Báo cáo khoa học: A study of microRNAs in silico and in vivo: diagnostic and therapeutic applications in cancer pot

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MINIREVIEWA study of microRNAs in silico and in vivo: diagnostic andtherapeutic applications in cancerScott A. Waldman1and Andre Terzic21 Departments of Pharmacology and Experimental Therapeutics and Medicine, Thomas Jefferson University, Philadelphia, PA, USA2 Departments of Medicine, Molecular Pharmacology & Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester,MN, USACancer is a leading cause of mortality in the USA,with  25% of deaths attributable to neoplasia [1,2].Worldwide, cancer-related global mortality followsonly cardiovascular and infectious diseases [3]. In thiscontext of expanded incidence and growing prevalence,clinical oncology is poised for unprecedented innova-tion. Through harnessing discoveries in disease patho-biology, increasingly propelled by the development ofhigh-throughput technologies including genomics, pro-teomics and metabolomics, modern cancer biologyoffers previously unavailable diagnostic and thera-peutic paradigms tailored to meet the needs of indi-viduals and populations [4]. Transforming clinicalmanagement is predicated on translation of the newscience into application of advanced markers and tar-gets for personalized cancer prediction, prevention,diagnosis and treatment [4–6].Indeed, the epigenetic, genetic and postgenetic cir-cuits restricting cell destiny are becoming increasinglydecoded, and their dysfunction is being linked to line-age-dependence underlying tumorigenesis [2,7]. Criticalin cell-fate specification is the post-transcriptional reg-ulation of gene expression by microRNAs (miRNAs)(Fig. 1) [8], which arise as transcripts from cognategenes in noncoding regions of chromosomes. miRNAsundergo nuclear and cytoplasmic processing [8,9], pro-ducing the targeting core of a multimeric complex byhybridizing with mRNA molecules resulting in theirsequestration or degradation, thereby defining thegenes available for lineage commitment [10,11]. This isthe most recent addition to the hierarchical spectrumof molecular mechanisms defining nuclear–cytoplasmicinformation exchange [12] and forms the interfaceamong transcriptional, translational and post-transla-tional regulation [13] . Significantly, miRNAs representa regulatory, rather than a structural, mechanism thatco-ordinates normal gene expression and whose dysre-gulation underlies neoplastic transformation [8,10,11].Keywordsbiomarkers; cancer; diagnosis; individualizedtherapy; microRNA; prediction; prognosisCorrespondenceS. A. Waldman, 132 South 10th Street,1170 Main, Philadelphia, PA 19107, USAFax: +1 215 955 5681Tel: +1 215 955 6086E-mail: scott.waldman@jefferson.edu(Received 28 August 2008, revised 7December 2008, accepted 9 January 2009)doi:10.1111/j.1742-4658.2009.06934.xThere is emerging evidence of the production in human tumors of abnormallevels of microRNAs (miRNAs), which have been assigned oncogenicand ⁄ or tumor-suppressor functions. While some miRNAs commonly exhibitaltered amounts across tumors, more often, different tumor types produceunique patterns of miRNAs, related to their tissue of origin. The role ofmiRNAs in tumorigenesis underscores their value as mechanism-basedtherapeutic targets in cancer. Similarly, unique patterns of altered levels ofmiRNA production provide fingerprints that may serve as molecularbiomarkers for tumor diagnosis, classification, prognosis of disease-specific outcomes and prediction of therapeutic responses.AbbreviationsCLL, chronic lymphocytic leukemia; miRNA, microRNA; PTEN, phosphatase and tensin homolog.FEBS Journal 276 (2009) 2157–2164 ª 2009 The Authors Journal compilation ª 2009 FEBS 2157miRNAs and cancerThe essential nature of this novel mechanism indeliblypatterning gene expression in cell-lineage specification[8], in the context of the established model of cancer asa genetic disease in which pathobiology recapitulatescell and tissue ontogeny [14,15], naturally implicatesmiRNAs in neoplastic transformation. In fact, analtered level of miRNA production is a defining traitof tumorigenesis [16,17]. While the production of somemiRNAs is universally altered in tumors, more oftenunique patterns of miRNA production reflect the line-age-dependence of tumors, relating to their tissues oforigin [16–22]. Similarly, fundamental processes under-lying tumorigenesis, including genomic instability, epi-genetic dysregulation and alterations in the expression,or function, of regulatory proteins, directly alter thecomplement of miRNAs produced by cancer cells [8].Additionally, miRNAs regulate key components inte-gral to tumor initiation and progression, includingtumor suppressors and oncogenes [8,17,23]. Further-more, miRNA signatures are a more informativesource for classification of tumor taxonomy than geno-mic profiling [16]. Moreover, miRNAs can serve asunique targets for diagnostic imaging in vivo for taxo-nomic classification of tumors [24]. The emerging roleof miRNAs in neoplasia highlights their potential valueas mechanism-based therapeutic targets and biomarkersfor diagnosis, prognosis of disease-specific outcomesand prediction of therapeutic responses [25]. Whilethere are numerous detailed reviews in this field, thepurpose of this minireview was to provide, in overview,a summary of the potential application of miRNAs asdiagnostic and therapeutic targets in cancer.miRNAs as mechanism-basedtherapeutic targets in cancerThe case for miRNAs as tumor suppressors and onc-ogenes reflects their loss or gain, respectively, as afunction of neoplastic transformation, their dysregula-tion in different tumors, the relevance of their mRNAtargets to mechanisms underlying tumorigenesis andtheir ability to alter tumorigenesis directly in modelcells and organisms (Fig. 2; Table 1) [8,26,27]. Typi-cally, miRNAs that serve as oncogenes are present athigh levels, which inhibit the transcription of genesencoding tumor suppressors. Conversely, tumor-suppressor miRNAs are present at low levels, resultingin the overexpression of transcripts encoded by onco-genes.miRNA tumor suppressorsThe best characterized tumor-suppressor miRNAs aremiR-15a and miR-16-1. B-cell chronic lymphocyticleukemia (CLL) is the most common adult leukemia indeveloped countries and is universally associated withthe loss of chromosomal region 13q14 [8,27,28]. WithinProtein-coding genemRNA degradaƟon TranslaƟonal repressionTranscripƟonof mRNATranscripƟon of pri-microRNANucleusExporƟn 5DicerLoqs/TRBPRan-GTPPri-microRNADroshaDGCRSOrProcessingof pri-microRNAsinto pre-microRNAProcessing ofpre-microRNA intosmall RNA duplexesDelivery ofRISC-microRNAcomplexRISCAnTransport ofpre-microRNA intothe cytoplasmCytoplasmPre-microRNAMicroRNA geneFig. 1. miRNA generation and gene regulation [9]. Mature miRNAsof about 22 nucleotides originate from primary miRNA (pri-miRNA)transcripts. Nuclear pri-miRNAs of hundreds to thousands of basepairs are converted into stem–loop precursors (pre-miRNA), ofabout 70 nucleotides, by Drosha, an RNase III endonuclease, andby Pasha, a homologue of the human DiGeorge syndrome criticalregion gene 8 (DGCR8). Precursor miRNAs (pre-miRNAs) undergocytoplasmic translocation, which is mediated by exportin 5 in con-junction with Ran-GTP, and are subsequently processed into RNAduplexes of about 22 nucleotides by Dicer, an RNase III enzyme,and Loqacious (Loqs), a double-stranded RNA-binding-domainprotein that is a homologue of the HIV transactivating responseRNA-binding protein (TRBP). The functional strand of the miRNAduplex guides the RNA-induced silencing complex (RISC) to themRNA target for translational repression or degradation. Figurereproduced from a previous publication [9].Applications in cancer for microRNAs S. A. Waldman and A. Terzic2158 FEBS Journal 276 (2009) 2157–2164 ª 2009 The Authors Journal compilation ª 2009 FEBSthis deletion is a region of  30 kb in which miR-15aand miR-16-1 reside, which are lost in  70% ofpatients with CLL [29]. Similarly, the loss of chromo-somal region 13q14, including miR-15a and miR-16-1,occurs in prostate cancer, mantle cell lymphoma andmultiple myeloma [29,30]. Tumor suppression by miR-15a and miR-16-1, in part, reflects inhibition of theexpression of the anti-apoptotic oncogenic protein Bcl-2,which is characteristically overexpressed in CLL,promoting the survival of leukemia cells [31]. Indeed,there is a reciprocal relationship between the expres-sion of miR-15a and miR-16-1 and of Bcl-2, and theheterologous production of these miRNAs suppressesBcl-2 levels [32]. Suppression is specifically mediatedby complementary binding sites for those miRNAs inthe 3¢-UTR of the Bcl-2 transcript [32]. Furthermore,heterologous expression of miR-15a and miR-16-1 pro-duces apoptosis in leukemia cell lines [32]. Moreover,mouse models of spontaneous CLL possess a mutationin the 3¢-UTR of miR-16-1 that is identical to muta-tions in patients with CLL and associated withdecreased production of that miRNA [33]. Heterolo-gous expression of miR-16-1 in CLL cells derived fromthose mice alters the cell cycle, proliferation and apop-tosis of these tumor cells [33].The miRNA, let-7, a phylogenetically conservedgene product that regulates the transition of cells fromproliferation to differentiation in invertebrates [34],ABCFig. 2. miRNA oncogenes and tumor suppressors [26]. (A) Normally, miRNA binding to target mRNA represses gene expression by blockingprotein translation or inducing mRNA degradation, contributing to homeostasis of growth, proliferation, differentiation and apoptosis.(B) Reduced miRNA levels, reflecting defects at any stage of miRNA biogenesis (indicated by question marks), produce inappropriate expres-sion of target oncoproteins (purple squares). The resulting defects in homeostasis increase proliferation, invasiveness or angiogenesis, ordecrease the levels of apoptosis or differentiation, potentiating tumor formation. (C) Conversely, overexpression of an oncogenic miRNAeliminates the expression of tumor-suppressor genes (pink), leading to cancer progression. Increased levels of mature miRNA could reflectamplification of the miRNA gene, a constitutively active promoter, increased efficiency in miRNA processing or increased stability of themiRNA (indicated by question marks). ORF, open reading frame. Figure reproduced from a previous publication [26].S. A. Waldman and A. Terzic Applications in cancer for microRNAsFEBS Journal 276 (2009) 2157–2164 ª 2009 The Authors Journal compilation ª 2009 FEBS 2159also serves as a tumor suppressor [27]. There are 12let-7 homologs in humans, forming eight distinct clus-ters of which four are localized to chromosomalregions lost in many malignancies [35]. In that context,the down-regulation of let-7 family members in lungcancer is associated with poor prognosis [22]. A rolefor these miRNAs in growth regulation and in theexpression of the tumorigenic phenotype is highlightedby the ability of heterologous let-7 expression in lungcancer cells in vitro to inhibit colony formation [36].Key downstream targets for let-7 include the humanRas family of proteins, oncogenes that are commonlymutated in many human tumors [23]. Indeed, KRasand NRas expression in human cells is regulated bylet-7 family members [27]. Moreover, loss of let-7expression in human tumors correlates with the over-expression of Ras proteins [23].miRNA oncogenesThe miR-17 cluster comprises a group of six miRNAs(miR-17-5p, miR-18a, miR-19a, miR-20a, miR-19b-1and miR-92) at 13q31–32, a chromosomal regionamplified in large B-cell lymphoma, follicular lym-phoma, mantle cell lymphoma and primary cutaneousB-cell lymphoma [37]. Consistent with their functionsas oncogenes, overexpression of this miRNA cluster isassociated with amplification of the 13q31–32 genomicregion in lymphoma cells in vitro [37,38]. These miR-NAs are overexpressed in many types of tumors,including lymphoma, colon, lung, breast, pancreas andprostate [17,38,39]. Interestingly, expression of themiR-17 cluster is induced by c-Myc, an oncogene over-expressed in many tumors. Heterologous expression ofc-Myc up-regulates expression of the miR-17 cluster,mediated by direct binding of that transcription factorto the chromosomal region harboring those miRNAs[40]. In turn, the miR-17 cluster appears to regulateseveral downstream oncogene targets. Thus, miR-19aand miR-19b may regulate phosphatase and tensinhomolog (PTEN), a tumor suppressor with a broadmechanistic role in human tumorigenesis, throughinteractions with complementary sites in the 3¢-UTRof this transcript [41]. Similarly, miR-20a may reducethe expression of transforming growth factor-b recep-tor II, a tumor suppressor frequently mutated in can-cer cells and which regulates the cell cycle, imposinggrowth inhibition [17]. The best-characterized target ofthe miR-17 cluster is the E2F1 transcription factorwhose expression is regulated by miR-17–5p and miR-20a [42]. In turn, E2F1 regulates cell cycle progressionby inducing genes mediating DNA replication and cellcycle control [43]. Beyond the regulation of key targetscontributing to transformation, the miR-17 clusterdirectly induces the tumorigenic phenotype. Hetero-logous expression of the miR-17 cluster increased pro-liferation in lung cancer cells in vitro [39]. Moreover,components of this cluster accelerate the process oflymphomagenesis in mice [44].The miRNA miR-21 is overexpressed in many solidtumors, including breast, colon, lung, prostate andstomach, and in endocrine pancreas tumors, glioblasto-mas and uterine leiomyomas [17,45–47]. This miRNAis encoded at chromosome 17q23.2, a genetic locusthat is frequently amplified in many tumors. Thetumorigenic effects of miR-21 are mediated, in part, bytargeting a number of mediators in critical cell-survivalpathways. Thus, in glioblastoma cells in vitro, miR-21modulates the expression of the common tumor sup-pressor PTEN, a central regulator of cell growth, pro-liferation and survival, which is mediated by thephosphatidylinositol3-kinase ⁄ Akt pathway [48]. Also,miR-21 regulates breast cancer cell growth by recipro-cally regulating apoptosis and proliferation, in partreflecting regulation of the anti-apoptotic protein,Bcl-2 [49]. Moreover, miR-21 controls expression ofthe tumor suppressor tropomyosin 1, whose over-expression in breast cancer cells suppresses anchorage-Table 1. miRNAs in tumorigenesis. CLL, chronic lymphocytic leukemia; B-CLL, B cell CLL.miRNA Gene locus Tumor types Gene targets ReferencesSuppressorsmir-15a, 16-1 13q14 CLL, prostate, mantle cell lymphoma, multiple myeloma BCL-2 [28–32]let-7 Eight clusters Lung, gastric RAS [22,23,26,34,35]Oncogenesmir-17 cluster 13q31-32 B-CLL, follicular lymphoma, mantle cell lymphoma,cutaneous B cell lymphoma, colon, lung, breast,pancreas, prostatePTENTGF-b RIIE2F1[17,36–38,40–43]mir-21 17q23.2 Breast, colon, lung, prostate, gastric, endocrine pancreas,glioblastomas, leiomyomasPTENBCL-2Tropomyosin I[17,44–50,54]Applications in cancer for microRNAs S. A. Waldman and A. Terzic2160 FEBS Journal 276 (2009) 2157–2164 ª 2009 The Authors Journal compilation ª 2009 FEBSindependent growth [50]. Beyond signaling analyses,elimination of miR-21 expression in glioblastoma cellsinduces caspase-dependent apoptosis, underscoring theimportance of this miRNA in mediating the survivalphenotype [51]. Similarly, antisense oligonucleotidesto miR-21 suppress the growth of breast cancer cellsin vitro and in xenografts in mice [48].miRNAs as biomarkers in cancerTheir fundamental role in development and differentia-tion, and their pervasive corruption in lineage-dependent mechanisms underlying tumorigenesis,suggest that miRNAs may be a particularly rich sourceof diagnostic, prognostic and predictive informationas biomarkers in cancer [8,26,52]. Differential produc-tion of miRNAs compared with their normal adja-cent tissue counterparts is a characteristic of everytype of tumor examined to date [8,52], a feature thatcould be particularly useful in diagnosing incidentcancers in otherwise normal tissues. Indeed, thisapproach discriminates normal and neoplastic tissuesin various cancer types, including CLL, breast cancer,glioblastoma, thyroid papillary carcinoma, hepatocel-lular carcinoma, lung cancer, colon cancer and endo-crine pancreatic tumors [8,17–22,26,45,52–54].Similarly, miRNA expression profiles provide a pow-erful source of molecular taxonomic information,with an accuracy for classifying tumors according totheir developmental lineage and differentiation statethat surpasses mRNA expression profiling [16,17].These observations suggest the utility of miRNAexpression profiling for identifying metastatic tumorsof unknown origin, which represent  5% of allmalignancies worldwide [16,17,52]. Also, differentialmiRNA expression patterns are associated with dis-ease prognosis [8,52]. Specific patterns of miRNAexpression identified patients with pancreatic cancerwho survived for longer than 24 months, comparedwith those who survived for less than 24 months [53].In addition, the expression of specific miRNAs pre-dicted overall poor survival in patients with pancre-atic cancer [53]. Similarly, overexpression of specificmiRNAs was an independent prognostic variableassociated with advanced disease stage and decreasedsurvival in patients with colon cancer [54]. Beyonddiagnosis and prognosis, miRNA expression patternspredict responses to therapy, and overexpression ofoncogenic miRNAs was associated with improvedsurvival following adjuvant chemotherapy in patientswith colon cancer [54]. These observations highlightthe potential of miRNAs as biomarkers for diagnosis,taxonomic classification, prognosis, risk stratificationand prediction of therapeutic responses in patientswith cancer.Corruption of miRNA expression incancerThe genetic basis of cancer, in part, reflects chromo-somal re-arrangements encompassing translocations,deletions, amplifications and exogenous episomal inte-grations that alter gene expression. The essential roleof miRNAs in tumorigenesis predicts coincidencebetween the location of their encoding genes and thosecancer-associated chromosomal regions. Indeed, morethan half of the miRNA genes are located in cancer-associated genomic regions in a wide array of tumors,including lung, breast, ovarian, colon, gastric, liver,leukemia and lymphoma [28,35]. Conversely, chromo-somal regions harboring miRNAs are sites of frequentgenomic alterations involved in cancer [28,55]. Addi-tionally, the impact of chromosomal remodeling ongene copy number directly translates to altered miR-NA expression [19,28,55]. Beyond structural re-organi-zation, epigenetic remodeling of chromosomal regionsharboring miRNA loci contributes to transformation,and tumor-suppressing miRNAs silenced by CpGisland hypermethylation result in the dysregulation ofessential proteins responsible for accelerating the cellcycle, including cyclin D and retinoblastoma [56,57].Moreover, alterations in the machinery responsible forprocessing miRNA contributes to tumorigenesis, andimpairment of Dicer enhances lung tumor developmentin experimental mouse models and is associated withpoor prognosis in patients with lung cancer [58–60].Therapeutic targeting of miRNAsThe causal role of miRNAs in molecular mechanismsunderlying transformation, and the contribution ofspecific miRNA species to lineage-dependent tumori-genesis, suggest that these molecules could serve astherapeutic targets in the prevention and treatment ofcancer [61]. In the context of established therapeuticparadigms in medical oncology, individualized therapywith miRNAs could re-establish the expression ofsilenced miRNA tumor suppressors, whereas antisenseoligonucleotides could silence overexpressed oncogenicmiRNAs [8,28,52,61]. Indeed, antisense oligonucleo-tides (with modified RNA backbone chemistry resis-tant to nuclease degradation) targeted to miRNAsequences irreversibly eliminate the overexpression ofoncogenic miRNAs [61]. Similarly, locked nucleic acidanalogs resist degradation and stabilize the miRNAtarget–antisense duplex required for silencing [62].S. A. Waldman and A. Terzic Applications in cancer for microRNAsFEBS Journal 276 (2009) 2157–2164 ª 2009 The Authors Journal compilation ª 2009 FEBS 2161Moreover, single-stranded RNA molecules (termedantagomirs), complementary to oncogenic miRNAs,silence miRNA expression in mouse models in vivo[63]. The specificity of targeting inherent in nucleic acidbase complementarity, coupled with their mechanisticrole in neoplastic transformation, make miRNAsattractive therapeutic targets for future translation.SummarymiRNAs represent one fundamental element of theintegrated regulation of gene expression underlyingnuclear–cytoplasmic communication. Disruption ofthese regulatory components in processes underlyingtumor initiation and promotion contributes to thegenetic basis of neoplasia. Beyond molecular mecha-nisms underlying pathophysiology that constitute ther-apeutic targets, unique patterns of miRNA expressioncharacterizing lineage-dependent tumorigenesis offerunique opportunities to develop biomarkers for diag-nostic, prognostic and predictive management ofcancer. These novel discoveries are positioned tolaunch a transformative continuum, linking innovationto patient management. Advancement of these novelparadigm-shifting concepts into patient application willproceed through development and regulatory approvalto establish the evidence basis for integration ofmiRNA-based diagnostics and therapeutics into clini-cal practice.AcknowledgementsThe authors are supported by grants from the NIH(SAW, AT), Targeted Diagnostic and Therapeutics,Inc. (SAW), and the Marriott Foundation (AT). SAWis the Samuel M. V. Hamilton Endowed Professorof Thomas Jefferson University. AT is the MarriottFamily Professor of Cardiovascular Research at theMayo Clinic. SAW is a paid consultant to Merck.References1 American Cancer Society (2006) Cancer Statistics 2006.American Cancer Society, Atlanta, GA.2 Dalton WS & Friend SH (2006) Cancer biomarkers –an invitation to the table. 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Transforming clinicalmanagement
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