chemoresistance, cancer stem cells, and mirna influences: the

Review ArticleChemoresistance Cancer Stem Cells andmiRNA Influences The Case for Neuroblastoma

Alfred Buhagiar1 and Duncan Ayers23

1School of Clinical Sciences Faculty of Medicine and Dentistry University of Bristol Bristol BS8 1TH UK2Centre for Molecular Medicine and Biobanking University of Malta Msida MSD 2080 Malta3Faculty of Medical and Human Sciences The University of Manchester Manchester M1 7DN UK

Correspondence should be addressed to Duncan Ayers duncanayersgooglemailcom

Received 29 April 2015 Revised 26 June 2015 Accepted 1 July 2015

Academic Editor Nils Ole Schmidt

Copyright copy 2015 A Buhagiar and D Ayers This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Neuroblastoma is a type of cancer that develops most often in infants and children under the age of five years Neuroblastomaoriginates within the peripheral sympathetic ganglia with 30 of the cases developing within the adrenal medulla although it canalso occur within other regions of the body such as nerve tissue in the spinal cord neck chest abdomen and pelvis MicroRNAs(miRNAs) regulate cellular pathways differentiation apoptosis and stem cell maintenance Such miRNAs regulate genes involvedin cellular processes Consequently they are implicated in the regulation of a spectrum of signaling pathways within the cell Inessence the role of miRNAs in the development of cancer is of utmost importance for the understanding of dysfunctional cellularpathways that lead to the conversion of normal cells into cancer cells This review focuses on highlighting the recent importantimplications of miRNAs within the context of neuroblastoma basic research efforts particularly concerning miRNA influences oncancer stem cell pathology and chemoresistance pathology for this condition together with development of translational medicineapproaches for novel diagnostic tools and therapies for this neuroblastoma

1 Introduction

Neuroblastoma (NB) is a paediatric cancer deriving from theneural-crest cells [1] The condition is commonly inflictedupon young children prior to the age of five years and inthe USAUK it accounts for 7-8 of childhood cancers [2ndash4] Tumourigenesis typically occurs in the adrenal glandsympathetic ganglia and paraganglia or along the spinal cord[5] It is a highly heterogeneous disease exhibiting variationin clinical appearance from localized to metastatic tissue andcan undergometastasis to the liver bones brain and skin [6]

2 Origin of NB

Two major causes have been identified in the origin of thedisease

The first cause is Familial origin which is identified inthe PHOX2B gene [7] This loss-of-function mutation is also

present in other congenital diseases such as Hirschsprungrsquosdisease and congenital central hypoventilation syndrome [8]In addition activatingmutations in the anaplastic lymphomakinase gene have been identified as the leading cause offamilial NB [8ndash10] ALK forms part of the tyrosine kinasesreceptors which are associated with cell surface receptors [11]During early development of nerve cells it is thought theALKgene helps in the proliferation of the nerve cells and theireventual regulation with data highlighting that 8 of NBcases are due to mutations in the ALK gene [12] However itis not excluded that other genes could be identified as playingmajor roles in the development of familial NB followingfuture research efforts [8]

The second cause is Sporadic origin which results inchromosomal losses [13] such as loss of the 1p3631 heterozy-gosity and occurs in 36 of primary tumours Chromosomegains can also occur such as MYCN amplification resultingin diploid or tetraploid DNA content within the affected

Hindawi Publishing CorporationAnalytical Cellular PathologyVolume 2015 Article ID 150634 8 pageshttpdxdoiorg1011552015150634

2 Analytical Cellular Pathology

cells [13] Similar to other cancers NB manifests itself ingenetic alteration [14] of genes responsible for cell growthcycle and immunity including phenotypic changes thatinhibit differentiation Research conducted over a numberof years reveals that the transcription factor MYCN [15] isthe most important oncogene [1] MYCN acts mainly bydysregulating downstream genes involved in key pathwaysthat affect NB formation with putative effects by KIFAP3OPHN RGS7 ODC1 TOP2A TWIST1 and TYMS on thesame gene [16] Moreover a recent study revealed thatalthough the MYCN gene expression was not amplified ahigh level of MYC proteins was present in NB patient group[17] Additionally transgenic animal model studies indicatedthat tumourigenesis does not require gene amplification [18]Conversely in the presence of abnormal MYCN expressionduring the formation of the neural crest the precursorcells transform into tumourigenic neuroblasts due to theupregulated MYCN protein level [19] This pathway wasconfirmed with the LIN28b gene A genomic aberration inthis gene results in repression of a set of microRNAs of thelet-7 familyThe let-7miRNAs function as tumor suppressorsthrough the silencing of oncogenes such as RAS MYC andCDK6 The outcome from this suppression was an elevatedMYCN protein expression that was elucidated in mousemodels An interesting fact is that LIN28b is a homologue ofLIN28 one of the regulators for pluripotency in stem cells incombination with NANOG OCT34 and SOX2 [20]

The physiological effect of theMYCN gene is highly influ-ential Intriguingly it has the ability to activate angiogenicfactors [21] leading to the formation of novel blood vesselsto ensure an adequate supply of nutrients hence repressingangiogenic inhibitors

Following the existence of miRNA technology researchwas focused on the relationship between MYCN [22] andmiRNAs Recent studies [23] highlighted that the generegulates a number of miRNAs A selection of these activatedmiRNAs is associated with clinically aggressive cancer condi-tions that include themiR-17-92 cluster miR-18amiR-7miR-128 miR-380-5p and miR-558

3 Clinical Outcomes

Current treatments inNB are varied due to the heterogeneousnature of the disease The outcome of the treatment dependson a multitude of factors including age of patient histologygenetic abnormalities [24] and stage of disease NB is a highrisk disease with almost 20of children experiencing relapse[25] Poor prognosis of the disease leads to inadequate ther-apy undetected residual tumour and inefficient modalitiesof treatment this leads to the need to standardize criteriafor evaluation of the disease Consequently a stage and riskclassification was developed for clinical presentations of NB[26] A panel of experts the International NB Staging System(INSS) bases its categorization on the stage of the diseaseand subsequent removal by surgery [27] If the disease doesnot need surgery another panel (the International NB RiskGroup Staging System INRGSS) bases its categorizationon clinical pretreatment [28] Data collected from imagingincluding CT scans and MRI give an evaluation of the

disease In addition to the acquired imaging data bonemarrow biopsy and status of theMYCN gene are also utilizedfor NB risk classification Through the application of thesecriteria new improved therapies with high survivabilitypercentage could be achieved

4 MiRNAs and Cancer

Since their discovery in 1993 in Caenorhabditis elegans[29] novel miRNA sequences have been identified in bothplants and animals with the database cataloging all miRNAsequences still increasing in number [30] Such miRNAs aredefined as single strands of not more than 25 nucleotides thatare generated from genes located on the chromosome [30]The generation of these miRNAs follows a four-step processinvolving the following [31] (i) cropping this involves theheterodimer Drosha cleaving the mature pri-miRNA into asmaller size called the pre-miRNA (ii) exportation this pre-miRNA is exported from the nucleus by combining withExportin-5 and Ran-GTP (iii) dicing once in the cytoplasmthey are cleaved into a smaller strand by RNase III enzymeknown as the dicer releasing the two small complementaryshort strands (iv) formation of the RNA Interference Silenc-ing Complex (RISC) complex a ribonucleoprotein complexforming part of the argonaute family one strand (the guide)forms a complex with ribonucleoprotein while the otherstrand (the passenger) is destroyed The complex then bindsto the mRNA leading to translational repression

Since their discovery the premise was established thatthere is a connection between miRNA activity and cancer[32] The tumorigenic effect of miRNAs is typically inducedby the dysregulation in miRNA expression through multiplemechanisms that include translocation deletion mutationsand rearrangements [32] High-throughput screening studiesand functional genomics research revealed the significantvariations in miRNA expression profiles of normal cellsin comparison with the cancer inflicted counterpart cells[30] This striking evidence led to the concept of themiRnome which is the characteristic malignant form Itwas also elucidated that most cancer conditions demonstratean overall downregulation in over 50 of the miRnomersquosindividual miRNAs though a few key tumourigenic miRNAswere found to be upregulated [33] A feature of miRNAsis their tissue specificity Apparently miRNA expression ismodulated according to the cancer cell population whichis different from that of a normal cell population [30] (seeTable 1) To be tumorigenicmiRNAsmust induce productionof growth factors (eg let-7) [34] be unresponsive to externalantigrowth factors (eg miR-1719) [35] and avoid cellapoptosis (eg miR-34a) [30] indefinite proliferation (egmiR-372373) [36] blood vessels formation also known asangiogenesis (eg miR-210) [37] metastasis and migrationwith an increase in tumor macrophages and inflammation(eg miR-10b) [38 39]

There are already 4469 miRNAs discovered ofwhich 1881 are precursors and 2588 are mature (httpwwwmirbaseorg) and the list is increasing To a largeextent some of the miRNAs involved in specific types ofcancer progression have been identified [32 33]

Analytical Cellular Pathology 3

Table 1 List of miRNAs identified to influence clinical progressionin specific cancer conditions

Cancer type miRNA

Lung cancer miR-21 miR-125 miR-574-5p miR-155 miR-197andmiR-182

Breast cancer miR-10a miR-210 miR-222 miR-203 andmiR-29a

Prostate cancer miR-375 miR-9 miR-141 andmiR-200b

Colon cancer miR-221 miR-17-5 miR-29b-2 miR-223miR-128b miR-24-1 andmiR-155

Stomachcancer

miR-21 miR-191 miR-223 miR-107 miR-214miR-221 andmiR-25

5 Chemoresistance Cancer Stem Cells andmiRNA Influences

One of the modalities in treating cancer is chemotherapyand a recurring problem encountered during cancer treat-ment is chemoresistance Resistance to chemotherapy isbelieved to cause over 90 failure [40] in metastatic cancerThis therapeutic failure is attributed to two mechanismsintrinsic and extrinsic resistance [41] Intrinsic resistanceoriginates from cancer cells that have already the capabilityof withstanding chemotherapy [42] Extrinsic resistance isthe acquired capability of counteracting chemotherapy viagenetic and epigenetic mutations in genes during continualchemotherapeutic treatments [43] Seven major mechanismshave been presently elucidated [44] to explain multi drugresistance (MDR) in cancer

(A) Genetic alterations that empower the cells with anadded function in their enzymatic pathways such as thewell-studied PI3KAktmTOR [45] The phosphorylation bythese enzymes produces substrates that regulate apoptosisThese substrate proteins regulate cell cycle activity by beinginactivated due to phosphorylation and consequently sus-pending apoptosis [46 47] Another example is the p53mutation which is a well-known tumour suppressor [48]Mutation within the Tp53 gene results exacerbates metastasisand invasiveness [49] Compared with other cancers whichexhibit tumour expression via loss of function mutation p53suffers from point mutation [50] resulting in a single aminoacid substitution The mutation alters the resistance to drugtoxicity by downregulating genes responsible for apoptosis[51]

(B) Drug export modulations that are mediated by theATP-binding cassette (ABC) genes [43 52] chemoresistanceoccurs since MDR proteins actively pump drugs outside thetumour cell membrane thus reducing the intracellular effectsof the drug on the tumour cell

(C) DNAmutations that allow cancer cells to accumulategenetic changes that favour selection towards chemoresis-tance [53] this predisposition towards transformationmakescancer cells more resistant to chemotherapy

(D) Inhibition of apoptosis by inactivation of genes thatencode for caspasesThe latter are cysteine proteases that playan essential role in programmed cell death [54] The failureof therapies to kill cancer cells is mainly due to the drugs that

are oriented towards inducing apoptosis Tumour cells havemanaged to [55] avoid cell death by overexpressing proteinswhich have antiapoptotic properties

(E) The cellular environment also plays an importantrole in MDR It was elucidated that the hypoxic conditionstypically prevailing in tumour cells induce such cells toproduce hypoxia inducible factors The chaotic conditionsand aggressive proliferation of cancer cause oxygen insuffi-ciency [56 57] These hypoxic factors elicit a multitude offactors such as gene expression protein overexpression andantiapoptotic inhibitors which collectively compromise theeffectiveness of chemotherapies [58]

(F) Stromal cells which are a form of connective tissueand are also developed in cancer In this microenvironmentit was established that these stromal cells together withmacrophages synonymous with inflammation and endothe-lial cells offer a large influence to the cancer cells in theirprogression and metastasis [59] Cancer-associated fibrob-lasts secrete protein chemokines which promote metastasisin cancer stem cells [60]

(G)The role of cancer stem cells is also amajor contribut-ing factor in the resurgence of cancer Stem cells have thecapacity to renew and differentiate into diverse specific celltypes [61] Stem cells have been identified from three sourcesthe inner cell mass of embryos induced pluripotent fromnormal somatic cells [62] and somatic adult stem cells [63]In 1994 it was discovered that cancer stem cells [64] exist inleukemia but since then they have been discovered in othersolid tumors Similarly to normal stem cells these cancerstem cells (CSCs) have the ability to regenerate and producecells that differentiate into a tumour condition which exhibitsMDR properties [65]

Asymmetric division in CSCs enables self-renewal andreconstitutes the tumour cells synonymous of remission [66]By definition asymmetric division is the homeostatic controlof cells that is maintained by producing copies identicalto itself plus differentiated cells These differentiated cellswill be carrying the different characteristics attributed toexposure of external signals and or genetic mutations thatmaintain tumourogenic capabilities [67] Tumor-initiatinggenetic aberrations are usually affected [68] via signalingpathways such as Wnt Notch Oct-4 and Hedgehog Thesimilarity of normal stem cells and CSCs is mediated throughthese pathways [69] InWnt120573 controls differentiation Notchproteins located on cell membranes are implicated in anumber of stem cells including neuronal and haematopoietictissue [70] Oct-4 which is a transcription factor regulatesembryonal carcinomas [71] and the maintaining of undiffer-entiated carcinoma cells and also in pancreatic cancer [72]Furthermore it was also recognized that adult stem cellsthat were converted into CSCs engage in oncogenic pathwaysinvolving these genetic aberrations [73 74] It was alsoelucidated that miRNAs are able to promote reprogrammingof cells even in induced pluripotent stem cell lines such thatcells become independent from their origin [75] It was laterrecognized that transcription factor STAT3 is required forthe maintenance of multipotency [76] in glioblastoma stemcells It was also established that NB cell lines with CD114+CSC expression markers demonstrated that such cells have


a cell cycle typical for induced pluripotent and embryonicstem cells [77] Thus in the face of these facts cancer stemcells show the same chemoresistance properties exhibited bynormal stem cells and it is very hard to design new drugsbecause of the toxicity to normal cells

Clearly the clinical obstacle associated with drug resis-tance is the reduced effect of chemotherapeutic drugs mainlydue to efflux from the targeted cells via the ABC transportercassette and P-glycoprotein (P-gp) which is a subfamilyB member (ABCB1) [78] P-gp in humans is encoded bythe ABCB1 gene [79] Studies have elucidated that miRNAsplay a major role in the metabolism and subsequent uptakeof the drug therapy [80] Treatment of MCF-7 breast car-cinoma cell line with antagomiR-451 via transfection anddoxorubicin revealed an augmented sensitivity to the druguptake [81] The accumulation of the drug was enhancedthroughmiR-451 activity which influenced the P-gp pathway[82] Furthermore research elucidated that miRNAs play arole in the metabolism of chemotherapeutic drugs and theirassociated membrane transporters and receptors [79] Aninteresting property of stem cells which differentiates themfrom other cells is their ability to express the ABC transportermechanism through the encoding genes ABCB1 ABCG2and ABCC1 at high levels [83] This high level of expressionmakes them efficient in achievingmultidrug resistance It waselucidated thatmiR-328 regulates the expression ofABCG2 inMCF-7 cells [80] which were transfected by an antagomiR formiR-328 further enhancing the similarity between normalstem cells and cancer stem cells It was also reported thatin pancreatic cancer miRNAs play a crucial role in theinduction ofMDRUsingmiRdeep2 an algorithmic softwarefour distinct miRNAs (miR-181a-5p miR-218-5p miR-130a-3p and miR-424-3p) were identified to be downregulatedwith a subsequent decrease in MDR [84]

6 miRNAs and NB

MicroRNAs which are also involved [85] in the transcrip-tional process can regulate the expression of these genes (seeTable 2)The development of NB depends on these expressedgenes and the key role that miRNAs play in their expressionCancer epidemiology has elucidated that frequently miRNAsare located on genomic regions and fragile sites that areimplicated in the disease [86] The best studied oncomiRcases that exhibited a specific miRNA signature for NB aremiR-17-92 and miR-21 The polycistronic miR-17-92 consistsof seven miRNAs that regulate the PTEN E2Fs and TGF-120573receptor II sites [35] and has shown that the transcription ofthe cluster is regulated by MYCN an oncogene responsiblefor tumourigenesis The cluster inhibits p21 gene responsible[87] for cell cycle progression and apoptosis ensuing inMYCN amplified NB cells making them more resistant tochemotherapy Other NB miRNAs are [88] dysregulated asshown in Table 2

The role ofmiRNAs in cancer treatment is very promisingbut still highly complex An all-inclusive approach is apossible route to overcome MDR combined with a person-alized therapy MiRNA profiling can predict the outcome ofresponse to treatmentThroughmodulation of the expression

Table 2 Previous research identifying miRNAs involved in NBpathogenesis and clinical progression

miRNA Dysregulatedexpression Target gene References

miR-17-92lowast UpregulatedDKK3 CDKN1ABIM and MEF2D

ESR1[22 89ndash91]

miR-21 Upregulated PTEN [92]miR-128 Upregulated NTRK [93]miR-380-5p Upregulated p53 [94]miR-558 Upregulated HPSE [95]miR-375 Upregulated ELAVL4 [96]let-7 Downregulated MYCN [19 97]miR-9 Downregulated MMP-14 [98]miR-15 Downregulated BcL2 [99 100]miR-103 Downregulated CDK5R1 [101 102]miR-107 Downregulated CDK5R1 [101 102]miR-124 Downregulated SOX9and PTBP1 [96 103 104]miR-29a Downregulated Cdk6 and CDC6 [105]miR152 Downregulated DNMT1 [106]miR-125b Downregulated TrkC [107]

miR-204 Downregulated BCL2 andNTRK2 [108]

miR-363 Downregulated ADAM15 andMYO1B [109]

miR-335 Downregulated SOX4 and TNC [109]lowastIncluding miR-18a miR-19a miR-20a and miR-92

levels of these miRNAs cancer cell lines demonstrated amarked response to therapeutic agents [110] Through cross-validation analysis miRNAs circulating in the blood can bescreened and used as a diagnostic tool in early detectionof cancer [111] Therefore their detection is also useful asbiomarkers in predicting the response to treatment in aparticular tumour although more research is needed tovalidate precisely the response It has been observed that30 of mammalian physiological processes are regulated bymiRNAs and [112] therefore one can implicate that tumourregression can be regulated via these physiological pathwaysby modulating tumour suppressor miRNAs Safe protocolsfor clinical trials in targeting cancer are still the biggesthurdle the mode of delivery of these modulators is still inits infancy

7 Conclusion

A pressing challenge in cancer treatment is to overcomeMDR The clinical value of miRNAs in pediatric tumours isvery hopeful considering the growing number of scientificliterature Therefore it is imperative that further researchis increased further especially directed towards the use ofmiRNA-targeted therapy A recent literature study revealedthat out of 11000 articles on miRNA [112] and cancer onlyabout 500 articles werewritten directly or indirectly related tocancer therapy viamiRNAmodulation It is an attractive field


in the research of oncology especially when one considers thefailure in current use of xenobiotics and radiation Combinedwith cancer stem cell understanding miRNA offers a newway of how to control remission and metastasis in tumourswith a better prognosis

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

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[6] L Moreno L V Marshall and A D J Pearson ldquoAt thefrontier of progress for paediatric oncology the neuroblastomaparadigmrdquo British Medical Bulletin vol 108 no 1 pp 173ndash1882013

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[8] J M Maris ldquoRecent advances in neuroblastomardquo The NewEngland Journal of Medicine vol 362 no 23 pp 2202ndash22112010

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[65] P Borst ldquoCancer drug pan-resistance pumps cancer stem cellsquiescence epithelial to mesenchymal transition blocked celldeath pathways persisters or whatrdquo Open Biology vol 2 no 5Article ID 120066 2012

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[68] Z Yu T G Pestell M P Lisanti and R G Pestell ldquoCancer stemcellsrdquo International Journal of Biochemistry and Cell Biology vol44 no 12 pp 2144ndash2151 2012

[69] I Ischenko H Seeliger M Schaffer K-W Jauch and C JBruns ldquoCancer stem cells how can we target themrdquo CurrentMedicinal Chemistry vol 15 no 30 pp 3171ndash3184 2008

[70] S Chiba ldquoNotch signaling in stem cell systemsrdquo Stem Cells vol24 no 11 pp 2437ndash2447 2006


[71] H J Kraft S Mosselman H A Smits et al ldquoOct-4 regu-lates alternative platelet-derived growth factor 120572 receptor genepromoter in human embryonal carcinoma cellsrdquo Journal ofBiological Chemistry vol 271 no 22 pp 12873ndash12878 1996

[72] L Gao Y Yang H Xu et al ldquoMiR-335 functions as a tumorsuppressor in pancreatic cancer by targeting OCT4rdquo TumourBiology vol 35 no 8 pp 8309ndash8318 2014

[73] P A Beachy S S Karhadkar and D M Berman ldquoTissue repairand stem cell renewal in carcinogenesisrdquo Nature vol 432 no7015 pp 324ndash331 2004

[74] L Li andW BNeaves ldquoNormal stem cells and cancer stem cellsthe niche mattersrdquo Cancer Research vol 66 no 9 pp 4553ndash4557 2006

[75] P NeveuM J Kye S Qi et al ldquoMicroRNAprofiling reveals twodistinct p53-related human pluripotent stem cell statesrdquo CellStem Cell vol 7 no 6 pp 671ndash681 2010

[76] M M Sherry A Reeves J K Wu and B H Cochran ldquoSTAT3is required for proliferation and maintenance of multipotencyin glioblastoma stem cellsrdquo Stem Cells vol 27 no 10 pp 2383ndash2392 2009

[77] D M Hsu S Agarwal A Benham et al ldquoG-CSF recep-tor positive neuroblastoma subpopulations are enriched inchemotherapy-resistant or relapsed tumors and are highlytumorigenicrdquo Cancer Research vol 73 no 13 pp 4134ndash41462013

[78] MMGottesman T Fojo and S E Bates ldquoMultidrug resistancein cancer role of ATP-dependent transportersrdquoNature ReviewsCancer vol 2 no 1 pp 48ndash58 2002

[79] T Zheng J Wang X Chen and L Liu ldquoRole of microRNA inanticancer drug resistancerdquo International Journal of Cancer vol126 no 1 pp 2ndash10 2010

[80] Y-Z Pan M E Morris and A-M Yu ldquoMicroRNA-328negatively regulates the expression of breast cancer resistanceprotein (BCRPABCG2) in human cancer cellsrdquo MolecularPharmacology vol 75 no 6 pp 1374ndash1379 2009

[81] H Zhu H Wu X Liu et al ldquoRole of MicroRNA miR-27a andmiR-451 in the regulation of MDR1P-glycoprotein expressionin human cancer cellsrdquo Biochemical Pharmacology vol 76 no5 pp 582ndash588 2008

[82] O Kovalchuk J Filkowski J Meservy et al ldquoInvolvementof microRNA-451 in resistance of the MCF-7 breast cancercells to chemotherapeutic drug doxorubicinrdquoMolecular CancerTherapeutics vol 7 no 7 pp 2152ndash2159 2008

[83] M Dean T Fojo and S Bates ldquoTumour stem cells and drugresistancerdquo Nature Reviews Cancer vol 5 no 4 pp 275ndash2842005

[84] A Gisel M Valvano I G El Idrissi et al ldquoMiRNAs for thedetection of multidrug resistance overview and perspectivesrdquoMolecules vol 19 no 5 pp 5611ndash5623 2014

[85] Y Shi J Wang Z Xin et al ldquoTranscription factors andmicroRNA-co-regulated genes in gastric cancer invasion in exvivordquo PLoS ONE vol 10 no 4 Article ID e0122882 2015

[86] G A Calin C Sevignani C D Dumitru et al ldquoHumanmicroRNA genes are frequently located at fragile sites andgenomic regions involved in cancersrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 101 no 9 pp 2999ndash3004 2004

[87] L Fontana M E Fiori S Albini et al ldquoAntagomir-17-5p abol-ishes the growth of therapy-resistant neuroblastoma throughp21 and BIMrdquo PLoS ONE vol 3 no 5 Article ID e2236 2008

[88] H Mei Z-Y Lin and Q-S Tong ldquoThe roles of microRNAs inneuroblastomardquo World Journal of Pediatrics vol 10 no 1 pp10ndash16 2014

[89] J Loven N Zinin T Wahlstrom et al ldquoMYCN-regulatedmicroRNAs repress estrogen receptor-alpha (ESR1) expressionand neuronal differentiation in human neuroblastomardquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 107 no 4 pp 1553ndash1558 2010

[90] R L Stallings ldquoMicroRNA involvement in the pathogenesisof neuroblastoma potential for microRNAmediated therapeu-ticsrdquoCurrent Pharmaceutical Design vol 15 no 4 pp 456ndash4622009

[91] P Mestdagh A-K Bostrom F Impens et al ldquoThe miR-17-92microRNA cluster regulates multiple components of the TGF-120573 pathway in neuroblastomardquoMolecular Cell vol 40 no 5 pp762ndash773 2010

[92] Y Chen Y-H Tsai Y Fang and S-H Tseng ldquoMicro-RNA-21regulates the sensitivity to cisplatin in human neuroblastomacellsrdquo Journal of Pediatric Surgery vol 47 no 10 pp 1797ndash18052012

[93] M Guidi M Muinos-Gimeno B Kagerbauer E Martı XEstivill and Y Espinosa-Parrilla ldquoOverexpression of miR-128specifically inhibits the truncated isoformofNTRK3 and upreg-ulates BCL2 in SH-SY5Y neuroblastoma cellsrdquo BMC MolecularBiology vol 11 article 95 2010

[94] A Swarbrick S LWoods A Shaw et al ldquoMiR-380-5p repressesp53 to control cellular survival and is associated with poor out-come in MYCN-amplified neuroblastomardquo Nature Medicinevol 16 no 10 pp 1134ndash1140 2010

[95] H Qu L Zheng J Pu et al ldquomiRNA-558 promotes tumori-genesis and aggressiveness of neuroblastoma cells throughactivating the transcription of heparanaserdquo Human MolecularGenetics vol 24 no 9 pp 2539ndash2551 2015

[96] L Samaraweera K B Grandinetti R Huang B A Spenglerand R A Ross ldquoMicroRNAs define distinct human neurob-lastoma cell phenotypes and regulate their differentiation andtumorigenicityrdquo BMC Cancer vol 14 article 309 2014

[97] A M Lozier M E Rich A P Grawe et al ldquoTargetingornithine decarboxylase reverses the LIN28Let-7 axis andinhibits glycolytic metabolism in neuroblastomardquo Oncotargetvol 6 no 1 pp 196ndash206 2015

[98] H ZhangMQi S Li et al ldquoMicroRNA-9 targetsmatrixmetal-loproteinase 14 to inhibit invasion metastasis and angiogenesisof neuroblastoma cellsrdquo Molecular Cancer Therapeutics vol 11no 7 pp 1454ndash1466 2012

[99] W C S Cho ldquoOncomiRs the discovery and progress ofmicroRNAs in cancersrdquo Molecular Cancer vol 6 article 602007

[100] A Bottoni D Piccin F Tagliati A Luchin M C Zatelli andE C D Uberti ldquomiR-15a and miR-16-1 down-regulation inpituitary adenomasrdquo Journal of Cellular Physiology vol 204 no1 pp 280ndash285 2005

[101] S Moncini A Salvi P Zuccotti et al ldquoThe role of miR-103 andmiR-107 in regulation of CDK5R1 expression and in cellularmigrationrdquo PLoS ONE vol 6 no 5 Article ID e20038 2011

[102] P Zuccotti C Colombrita SMoncini et al ldquoHnRNPA2B1 andnELAV proteins bind to a specific U-rich element in CDK5R131015840-UTR and oppositely regulate its expressionrdquo Biochimica etBiophysica ActamdashGene Regulatory Mechanisms vol 1839 no 6pp 506ndash516 2014

[103] L-C Cheng E Pastrana M Tavazoie and F Doetsch ldquoMiR-124 regulates adult neurogenesis in the subventricular zone stem


cell nicherdquo Nature Neuroscience vol 12 no 4 pp 399ndash4082009

[104] X Cao S L Pfaff and F H Gage ldquoA functional study of miR-124 in the developing neural tuberdquo Genes amp Development vol21 no 5 pp 531ndash536 2007

[105] I Y Cheung T A Farazi I Ostrovnaya et al ldquoDeepMicroRNAsequencing reveals downregulation of miR-29a in neuroblas-toma central nervous system metastasisrdquo Genes Chromosomesand Cancer vol 53 no 10 pp 803ndash814 2014

[106] S Das N Foley K Bryan et al ldquoMicroRNAmediates DNA de-methylation events triggered by retinoic acid during neuroblas-toma cell differentiationrdquo Cancer Research vol 70 no 20 pp7874ndash7881 2010

[107] P Laneve L Di Marcotullio U Gioia et al ldquoThe inter-play between microRNAs and the neurotrophin receptortropomyosin-related kinase C controls proliferation of humanneuroblastoma cellsrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 104 no 19 pp 7957ndash7962 2007

[108] J Ryan A Tivnan J Fay et al ldquoMicroRNA-204 increasessensitivity of neuroblastoma cells to cisplatin and is associatedwith a favourable clinical outcomerdquo British Journal of Cancervol 107 no 6 pp 967ndash976 2012

[109] J Qiao S Lee P Paul et al ldquoMiR-335 andmiR-363 regulation ofneuroblastoma tumorigenesis andmetastasisrdquo Surgery vol 154no 2 pp 226ndash233 2013

[110] P E Blower J-H Chung J S Verducci et al ldquoMicroRNAsmodulate the chemosensitivity of tumor cellsrdquo Molecular Can-cer Therapeutics vol 7 no 1 pp 1ndash9 2008

[111] J Wang J Chen P Chang et al ldquoMicroRNAs in plasma ofpancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of diseaserdquo Cancer Prevention Research vol2 no 9 pp 807ndash813 2009

[112] F H Sarkar EdMicroRNA Targeted CancerTherapy SpringerNew York NY USA 2014

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


cells [13] Similar to other cancers NB manifests itself ingenetic alteration [14] of genes responsible for cell growthcycle and immunity including phenotypic changes thatinhibit differentiation Research conducted over a numberof years reveals that the transcription factor MYCN [15] isthe most important oncogene [1] MYCN acts mainly bydysregulating downstream genes involved in key pathwaysthat affect NB formation with putative effects by KIFAP3OPHN RGS7 ODC1 TOP2A TWIST1 and TYMS on thesame gene [16] Moreover a recent study revealed thatalthough the MYCN gene expression was not amplified ahigh level of MYC proteins was present in NB patient group[17] Additionally transgenic animal model studies indicatedthat tumourigenesis does not require gene amplification [18]Conversely in the presence of abnormal MYCN expressionduring the formation of the neural crest the precursorcells transform into tumourigenic neuroblasts due to theupregulated MYCN protein level [19] This pathway wasconfirmed with the LIN28b gene A genomic aberration inthis gene results in repression of a set of microRNAs of thelet-7 familyThe let-7miRNAs function as tumor suppressorsthrough the silencing of oncogenes such as RAS MYC andCDK6 The outcome from this suppression was an elevatedMYCN protein expression that was elucidated in mousemodels An interesting fact is that LIN28b is a homologue ofLIN28 one of the regulators for pluripotency in stem cells incombination with NANOG OCT34 and SOX2 [20]

The physiological effect of theMYCN gene is highly influ-ential Intriguingly it has the ability to activate angiogenicfactors [21] leading to the formation of novel blood vesselsto ensure an adequate supply of nutrients hence repressingangiogenic inhibitors

Following the existence of miRNA technology researchwas focused on the relationship between MYCN [22] andmiRNAs Recent studies [23] highlighted that the generegulates a number of miRNAs A selection of these activatedmiRNAs is associated with clinically aggressive cancer condi-tions that include themiR-17-92 cluster miR-18amiR-7miR-128 miR-380-5p and miR-558

3 Clinical Outcomes

Current treatments inNB are varied due to the heterogeneousnature of the disease The outcome of the treatment dependson a multitude of factors including age of patient histologygenetic abnormalities [24] and stage of disease NB is a highrisk disease with almost 20of children experiencing relapse[25] Poor prognosis of the disease leads to inadequate ther-apy undetected residual tumour and inefficient modalitiesof treatment this leads to the need to standardize criteriafor evaluation of the disease Consequently a stage and riskclassification was developed for clinical presentations of NB[26] A panel of experts the International NB Staging System(INSS) bases its categorization on the stage of the diseaseand subsequent removal by surgery [27] If the disease doesnot need surgery another panel (the International NB RiskGroup Staging System INRGSS) bases its categorizationon clinical pretreatment [28] Data collected from imagingincluding CT scans and MRI give an evaluation of the

disease In addition to the acquired imaging data bonemarrow biopsy and status of theMYCN gene are also utilizedfor NB risk classification Through the application of thesecriteria new improved therapies with high survivabilitypercentage could be achieved

4 MiRNAs and Cancer

Since their discovery in 1993 in Caenorhabditis elegans[29] novel miRNA sequences have been identified in bothplants and animals with the database cataloging all miRNAsequences still increasing in number [30] Such miRNAs aredefined as single strands of not more than 25 nucleotides thatare generated from genes located on the chromosome [30]The generation of these miRNAs follows a four-step processinvolving the following [31] (i) cropping this involves theheterodimer Drosha cleaving the mature pri-miRNA into asmaller size called the pre-miRNA (ii) exportation this pre-miRNA is exported from the nucleus by combining withExportin-5 and Ran-GTP (iii) dicing once in the cytoplasmthey are cleaved into a smaller strand by RNase III enzymeknown as the dicer releasing the two small complementaryshort strands (iv) formation of the RNA Interference Silenc-ing Complex (RISC) complex a ribonucleoprotein complexforming part of the argonaute family one strand (the guide)forms a complex with ribonucleoprotein while the otherstrand (the passenger) is destroyed The complex then bindsto the mRNA leading to translational repression

Since their discovery the premise was established thatthere is a connection between miRNA activity and cancer[32] The tumorigenic effect of miRNAs is typically inducedby the dysregulation in miRNA expression through multiplemechanisms that include translocation deletion mutationsand rearrangements [32] High-throughput screening studiesand functional genomics research revealed the significantvariations in miRNA expression profiles of normal cellsin comparison with the cancer inflicted counterpart cells[30] This striking evidence led to the concept of themiRnome which is the characteristic malignant form Itwas also elucidated that most cancer conditions demonstratean overall downregulation in over 50 of the miRnomersquosindividual miRNAs though a few key tumourigenic miRNAswere found to be upregulated [33] A feature of miRNAsis their tissue specificity Apparently miRNA expression ismodulated according to the cancer cell population whichis different from that of a normal cell population [30] (seeTable 1) To be tumorigenicmiRNAsmust induce productionof growth factors (eg let-7) [34] be unresponsive to externalantigrowth factors (eg miR-1719) [35] and avoid cellapoptosis (eg miR-34a) [30] indefinite proliferation (egmiR-372373) [36] blood vessels formation also known asangiogenesis (eg miR-210) [37] metastasis and migrationwith an increase in tumor macrophages and inflammation(eg miR-10b) [38 39]

There are already 4469 miRNAs discovered ofwhich 1881 are precursors and 2588 are mature (httpwwwmirbaseorg) and the list is increasing To a largeextent some of the miRNAs involved in specific types ofcancer progression have been identified [32 33]



Cancer type miRNA





Stomachcancer
















6 miRNAs and NB






ESR1[22 89ndash91]






7 Conclusion






References



























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Cancer type miRNA





Stomachcancer
















6 miRNAs and NB






ESR1[22 89ndash91]






7 Conclusion






References



























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















6 miRNAs and NB






ESR1[22 89ndash91]






7 Conclusion






References



























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















References



























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of









































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















chemoresistance, cancer stem cells, and mirna influences: the

Documents