]. Mostly hypomethylation, loss of methylation, paralleled with a decrease in the DNA expression levels of methyltransferases (DNMTs; DNMT1, DNMY3a, and DNMT3b) and methyl CpG binding proteins (MeCP2) was associated with radiation-induced changes[25,29].

    In many of these studies, the global DNA hypomethylation observed post-irradiation along with the decreased expression of proteins involved in maintaining the correct genomic methylation patterns suggest that these changes might play a role in cellular response[6,25,29]. X-ray irradiation of mice was also shown to affect methylation of the promoter of the p16 tumour suppressor in a sex- and tissue-specific manner, but not the methylation status of O-6-methylguanine-DNA methyltransferase (MGMT)[31]. It was suggested that the radiation-induced hypomethylation patterns might result in genomic instability and reshuffling of the hereditary material via chromosomal instability or reactivation of transposable elements, allowing the cells to survive in the radiation environment.

    DNA damage and genomic instability were manifested as reproductive cell death, reduced cloning efficiency at successive passages, increased apoptosis, and an increased proportion of chromosome aberrant cells after irradiation, while the cellular responses to ionizing radiation are shown to be predominantly associated with DNA hypermethlyation of certain CpG dinucleotides and pericentromeric spermidine N1-acetyltransferase 2 (SAT2) satellite sequences. Non-specific DNA hypomethylation is also observed. The majority of the hypermethylated sequences detected are repeat elements. Aberrant methylation status of repeat elements and SAT2 satellite sequences are known to affect cell survival and genomic instability[32,33]. Based on these observations, the authors suggested that methylation alterations following radiation exposure are involved in.

    Exposures to low linear energy transfer (LET) gamma-rays (-rays) were also shown to result in dose-dependent global hypomethylation in the C-1300 N1E-115 (mouse), CHO K-1 (hamster), V79A03 (hamster), and Hela S-3 (human) cell lines[23]. However, another study using one of the same cell lines, CHO K-1, showed no change in methylation after X-ray exposure[5]. The different outcomes in these two studies might suggest differences in changes in epigenetic profiles after different types of radiations. The latter study also showed global hypomethylation in mouse liver tissue after X-rays exposure but demonstrated no change in mouse brain or spleen tissue[5]. Even though each of these studies was performed post-low LET irradiation, different responses were observed.

    There are interesting reports on the relationship between a DNA methyltransferase inhibitor (5-aza-2'-deoxycytidine) and radiation sensitivity in colon cancer. Genomic hypomethylation induced by 5-azacytidine results in enhanced radiation sensitivity in coloncancer[34,35]. Promoter-CpG islands of five previously identified radioresistance-related genes (TOPO2A, PLXDC2, ETNK2, GFI1, and IL12B) were significantly altered in the radioresistant laryngeal cancer cells. Furthermore, the demethylation of these gene promoters with a DNA methyltransferase inhibitor (5-aza-2'-deoxycytidine) increased their transcription levels. Treatment with 5-aza-2'-deoxycytidine also sensitized the radioresistant laryngeal cancer cells to irradiation, indicating that changes in DNA methylation contributed to their radioresistance[36]. In addition, breast cancer cells treated with fractionated IR showed several locus-specific DNA methylation alterations, which were mostly loss of methylation (TRAPP9, FOXC1, and LINE1)[37]. Together with the evidence for altered promoter methylation in particular cancers[32,38], these data provide a link among radiation exposure, epigenetics and carcinogenesis. Radiation-induced global DNA hypomethylation and promoter hypermethylation may play roles in the maintenance of the genomic instability.

    So far, studies have already indicated the global hypo- and hypermethylation changes in the irradiated cells. However, it remains to know which genes in methylation changes are more important for cells after irradiation.

 

Chromatin remodelling

Chromatin remodelling is involved in many biological processes including gene expression, DNA replication and repair, chromosome condensation, segregation and apoptosis[39]. Gene transcription is controlled by histone modifications in chromatin. Positioning of the nucleosome with its 147 base pairs of DNA wrapped around the octamer of the core histones, H2A, H2B, H3, and H4, in conjunction with the above modifications of histones, modulates the normal epigenome in terms of maintaining gene expression patterns and normal chromosome structure and function[40].

    Carcinogenesis not only alter DNA methylation but also cause global changes in the levels of proteins that participatein chromatin modifications, polycomb-complex components, and in histone modifications by acetylation and methylation of lysine residues on histones H3 and H4[41,42]. The strong dependence between DNA methylation and chromatin modifications for DNA packaging is known. Furthermore, histone modification and DNA methylation closely interact in the setting of the transcriptional states of chromatin. Especially in cancer cells, silenced genes regulated by DNA hypermethylation can be models to examine the chromatin control of gene expression. When such genes are expressed with no methylation, their promoters have virtually identical distribution of the active marks, H3K9acetyl and H3K4me[30,43]. In contrast, when silenced genes are associated with hypermethylation, the distribution of these active marks is severely decreased, and virtually every histone methylation mark, including mono-, di-, and trimethylation of H3K9 and H3K27 that has been associated with transcriptional repression, is enriched[30].

    Phosphorylation of histone H2AX at serine 139 (H2AX) is one of the most extensively studied histone modifications[44]. H2AX is used as an early marker for induction and repair of DNA double-strand breaks[45,46]. It also appears to play a functional role in the DNA repair process, maintenance of genome stability, and the early stages of cancer[47,48].

    Histone deacetylases (HDACs) catalyze the removal of acetyl groups on the histone tail, resulting in a transcriptionally inactive heterochromatic state[11]. Likewise, SIN3A (part of an HDAC repressor complex) is downregulated in NSCLC[49]. Relative to normal lung cells, lung cancer cells undergo H4K5/H4K8 hyperacetylation, H4K12/H4K16 hypoacetylation, and H4K20me3. Lower global levels of H4K20me3 can be detected in precursor lesions and is particularly common in squamous cancers[50].

    Epigenetic silencing of transcription also occurs through post-translational histone modification, chromatin remodelling and changes in the nuclear positioning of genes[18]. Deregulation of these and other chromatin processes have been linked to the development and progression of cancer[39,51,52]. Some chromatin remodelling modifications observed in cancer cells are alterations in the histone acetyation/deacetylation balance, increased or decreased poly-adenosine diphosphate (ADP)-ribosylation band failures in ATP-dependent chromatin remodelling mechanisms[53]. Deregulation of histone acetylation can lead to carcinogenesis in three ways. Histone hypoacetylation at certain promoter regions, induced by decreased HAT activity or increased HDAC activity, can silence tumour suppressor genes. Conversely, histone hyperacetylation at other promoter regions, induced by elevated HAT activity or decreased HDAC activity, can lead to the activation of oncogenes. Thirdly, carcinogenesis can be triggered by aberrant recruitment of HAT or HDAC[11].

 

Chromatin remodelling and radiation

IR induced DNA damage response generally occur in special euchromatic and heterochromatic regions. Chromatin immunoprecipitation (ChIP) and immunofluorescence analysis were used to explore the distribution of H2AX. ChlP experiments showed higher H2AX signal after IR in histone H3 trimethylated lysine 4 (H3K4me3), compared to lysine 9 (H3K9me3) enriched chromatin fragments, and this strengthen the dependence of IR-induced DNA damage response on the chromatin region[54]. However, few studies try to investigate the radiation-induced histone modifications to indicate the epigenetic mechanism.

    Radiation-induced phosphorylation of H2AX was extensively studied as a measure of DSB accumulation in irradiated cells[55,56]. H2AX accumulates in the nucleus at DSBs forming the H2AX loci, and a direct correlation has been found between H2AX phosphorylation and the number of DSBs resulting from radiation. Therefore, H2AX is crucially important for the repair of DNA strand breaks and for the maintenance of genome stability[44].

   X-ray irradiation in a mouse model induced a decrease in trimethylation of histone H4K20 in the thymus and, eventually, resulted in an overall relaxation of the chromatin organization in cells. In addition, gamma-irradiation can result in relaxation of the chromatin structure around the DSB immediately after exposure. However, after some time, the methylation of H3K9 increased and the chromatin restored to the condensed state[57]. The epigenetic mechanisms on histone modification after radiation exposure still remain to be explored.

    In mice, radiation exposure led to decreased trimethylation of histone H4 lysine which might result in relaxed heterochromatin organisation and would impair genome stability[26]. It has been shown in human cells that euchromatic regions were more susceptible to radiation-induced DNA damage and H2AX accumulation[58-60]. Cells exposed to -rays showed chromatin decondensation at sites of double-strand breaks[61]. The changes were manifested as a decrease in intensity of chromatin labeling, increased histone H4 lysine 5 acetylation, and decreased histone H3 lysine 9 dimethylation. Forty minutes post-irradiation, these changes induced by radiation exposure were replaced by histone modifications typical for condensed chromatin (decreased acetylation of histone H4 lysine 5 and increased methylation of histone H3 lysine 9). The data suggested a requirment to convert from less to more condensed chromatin after DNA repair. Another study observed rapid binding of SWI/SNF complexes to chromatin in regions of double-strand breaks via interaction with H2AX, suggesting that the repair mechanisms were facilitated by SWI/SNF complex promotion of H2AX phosphorylation[29]. The role of ataxia telangiectasia mutated (ATM) in some of the chromatin changes in response to radiation and as a result its potential role in cellular response to ionizing radiation have been implicated[63]. In response to double-strand break induction, Kruppel-associated box (KRAB) associated protein (KAP-1) is phosphorylated in an ATM-dependent manner[64]. Phosphorylated KAP-1 leads to eu-chromatinisation. Therefore, these results suggested that chromatin relaxation is a fundamental pathway in the DNA damage response and that ATM and KAP-1 are its primary mediators. It was also suggested that ATM-dependent heterochromatin relaxation is specifically required for the repair of double-strand breaks located within heterochromatin[65]. Another study identified another signaling cascade that helps initiate the DNA damage response by altering chromatin[66]. These studies indicate that exposure to radiation affects chromatin remodelling in association with DNA damage and DNA repair. Radiation-induced aberrations in chromatin remodelling can lead to DNA damage and impaired DNA repair. This compromised DNA repair and relaxed heterochromatin contribute to the initiation of genomic instability.

 

MicroRNA

MicroRNAs (miRNAs) belong to a class of single strand, small noncoding RNAs of 19-25 nucleotides (nts) in length that regulate diverse developmental and pathological processes in eukaryotic organisms[67-69]. It can regulate negatively the expression of up to hundreds of messenger RNA (mRNA) targets and are dysregulated frequently in lung cancer. Depending on their genomic locations, miRNA genes can be transcribed from two different pathways: intergenic miRNAs are transcribed by RNA polymerase II as primary miRNAs (pri-miRNAs) with independent transcription units. The primary transcripts (pri-miRNAs) are generated by polymerase II and stabilized by 5' capping and 3' polyadenylation[70]. The distinct hairpin secondary structure of pri-miRNA is recognized by the microprocessor complex (Drosha and DGCR8) and then specifically cleaved at the base of stem-loop releasing a 60-80 nts pre-miRNA. A pre-miRNA of the hairpin or stem-loop structure is exported into cytoplasm by exportin 5, and further processed and cleaved by Dicer to yield the mature miRNA. Mature miRNAs lead to translational repression or mRNA degradation of the target protein-coding genes by binding to complementary sequence within 3' untranslated region (3' UTR) of their target mRNAs[71]. After completing its task, the mature miRNA is degraded by the 5'-3' exoribonuclease or 3'-5' exoribonucleases. In cancer cells, approximately 50% of annotated miRNA genes are mapped to fragile sites of the human genome, deletion of which is recurrently identified in cancer[72]. Over the past decades, it has become clear that aberrantly expressed miRNAs contribute to the initiation or progression of human cancers[73]. Moreover, emerging evidence demonstrated that miRNAs can function as oncogenes or tumor suppressors[74].

 

MicroRNA expression and radiation

MiRNAs as critical gene regulators can influence signaling pathways that alter multiple cellular processes, including the DNA damage response(DDR) after IR. Increasing evidence demonstrates that the expression levels of miRNAs significantly change after IR, which suggests that miRNA play important roles in the IR-caused DDR[75]. While changes in expression profiles of miRNA have been observed following irradiation in mouse and human cells[76,77], the first evidence for functional importance of a miRNA in radiation responses was shown in Drosophila[78]. Following irradiation of fly larvae, the bantam miRNA was shown to be up-regulated. This miRNA in turn was shown to bind to the 3'-UTR of the pro-apoptotic gene and affect its post-transcriptional down-regulation. This miRNA-mediated gene repression resulted in decreased apoptosis induced by radiation and increased larvae survival. In mouse embryonic stem cells, a group of miRNA and their putative gene targets that are potentially involved in response to DNA damage, were identified post-irradiation[76].

    In whole body irradiated mice, the spleen and thymus tissues showed sex-specific deregulation of miRNA expression. Among these, miRNA-34a (miR-34a) and miR-7 were thought to be involved in counteracting radiation induced hypomethylation[79]. MiR-709 target the Brother of the Regulator of Imprinted Sites (BORIS), an important regulator of DNA methylation and imprinting[80]. This study showed that the radiation induced DNA damage resulted in increased miR-709 expression in exposed testes and decreased levels of BORIS prevent massive aberrant erasure of DNA methylation, resulted in downregulation of miRNA levels.

   MiR-421 in neuroblastoma and HeLa cells downregulates ATM kinase, which is a crucial integrator of DNA DSBs repair machinery. Ectopic expression of miR-421 leads to S-phase cell cycle checkpoint changes and an increase in radiosensitivity[81]. Recently, more miRNAs, including miR-18a, miR-100, miR-101, miR-181, have been identified as novel regulators to control the protein level of ATM[82-85]. BRCA1, a critical tumor suppressor, is also recruited to DNA damage lesions, in which it facilitates DNA repair. The level of BRCA1 is regulated by miR-182, miR-146a, and 146b-5p and may impact breast cancer therapy and by defering from homologous recombination[86,87]. MiR-18a attenuates cellular repair of DNA double-strand breaks by directly suppressing ATM. Ectopic expression of miR-18a significantly inhibited the repair of DNA damage induced by etoposide, leading to accumulation of DNA damage, increase in cell apoptosis and poor clonogenic survival[88]. Overexpression of miR-24, the first miRNA found to target H2AX, down-regulates the level of H2AX, resulting in higher sensitivity of cells to IR[89]. Alternatively, the expression of miR-101 and miR-34a downregulated DNA-PKcs and p53 binding protein1, respectively, impeding the NHEJ repair pathway[84,90]. The tumor suppressor p53 has a central role in the activation of genes in multiple pathways, including cell-cycle regulation, tumor suppression, and apoptosis. miR-125b and miR-504 have been identified as negative regulators of p53 in several types of human cells[91,92]. Interestingly, miR-605, and miR-143/miR-145 are post-transcriptionally activated by p53 and, subsequently, target Mdm2, leading to rapid accumulation of p53[93,94]. Radiation treatment downregulate the levels of miR-521 and upregulate DNA repair protein Cockayne syndrome protein A (CSA). Similarly, ectopic inhibition of miR-521 results in increased CSA protein levels and plays an important role in the radiosensitivity of prostate cancer cell lines[95]. Other miRNAs, such as miR-34, miR-21, have been shown to regulate the expression of important DDR network proteins BCL2, manganese superoxide dismutase (MnSOD), and MSH2, respectively[96,97]. Following gamma-irradiation of human lung carcinoma A549 and human B lymphoblastic cells IM9, a number of miRNA showed more than 2-fold changes in irradiated cells[98,99]. The target genes were involved in apoptosis, regulation of cell cycle, and DNA damage and repair. A study involving gamma-irradiation of human B lymphoblast cell lines showed dose-dependent changes in miRNA expression[100].

    Low dose X-rays irradiated cells (0.05 Gy) demonstrated a decrease in miR-20 and miR-21[101]. MiR-20 and miR-21 also increase in tumorigenesis and miR-21 is considered as an onco-miRNA. In high dose irradiated cells (10 Gy), miR-197 is upregulated. Carcinogenic characteristics are observed in normal cells following injection of miR-197, suggesting that stimulation of expression of miR197 by high dose radiation can lead to the progression of tumorigenesis. In addition, ionizing radiation-induced oxidative stress has been shown to play a role in altering miRNA expression[101]. The role of miRNA in the immune system and in inflammation has been reviewed in the literature[102,103]. The mechanism of epigenetic regulation in vivo is thought to be linked to inflammatory processes in the radiation response. Therefore, these miRNA play important roles in the initiation and/or perpetuation[104].

    In vitro three-dimensional (3D) growth of tumors is a cell culture model that more closely mimics the features of the in vivo environment and is being used increasingly in the field of biological and medical research[105]. It has been demonstrated that cancer cells cultured in 3D matrices are more radio-resistant compared to cells in monolayers[106]. However, the mechanisms causing this difference remain unclear. Our experimental results showed that more miRNAs were down regulated in three dimensional (3D) cultured human lung epithelial cells (HBED-3KT), compared to the two dimensional (2D) cultured HBEC-3KT cells after X-ray irradiation and carbon-beam irradiation as well. The significantly different expression of miRNAs such as miR-1202, miR-1290, miR-205 may be crucial in inhibiting the expression of target proteins and, therefor, lead to the different cellular response in 2D and 3D cultured cells[107].

    Together, these studies suggest that radiation exposure alters miRNA profiles in a way that can affect oxidative stress, DNA damage, DNA repair, regulation of cell cycle, apoptosis, tumorigenesis and changes in DNA methylation. MiRNA serve as integrators of the cellular response to ROS and DNA strand breaks, both of them are results of ionizing radiation. Further investigation of miRNA impact on cellular sensitivity to DNA-damaging agents will be in favor of cancer therapy.

 

Conclusion and perspective

Based on above mentioned, we think that radiation exposure can induce epigenetic changes including alterations in DNA methylation, chromatin remodelling and miRNA expression. Epigenetic changes are linked to alterations in global, repeat element and tumour suppressor promoter methylation. Radiation exposure can induce relaxed heterochromatin organisation. At low doses radiation, miRNA changes are involved in suppressing radiation-induced apoptosis, stimulating DNA repair, counteracting radiation-induced damage, and suppressing the progression of cancer but higher doses of radiation lead to tumorigenic progression. However, some mechanisms underlying the radiation-induced cellular response such as genomic instability still remains largely unknown. The evidence presented in this review supports that epigenetic mechanisms may be involved in. Induction of epigenetic changes may be an initiating factor in the instability. These changes are heritable and persist in the progeny of the irradiated cells. Additionally or alternatively, epigenetic alterations may be a late arising delayed effect of irradiation driving the perpetuation of the cellular response. Epigenetic regulation has recently been established as an emerging tool of cancer therapy. Therefore, the understanding of the epigenetic mechanism in cancer and radiation-induced cellular response is required for the development of cancer radiotherapy. It is also imperative to investigate more precise mechanisms involving in specific gene or protein in order to better control carcinogenesis or prevent human from radiation risk.

 

Acknowledgements

The work was supported by the National Nature Science Foundation of China to BH [31170803, U1432121], and the National Key Scientific Instrument and Equipment Development Project of China to BH [2012YQ03014210].

 

REFERENCES 

1.   Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nature Reviews Genetics 2007; 8: 253–262

2.   Szyf M. Epigenetics, DNA methylation, and chromatin modifying drugs. Ann Rev Pharmacol Toxicol 2009; 49: 243–263

3.   Lewin B. Genes IX. 2008

4.   Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nature Reviews Genetics 2002; 3: 415–428

5.   Tawa R, Kimura Y, Komura J, Miyamura Y, Kurishita A, Sasaki MS, Sakurai H, Ono T. Effects of X-ray irradiation on genomic DNA methylation levels in mouse tissues. Journal of Radiation Research 1998; 39: 271–278

6.   Pogribny I, Raiche J, Slovack M, Kovalchuk O. Dose dependence, sex- and tissue-specificity and persistence of radiation-induced genomic DNA methylation changes. Biochemical and Biophysical Research Communications 2004; 320: 1253–1261

7.   Kovalchuk O, Baulch JE. Epigenetic changes and nontargeted radiation effects – is there a link? Environmental and Molecular Mutagenesis 2008; 49: 16–25

8.   Chim CS, Liang R, Kwong YL. Hypermethylation of gene promoters in hematological neoplasia. Hematological Oncology 2002; 20: 167–176

9.   Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007; 128: 683–692

10.  Robertson KD. DNA methylation and human disease. Nat Rev Genet2005; 6: 597–610

11.  Esteller M. Epigenetics in cancer. New England Journal of Medicine 2008; 358: 1148–59

12.  Jones, P.A.; Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3: 415–428

13.  Herman, J.G.; Baylin, S.B. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003; 349: 2042–2054

14.  Antequera, F.; Bird, A. CpG islands as genomic footprints of promoters that are associated with replication origins. Curr Biol 1999; 9: 661–667

15.  Bestor TH. The DNA methyltransferases of mammals. Human Molecular Genetics 2009; 9: 2395–2402

16.  Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novomethylation and mammalian development. Cell 1999; 99: 247–257

17.  Goll MG, Kirpekar F, Maggert KA, Yoder JA, Hsieh CL, ZhangX, Golic KG, Jacobsen SE, Bestor TH. Methylation of tRNA Asp by the DNA methyltransferase homolog Dnmt2. Science 2006; 311: 395–398

18.  Goll MG, Kirpekarb F, Maggert KA, Yoder JA, Hsieh CL, Zhang X, Golic KG, Jacobsen SE, Bestor TH. Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 2006; 311: 395-398

19.  Jurkowski TP, Meusburger M, Phalke S, Helm M, Nellen W, Reuter G, Jeltsch A. Human DNMT2 methylates tRNA(Asp) molecules using a DNA methyltransferase-like catalytic mechanism. RNA 2008; 14:1663–1670

20.  Schaefer M, Pollex T, Hanna K, Tuorto F, Meusburger M, Helm M, Lyko F. RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes Dev 2010; 24: 1590-1595

21.  Elhardt W, Shanmugam R, Jurkowski TP, Jeltsch A. Somatic cancer mutations in the DNMT2 tRNA methyltransferase alter its catalytic properties. Biochimie 2015; 112: 66-72

22.  Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010; 28: 1057–1068

23.  Laird PW. Cancer epigenetics. Hum Mol Genet 2005; 14: 65–76

24.  Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. New England Journal of Medicine 2003; 349: 2042–2054

25.  Xu GL, Bestor TH, Bourc’his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Pe´quignot E. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 1999; 402: 187–191

26.  Kalinich JF, Catravas GN, Snyder SL. The effect of g irradiation on DNA methylation. Radiation Research 1989; 117: 185–197

27.  Kovalchuk O, Burke P, Arkhipov A, Kuchma N, James SJ, Kovalchuk I, Pogribny I. Genome hypermethylation in Pinussilvestris of Chernobyl-a mechanism for radiation adaptation? Mutation Research 2003; 529: 13–20

28.  Raiche J, Rodriguez-Juarez R, Pogribny I, Kovalchuk O. Sex and tissue specific expression of maintenance and de novo DNA methyltransferases upon low dose X-irradiation in mice. Biochemical and Biophysical Research Communications 2004; 325: 39–47

29.  Pogribny I, Koturbash I, Tryndyak V, Hudson D, Stevenson SM, Sedelnikova O, Bonner W, Kovalchuk O. Fractionated low-dose radiation exposure leads to accumulation of DNA damage and profound alterations in DNA and histone methylation in the murine thymus. Molecular Cancer Research 2005; 3: 553–561

30.  Koturbash I, Pogribny I, Kovalchuk O. Stable loss of global DNA methylation in the radiation-target tissue - a possible mechanism contributing to radiation carcinogenesis? Biochemical and Biophysical Research Communications 2005; 337: 526–533

31.  Koturbash I, Baker M, Loree J, Kutanzi K, Hudson D, Pogribny I, Sedelnikova O, Bonner W, Kovalchuk O. Epigenetic dysregulation underlies radiation-induced transgenerational genome instability in vivo. International Journal of Radiation Oncology Biology Physics 2006; 66: 327–330

32. Loree J, Koturbash I, Kutanzi K, Baker M, Pogribny I, Kovalchuk O. Radiation-induced molecular changes in rat mammary tissue: Possible implications for radiation-induced carcinogenesis. International Journal of Radiation Biology 2006; 82: 805–815

33.  McGarvey KM, Fahrner JA, Greene E, Martens J, Jenuwein T, Baylin SB. Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state. Cancer Res 2006; 66: 3541–3549

34.  Loree, J, Koturbash I, Kutanzi K, Baker M, Pogribny I, Kovalchuk O. Radiation-induced molecular changes in rat mammary tissue: Possible implications for radiation-induced carcinogenesis. Int J Radiat Biol 2006; 82: 805–815

35.  Raiche J, Rodriguez-Juarez R, Pogribny I, Kovalchuk O. Sex- and tissue-specific expression of maintenance and de novo DNA methyltransferases upon low dose X-irradiation in mice. Bio chem Biophys Res Commun 2004; 325: 39–47

36.  Kovalchuk O, Burke P, Besplug J, Slovack M, Filkowski J, Pogribny I. Methylation changes in muscle and liver tissues of male and female mice exposed to acute and chronic low-dose X-ray-irradiation. Mutation Research 2004; 548: 75–84

37.  Grønbæk K, Hother C, Jones PA. Epigenetic changes in cancer. Acta Pathologica Microbiologica, et Immunologica Scandinavica 2007; 115: 1039–1059

38.  Schuffenhauer S, Bartsch O, Stumm M, Buchholz T, Petropoulou T, Kraft S, Belohradsky B, Hinkel GK, Meitinger T, Wegner RD. DNA, FISH and complementation studies in ICF syndrome: DNA hypomethylation of repetitive and single copy loci and evidence for a trans acting factor. Human Genetics 1995; 96: 562–571

39.  Hofstetter B, Niemierko A, Forrer C, Benhattar J, Albertini V, Pruschy M, Bosman FT, Catapano CV, Ciernik IF. Impact of genomic methylation on radiation sensitivity of colorectal carcinoma. Int J Radiat Oncol Biol Phys 2010; 76: 1512–1519

40.  Cho HJ, Kim SY, Kim KH, Kang WK, Kim JI, Oh ST, Kim JS, An CH. The combination effect of sodium butyrate and 5-aza-2'-deoxycytidine on radiosensitivity in RKO colorectal cancer and MCF-7 breast cancer cell lines. World J Surg Oncol 2009; 7: 49-55

41.  Kim JS, Kim SY, Lee M, Kim SH, Kim SM, Kim EJ. Radioresistance in a human laryngeal squamous cell carcinoma cell line is associated with DNA methylation changes and topoisomerase II alpha. Cancer Biol Ther 2015;

42.  Kuhmann C, Weichenhan D, Rehli M, Plass C, Schmezer P, Popanda O. DNA methylation changes in cells regrowing after fractioned ionizing radiation. Radiother Oncol 2011; 101: 116–121

43.  Kaup S, Grandjean V, Mukherjee R, Kapoor A, Keyes E, Seymour CB, Mothersill CE, Schofield PN. Radiation-induced genomic instability is associated with DNA methylation changes in cultured human keratinocytes. Mutation Research 2006; 597: 87–97

44.  Wang GG, Allis CD, Chi P. Chromatin remodeling and cancer, Part I: Covalent histone modifications. Trends in Molecular Medicine 2007; 13: 363–372

45.  Jenuwein T, Allis CD. Translating the histone code. Science 2001; 293: 1074–1080

46.  Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 2005; 37: 391–400

47.  Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani SK. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 2005; 435: 1262–1266

48.  Nguyen, CT, Weisenberger DJ, Velicescu M, Gonzales F.A, Lin JC, Liang G, Jones PA. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'-deoxycytidine. Cancer Res 2002; 62: 6456–6461

49.  McGarvey KM, Fahrner JA, Greene E, Martens J, Jenuwein T, Baylin SB. Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state. Cancer Res 2006; 66: 3541–3549

50.  Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. Journal of Biological Chemistry 1998; 273: 5858–5868

51.  Fernandez-Capetillo O, Lee A, Nussenzweig M, Nussenzweig A. H2AX: The histone guardian of the genome. DNA Repair 2004; 3: 959–967

52.  Fillingham J, Keogh MC, Krogan NJ. Gamma H2AX and its role in DNA double-strand break repair. Biochemistry and Cell Biology 2006; 84: 568–577

53.  Yin B, Bassing CH. The sticky business of histone H2AX in V (D) J recombination, maintenance of genomic stability, and suppression of lymphoma. Immunologic Research 2008; 42: 29–40

54.  Srivastava N, Gochhait S, de Boer P, Bamezai RN. Role of H2AX in DNA damage response and human cancers. Mutation Research 2009; 681: 180–188

55.  Suzuki H, Ouchida M, Yamamoto H, Yano M, Toyooka S, Aoe M, Shimizu N, Date H, Shimizu K. Decreased expression of the SIN3A gene, a candidate tumor suppressor located at the prevalent allelic loss region 15q23 in non-small cell lung cancer. Lung Cancer 2008; 59: 24–31

56.  Van Den Broeck A, Ozenne P, Eymin B, Gazzeri S. Lung cancer: a modified epigenome. Cell Adh Migr 2010; 4: 107-113

57.  Brock MV, Herman JG, Baylin SB. Cancer as a manifestation of aberrant chromatin structure. Cancer Journal 2007; 13: 3-8

58.  Wang GG, Allis CD, Chi P. Chromatin remodeling and cancer, Part II: ATP-dependent chromatin remodeling. Trends in Molecular Medicine 2007; 13: 373–380

59.  Lafon-Hughes L, Di-Tomaso MV, Méndez-Acuña L, Martínez-López W. Chromatin-remodelling mechanisms in cancer. Mutation Research 2008; 658: 191–214

60.  Sak A, Kübler D, Bannik K, Groneberg M, Stuschke M. Dependence of radiation-induced H2AX phosphorylation on histone methylation: Evidence from the chromatin immunoprecipitation assay. Int J Radiat Biol 2015; 91:346-53

61.  Bonner WM, Redon CE, Dickey JS, Nakamura AJ, Sedelnikova OA, Solier S, Pommier Y. Gamma H2AX and cancer. Nat Rev Cancer 2008; 8: 957–967

62.  Pilch DR, Sedelnikova OA, Redon C, Celeste A, Nussenzweig A, Bonner WM. Characteristics of gamma-H2AX foci at DNA double-strand breaks sites. Biochem Cell Biol 2003; 81: 123–129

63.  Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaksinduce histone H2AX phosphorylation on serine 139. J Biol Chem 1998; 273: 5858–5868

64.  Celeste A, Fernandez-Capetillo O, Kruhlak MJ, Pilch DR, Staudt DW, Lee A, Bonner RF, Bonner WM, Nussenzweig A. Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol 2003; 5: 675–679

65.  Karagiannis TC, Harikrishnan KN, El-Osta A. Disparity of histone deacetylase inhibition on repair of radiation-induced DNA damage on euchromatin and constitutive heterochromatin compartments. Oncogene 2007; 26: 3963–3971

66.  Falk M, Lukasova E, Kozubek S. Chromatin structure influences the sensitivity of DNA to -radiation. Bio chimicaet Biophysica Acta 2008; 1783: 2398–2414

67.  Vasireddy RS, Karagiannis TC, El-Osta A. -radiation induced H2AX formation occurs preferentially in actively transcribing euchromatic loci. Cellular and Molecular Life Sciences 2010; 67: 291–294

68.  Falk M, Lukasova E, Gabrielova B, Ondrej V, Kozubek S. Chromatin dynamics during DSB repair. Biochimica et Biophysica Acta 2007; 1773: 1534–1545

69.  Park JH, Park EJ, Lee HS, Kim SJ, Hur SK, Imbalzano AN, Kwon J. Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting gamma-H2AX induction. EMBO Journal 2006; 25: 3986–3997

70.  Liu M, Hu WX. Functional role of ATM in the cellular response to DNA damage. Frontiers of Chemical Science and Engineering 2011; 5: 179-187

71.  Ziv Y, Bielopolski D, Galanty Y, Lukas C, Taya Y, Schultz DC, Lukas J, Bekker-Jensen S, Bartek J, Shiloh Y. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nature Cell Biology 2006; 8: 870–876

72.  Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Lobrich M, Jeggo PA. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Molecular Cell 2008; 31: 167–177

73.  Ayoub N, Jeyasekharan AD, Bernal JA, Venkitaraman AR. HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response. Nature 2008; 453: 682–686

74.  Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S, Kim VN. The nuclear RNase III Drosha initiates microRNA processing. Nature 2003; 425: 415–419

75.  Landthaler M, Yalcin A, Tuschl T. The human Di George syndrome critical region gene 8 and its D. Melano gaster homolog are required for miRNA biogenesis. Current Biology 2004; 14: 2162–2167

76.  Cai X, Hagedorn CH, Cullen BR. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 2004; 10: 1957–1966

77.  Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136: 215–233

78.  Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281–297

79.  Calin GA, Sevignani C, Dumitru CD Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 2004; 101: 2999–3004

80.  Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 2009; 10: 704–714

81.  Chen CZ. MicroRNAs as oncogenes and tumor suppressors. N Engl J Med 2005; 353: 1768–1771

82.  Metheetrairut C, Slack FJ. MicroRNAs in the ionizing radiation response and in radiotherapy. Curr Opin Genet Dev 2013; 23: 12–19

83.  Ishii H, Saito T. Radiation-induced response of microRNA expression in murine embryonic stem cells. Journal of Medicinal Chemistry 2006; 2: 555–563

84.  Maes OC, An J, Sarojini H, Wu H, Wang E. Changes in microRNA expression patterns in human fibroblasts after low-LET radiation. Journal of Cellular Biochemistry 2008; 105: 824–834

85.  Jaklevic B, Uyetake L, Wichmann A, Bilak A, English CN, Su TT. Modulation of ionizing radiation-induced apoptosis by bantam microRNA in Drosophila. Developmental Biology 2008; 320: 122–130

86.  Ilnytskyy Y, Koturbash I, Kovalchuk O. Radiation-induced bystander effects in vivo are epigenetically regulation in a tissue-specific manner. Environmental and Molecular Mutagenesis 2009; 50: 105–113

87.  Tamminga J, Kathiria P, Koturbash I, Kovalchuk O. DNA damage-induced upregulation of miR-709 in the germline downregulates BORIS to counteract aberrant DNA hypomethylation. Cell Cycle 2008; 7: 3731–3736

88.  Hu H, Du L, Nagabayashi G, Seeger RC, Gatti RA. ATM is down-regulated by N-Myc-regulated microRNA-421. Proc Natl Acad Sci USA 2010; 107: 1506–1511

89.  Song L, Lin C, Wu Z, Gong H, Zeng Y, Wu J, Li M, and Li J. miR-18a impairs DNA damage response through downregulation of ataxia telangiectasia mutated (ATM) kinase. PLoS One 2011; 6: e25454

90.  Wang Y, Yu Y, Tsuyada A, Ren X, Wu X, Stubblefield K, Rankin-Gee EK, and Wang SE. Transforming growth factor-beta regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM. Oncogene 2011; 30: 1470–1480

91.  Yan D, Ng WL, Zhang X, Wang P, Zhang Z, Mo YY, Mao H, Hao C, Olson JJ, Curran WJ, and Wang Y. Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation. PLoS One 2010; 5: e11397

92.  Yu Y, Wang Y, Ren X, Tsuyada A, Li A, Liu LJ, and Wang SE. Context-dependent bidirectional regulation of the MutS homolog 2 by transforming growth factor beta contributes to chemoresistance in breast cancer cells. Mol Cancer Res 2010; 8: 1633–1642

93.  Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, Beech J, Kulshrestha R, Abdelmohsen K, Weinstock DM, Gorospe M, Harris AL, Helleday T, Chowdhury D. MiR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell 2011; 41: 210–220

94.  M Garcia AI, Buisson M, Bertrand P, Rimokh R, Rouleau E, Lopez BS, Lidereau R, Mikaelian I, Mazoyer S. Downregulation of BRCA1 expression by miR-146a and miR- 146b-5p in triple negative sporadic breast cancers. EMBO Mol Med 2011; 3: 279–290

95.  Wu CW, Dong YJ, Liang QY, He XQ, Ng SS, Chan FK, Sung JJ, Yu J. MicroRNA-18a attenuates DNA damage repair through suppressing the expression of ataxia telangiectasia mutated in colorectal cancer. PLoS One 2013; 8: e57036

96.  Lal A, Pan Y, Navarro F, Dykxhoorn DM, Moreau L, Meire E, Bentwich Z, Lieberman J, Chowdhury D. miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells. Nat Struct Mol Biol 2009; 16: 492–498

97.  Yan D, Ng WL, Zhang X, Wang P, Zhang Z, Mo YY, Mao H, Hao C, Olson JJ, Curran WJ, Wang Y. Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation. PLoS One 2010; 5: e11397

98.  Kofman AV, Kim J, Park SY, Dupart E, Letson C, Bao Y, Ding K, Chen Q, Schiff D, Larner J, Abounader R. MicroRNA-34 a promotes DNA damage and mitotic catastrophe. Cell Cycle 2013; 12: 3500–3511

99.  Hu W, Chan CS, Wu R, Zhang C, Sun Y, Song JS, Tang LH, Levine AJ, and Feng Z. Negative regulation of tumor suppressor p53 by microRNA miR-504. Mol Cell 2010; 38: 689–699

100. Le MT, Shyh-Chang N, Khaw SL, Chin L, Teh C, Tay J, O’Day E, Korzh V, Yang H, Lal A, Lieberman J, Lodish HF, Lim B. Conserved regulation of p53 network dosage by microRNA-125b occurs through evolving miRNA-target gene pairs. PLoS Genet 2011; 7: e10022421

101. Xiao J, Lin H, Luo X, and Wang Z. miR-605 joins p53 network to form a p53: miR-605: Mdm2 positive feedback loopin response to stress. EMBO J 2011; 30: 524–532

102. Zhang J, Sun Q, Zhang Z, Ge S, Han ZG, and Chen WT. Loss of microRNA-143/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing theMDM2-p53 feedback loop. Oncogene, 2013; 32: 61–69

103. Josson S, Sung SY, Lao K, Chung LW, Johnstone PA. Radiation modulation of microRNA in prostate cancer cell lines. Prostate 2008; 68: 1599–1606

104. Welch C, Chen Y, Stallings RL. MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene 2007; 26: 5017–5022

105. Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, Sumani KM, Alder H, Amadori D, Patel T, Nuovo GJ, Fishel R, Croce CM. MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proc Natl Acad Sci USA 2010; 107: 21098–21103

106. Cha HJ, Shin S, Yoo H, Lee EM, Bae S, Yang KH, Lee SJ, Park IC, Jin YW, An S. Identification of ionizing radiation-responsive microRNAs in the IM9 human B lymphoblastic cell. International Journal of Oncology 2009b; 34: 1661-1668

107. Shin S, Cha HJ, Lee EM, Lee SJ, Seo SK, Jin HO, Park IC, JinYW, An S. Alteration of miRNA profiles by ionizing radiation in A549 human non-small cell lung cancer cells. International Journal of Oncology 2009; 35: 81–86

108. Cha HJ, Seong KM, Bae S, Jung JH, Kim CS, Yang KH, Jin YW, An S. Identification of specific microRNAs responding to low and high dose gamma-irradiation in the human lymphoblast line IM9. Oncology Reports 2009; 22: 863–868.

109. Simone NL, Soule BP, Ly D, Saleh AD, Savage JE, Degraff W, Cook J, Harris CC, Gius D, Mitchell JB. Ionizing radiation-induced oxidative stress alters miRNA expression. PLoS One 2009; 4: e6377

110. Sonkoly E, Pivarcsi A. MicroRNAs in inflammation. International Reviews of Immunology 2009; 28: 535–561

111. Davidson-Moncada J, Papavasiliou FN, Tam W. Micro-RNAs of the immune system: Roles in inflammation and cancer. Annals of the New York Academy of Sciences 2010; 1183: 183–194

112. Wright EG. Manifestations and mechanisms of nontargeted effects of ionizing radiation. Mutation Research 2010; 687: 28–33

113. Birgersdotter A, Sandberg R, Ernberg I. Gene expression perturbation in vitro–a growing case for three-dimensional (3D) culture systems. Semin Cancer Biol 2005; 15: 405–412

114. Storch K, Eke I, Borgmann K, Krause M, Richter C, Becker K, Schröck E, Cordes N. Three-dimensional cell growth confers radioresistance by chromatin density modification. Cancer Research 2010; 70: 3925-3934

115. Pan D, Xue G, Zhu JY, Hu BR. Ionizing radiation induced biological effects in three-dimensional cell cultures. Rendiconti Lincei 2014; 25: 81-86

 

Peer reviewers: An M Aerts, PhD, SCK•CEN, Environment, Health and Safety, Molecular and Cellular Biology, Radiobiology Unit, Boeretang 200, B-2400 Mol, Belgium; Wei Yang, Associate Professor, Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Jiangsu province, China.

 

 

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.