Dan, Tu

Dicker, Adam, MD, PhD

Simone, Nicole L

Wright, Christopher M

Name not available

microRNAs: The Short Link between Cancer and RT-Induced DNA Damage Response.

Jefferson Digital Commons

Thomas Jefferson UniversityJefferson Digital CommonsDepartment of Radiation Oncology Faculty Papers Department of Radiation Oncology6-4-2014microRNAs: The Short Link between Cancer andRT-Induced DNA Damage Response.Christopher M WrightThomas Jefferson UniversityTu DanDepartment of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University,Tu.Dan@jefferson.eduAdam Dicker MD, PhDThomas Jefferson University, adam.dicker@jefferson.eduNicole L SimoneDepartment of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University,Nicole.Simone@jefferson.eduLet us know how access to this document benefits youFollow this and additional works at: http://jdc.jefferson.edu/radoncfpPart of the Oncology CommonsThis Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of ThomasJefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarlypublications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers andinterested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion inDepartment of Radiation Oncology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, pleasecontact: JeffersonDigitalCommons@jefferson.edu.Recommended CitationWright, Christopher M; Dan, Tu; Dicker, Adam MD, PhD; and Simone, Nicole L, "microRNAs: TheShort Link between Cancer and RT-Induced DNA Damage Response." (2014). Department ofRadiation Oncology Faculty Papers. Paper 46.http://jdc.jefferson.edu/radoncfp/46OPINION ARTICLEpublished: 04 June 2014doi: 10.3389/fonc.2014.00133microRNAs: the short link between cancer and RT-inducedDNA damage responseChristopher M.Wright ,Tu Dan,Adam P. Dicker and Nicole L. Simone*Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA*Correspondence: nicole.simone@jeffersonhospital.orgEdited by:Daphne Haas-Kogan, University of California San Francisco, USAReviewed by:Chandan Guha, Albert Einstein College of Medicine, USAKeywords: radiation, DNA damage/response, microRNA, cancer, therapeutic target, oxidative stress, double-strand breaks, carcinogenesisDNA damage response (DDR) networkshave long been noted to be implicated incell death induced via ionizing radiation(1). These DNA damage sensing and sig-naling pathways establish control throughcell cycle checkpoints, cellular senescence,and apoptosis (2). When functioning prop-erly, DDR networks act as a barrier againsttumor growth while maintaining genomeintegrity. New discoveries have unveiledspecific roles of proteins in DDR net-works, which may serve as potential ther-apeutic targets and sensitizers to ionizingradiation (3).Unfortunately, although a clear connec-tion has been established between dys-functional DDR networks and malignancy,clinical trials targeting these pathways inthe oncology realm have shown limitedefficacy to date (4, 5). Lapsed regulationof DDR pathways in malignancy allowscells to bypass cellular checkpoints andprogress through the cell cycle with stalledreplication forks, incomplete DNA repli-cation, and other forms of DNA dam-age (6). This genomic instability is prop-agated through cellular generations result-ing in a neoplastic phenotype. A numberof specific pathognomonic DDR defectshave been identified in a number of can-cers, including the mismatch repair proteinMSH2 in colorectal cancer and the homol-ogous recombination proteins BRCA1 andBRCA2 in breast and ovarian cancers (7,8). Recent evidence suggests DDR mishapsmay occur at an early stage in some precan-cerous lesions, double-strand break (DSB)markers such as nuclear gamma-H2AX aresignificantly elevated (9).To further understand the role of DDRin malignancy, attention can be turned tothe investigation of microRNAs (miRs), asanother component of the DDR machin-ery in post-transcriptional gene regula-tion (10). miRs are small, non-codingRNA molecules that are complementaryto one or more messenger RNA molecules(mRNA) (11). This specific pairing leadsto the translational inhibition and degra-dation of the target mRNA. Global dysreg-ulation of miRNAs is frequently observedin malignancy and patterns of dysregula-tion seem to be dependent on cancer type(12). More recently, it has been demon-strated that miR expression is regulatedby DNA lesions and DDR proteins (13).It is suggested that miRs may play a reg-ulatory role in an intermediary timeframe,in between rapid post-translational proteinmodifications and delayed transcriptionalactivation of target genes (14).Our laboratory has previously shownthat normal human fibroblasts exhibitunique miRNA signatures when exposedto exogenous agents that induce oxidativeor genotoxic stress (15). A time course afterexposure showed changes in 17 miR speciesfollowing exposure to radiation, 23 afterH2O2 treatment, and 45 after etoposidetreatment. The miR signatures varied withdirect (etoposide) and indirect (H2O2)effects (Figure 1). Eight miRs were alteredspecifically by radiation and etoposide,suggesting these might be used to dis-cern direct DNA damage due to radiation.Alternatively, two miRs were altered withradiation and H2O2, suggesting these couldcomprise a signature of indirect DNA dam-age. These arrays did not demonstrate anysignificantly altered miRs that were uniqueto radiation alone. Interestingly, produc-tion of reactive oxygen species (ROS)increased with increasing doses of radia-tion. Additionally, pre-treatment with thethiol antioxidant cysteine decreased bothROS production and reversed the changesin the miRNA signature in response toirradiation.The miRs affected in our study arereflective of more recent literature inves-tigating individual miRs that are alteredin response to DDR (16). In fact, theyare implicated in more mechanisticstudies dealing with homologous recom-bination, non-homologous end joining,and base excision repair (17, 18). Post-transcriptional regulation of mRNAsmediated by miRs plays a fundamentalrole in adjusting DDR machinery. miR-421in neuroblastoma and HeLa cells down-regulates ATM kinase, which is a crucialintegrator of DNA DSBs repair machin-ery (19). Ectopic expression of miR-421leads to S-phase cell cycle checkpointchanges and an increase in radiosensitivity.Although it has not been clearly demon-strated that miRs directly mediate thechoice between homologous recombina-tion and NHEJ-mediated repair of a DSB,evidence suggests that miRs are at least inti-mately involved by targeting factors thatbelong to a specific pathway. Expressionof miR-182 directly downregulates BRCA1and defers from homologous recombina-tion (20). Alternatively, the expression ofmiR-101 and miR-34a would downregu-late DNA-PKcs and p53 binding protein1, respectively, impeding the NHEJ repairpathway (21, 22). Other miRNAs, suchas miR-34, miR-521, miR-21, have beenshown to regulate the expression of impor-tant DDR network proteins BCL2, man-ganese superoxide dismutase (MnSOD),and MSH2, respectively (23–25).Due to the miRNA regulation of DDRmachinery and to the clear connectionwww.frontiersin.org June 2014 | Volume 4 | Article 133 | 1Wright et al. miRs, malignancy, and DNA damageFIGURE 1 | Effects of cytotoxic stressors on microRNAs and protein expression interplay. DNAdamage may occur following exposure to genotoxic agents including ionizing radiation, etoposide, andhydrogen peroxide (H2O2) exposure. Ionizing radiation causes DNA damage both directly, by energeticdisruption of DNA integrity, and indirectly, as a result of the formation of intracellular free radicalsresulting in both double and single strand breaks. Similarly, DNA damage by H2O2 is produced by reactiveoxygen species formation while etoposide generates double-strand breaks mimicking the direct DNAdamage caused by radiation. (A) In response, damage-sensing repair molecules are recruited to the siteof DNA damage, triggering multiple protein-mediated repair cascades. In parallel, DNA damage activatesthe processing of miRNA precursors, eventually leading to expression of a common miRNA signatureproduced in response to genotoxic stress. Post-transcriptional regulation of mRNAs mediated by theseinduced miRNAs plays a fundamental role in adjusting DDR machinery (B), with complex interplaybetween protein and miRNA expression.between DDR dysregulation and a neoplas-tic phenotype,we believe miRs could definethe relationship between cancer and DDR.Our laboratory’s studies suggest that miRsserve as integrators of the cellular responseto ROS and DNA strand breaks, both ofwhich are results of ionizing radiation.It is our opinion that further investiga-tion of miR impact on cellular sensitivityto DNA-damaging agents could elucidatetherapeutic targets to combat cancer, asmiRs may provide the link between DDRand malignancy.ACKNOWLEDGMENTSThe work was supported in part by theKimmel Cancer Center’s NCI Cancer Cen-ter Support Grant P30 CA56036.REFERENCES1. Hall EJ, Giaccia AJ.Radiobiology for the Radiologist.Philadelphia, PA: Lippincott Williams & Wilkins(2012).2. Sancar A, Lindsey-Boltz LA, Unsal-Kaçmaz K, LinnS. 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MicroRNA-21 induces resistanceto 5-fluorouracil by down-regulating human DNAMutS homolog 2 (hMSH2). Proc Natl Acad SciU S A (2010) 107:21098–103. doi:10.1073/pnas.1015541107Conflict of Interest Statement: The authors declarethat the research was conducted in the absence of anycommercial or financial relationships that could beconstrued as a potential conflict of interest.Received: 15 April 2014; paper pending published: 07May 2014; accepted: 20 May 2014; published online: 04June 2014.Citation: Wright CM, Dan T, Dicker AP and SimoneNL (2014) microRNAs: the short link between cancerand RT-induced DNA damage response. Front. Oncol.4:133. doi: 10.3389/fonc.2014.00133This article was submitted to Radiation Oncology, asection of the journal Frontiers in Oncology.Copyright © 2014 Wright , Dan, Dicker and Simone.This is an open-access article distributed under the termsof the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums ispermitted, provided the original author(s) or licensor arecredited and that the original publication in this journalis cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted whichdoes not comply with these terms.www.frontiersin.org June 2014 | Volume 4 | Article 133 | 3

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