review article micrornas as important players and...

Review ArticleMicroRNAs as Important Players and Biomarkers inOral Carcinogenesis

Anjie Min1 Chao Zhu12 Shuping Peng3 Saroj Rajthala45

Daniela Elena Costea456 and Dipak Sapkota457

1Department of Oral and Maxillofacial Surgery Xiangya Hospital Central South University Changsha China2School of Stomatology Central South University Changsha China3Cancer Research Institute Central South University Changsha China4The Gade Laboratory for Pathology Department of Clinical Medicine Faculty of Medicine and Dentistry University of Bergen5021 Bergen Norway5Centre for Cancer Biomarkers (CCBIO) Faculty of Medicine and Dentistry University of Bergen 5021 Bergen Norway6Department of Pathology Haukeland University Hospital 5021 Bergen Norway7Department of Oncology and Medical Physics Haukeland University Hospital 5021 Bergen Norway

Correspondence should be addressed to Dipak Sapkota dipaksapkotak1uibno

Received 6 February 2015 Revised 14 May 2015 Accepted 18 May 2015

Academic Editor David Pauza

Copyright copy 2015 Anjie Min et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Oral cancer represented mainly by oral squamous cell carcinoma (OSCC) is the eighth most common type of humancancer worldwide The number of new OSCC cases is increasing worldwide especially in the low-income countries and theprognosis remains poor in spite of recent advances in the diagnostic and therapeutic modalities MicroRNAs (miRNAs) 18ndash25nucleotides long noncoding RNA molecules have recently gained significant attention as potential regulators and biomarkers forcarcinogenesis Recent data show that several miRNAs are deregulated in OSCC and they have either a tumor suppressive or anoncogenic role in oral carcinogenesis This review summarizes current knowledge on the role of miRNAs as tumor promotors ortumor suppressors in OSCC development and discusses their potential value as diagnostic and prognostic markers in OSCC

1 Introduction

Head and neck squamous cell carcinoma (HNSCC) consistsof a heterogeneous group of malignancies arising from oralcavity nasal cavity paranasal sinuses pharynx larynx andsalivary glands Oral cancer represented mainly by oralsquamous cell carcinoma (OSCC) is the most commontype of HNSCC OSCC is the eighth most common cancerworldwide accounting for more than 300000 new cases and145000 deaths in 2012 [1] Usually OSCC detection dependson the clinical examination of oral cavity followed by a biopsyfor histological analysis However despite the easy accessfor visual examination OSCC is often detected at advancedstages leading to severely reduced patient survival In spite ofthe recent advances in diagnosis and treatment modalitiesless than 50 of OSCC patients survive for 5 years [2] Late

diagnosis regional lymph node metastasis and recurrencesare the major causes related to the poor prognosis andreduced survival for OSCC patients [3 4] Thus reliablemolecular markers that can (i) provide earlier and moreprecise OSCC diagnosis (ii) predict prognosis and (ii) assignpatients to the best-targeted treatment available are urgentlyneeded

For almost three to four decades changes in proteincoding tumor suppressor genes andor oncogenes have beenthought to be the main drivers of tumor development [56] However the recent discovery of thousands of genesthat transcribe noncoding RNAs (including miRNAs) makesit obvious that cancer biology is even more complex thaninitially expected Several layers of molecular regulators(eg mRNA miRNA and protein) are involved in thedevelopment and maintenance of cancerous phenotypes

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 186904 10 pageshttpdxdoiorg1011552015186904

2 BioMed Research International

RISC

miRNA gene

Transcription

NucleusDrosha

Exportin 5

Dicer

Cytoplasm

Unwinding

Translationalrepression

mRNAdegradation

Regulation of geneexpression

miRNAmiRNAlowast duplex

Activation of oncogenesandor suppression of

tumor suppressor genes

Invasive OSCCgrowth

uarrProliferation and survival

metastatic potential of oralkeratinocytes

darrapoptosis and uarrinvasion andor

Figure 1 Schematic illustration demonstrating biogenesis and function of miRNA miRNA genes are transcribed into primary miRNA (pri-miRNA) by RNA polymerase IIIThese miRNAs are further converted into second precursors (pre-miRNA) by Drosha and are exported intocytoplasm by Exportin 5 Additional processing by Dicer produces miRNAmiRNAlowast duplex Only one strand of miRNAmiRNAlowast duplex ispreferentially assembled into the RNA-induced silencing complex (RISC) RISC acts on target mRNA(s) and leads to either translationalrepression or mRNA cleavage Suppression of tumor suppressive genes andor activation of oncogenes by miRNA lead to excessive cellproliferation and survival increased antiapoptosis and enhanced invasive and metastatic potential of oral keratinocytes resulting intoinvasive cancerous growth

Among them miRNAs 18ndash25 nucleotides long noncod-ing RNA molecules [7ndash9] have recently gained significantattention as potential regulators and biomarkers for humancarcinogenesis At the molecular level miRNA binds to31015840-untranslated region (31015840-UTR) of target mRNA(s) andsuppresses its expression by either translational repression ormRNA cleavage [10] (Figure 1) A single miRNA can regulateexpression andor function of hundreds of targetmRNAs andproteins and regulates several biological processes (eg cellproliferation differentiationmigration apoptosis and signaltransduction) important for cancer development [8 11ndash13](Figure 1)

Many recent studies have shown deregulated expressionof miRNAs in OSCC and OSCC-derived cell-lines comparedto their normal counterparts indicating their potential role inoral cancer development Accordingly several miRNAs havebeen shown to function either as tumor suppressors or astumor promoters in OSCCs (reviewed in [14 15]) In additionto their key biological functions in OSCC tumorigenesisexpression levels of several of miRNAs have been shown tocorrelate with clinicopathological variables [16] and to have adiagnostic and prognostic value in OSCC [15 17] For thesereasons miRNA has been a hot topic in cancer research forthe last few years and several studies about miRNAs in OSCC

have been published recently as summarized in Table 1 Thecurrent review aims to highlight the oncogenic and tumorsuppressive roles of miRNAs in OSCC development anddiscusses their potential value as diagnostic and prognosticmarkers for OSCC management

2 Methods

Literature search was performed by using the PubMeddatabase Following key words were used for the litera-ture search ldquooral cancer and miRNArdquo ldquooral cancer andmicroRNArdquo ldquooral squamous cell carcinoma andmiRNArdquo andldquooral squamous cell carcinoma and microRNArdquo Exclusioncriteria were articles not related to OSCCHNSCC andormiRNA purely descriptive articles articles lacking clinicalpathological correlation andor articles for which full textswere not available in English Only clinically relevant articlespublished within April 2015 were included in this reviewAdditionally individual articles retrieved manually from thereference list of the relevant papers were also included

3 miRNAs as Oncogenes in OSCC

A number of miRNAs have been shown to be upregulatedin OSCC and to function as oncogenes A well-studied

BioMed Research International 3

Table 1 Summary of miRNAs and associated signal pathwaystarget genes in OSCCHNSCC

miRNA Updownregulation Target genesassociated pathways Ref

miR-21 Up

PDCD4 [23]TPMI [16]RECK [26]CLU [22]DKK2-Wnt120573-catenin [18]Smad7-TGF1205731 [27]HACD44-NanogStat3-PDCD4 IAPs [24]

miR-31 Up FIH-HIF-EVGF [28]

miR-31lowast Up FGF3 [29]RhoA [32]

miR-134 Up WWOX [36]miR-146a Up IRK1 TRAF6 and NUMB [33]miR-155 Up CDC73 [39]

miR-7 Up RECK [26]IGF1R-Akt [45]

miR-9 Down CXCR4-Wnt120573-catenin [50]miR-1720a Down ITG1205738 [60]miR-29a Down MMP2 [57]

miR-34 Down E2F3 survivin and VEGF [64]SIRT6 [89]

miR-99a Down IGF1R [46]miR-124 Down ITGB1 [58]miR-125b Down ICAM2 [65]

miR-138 DownFOSL1 [52]VIM ZEB2 EZH2 [53]RhoC and RoCK2 [54]

miR-140-5p Down ADAM10 ERBB4 PAX6 and LAMC1 [90]miR-145 Down c-Myc Cdk6 [67]

miR-181a Down K-ras [91]Twist1 [56]

miR-205 Down IL-24 caspase-3-7 [92]and Axin-2 [93]

miR-218 Down mTOR-Rictor-Akt [48]miR-320 Down HIF-1120572-NRP1-VEGF [41]

miR-357 Down CIP2A-MYC [61]AEG-1MTDH [62]

miR-419-5p Down GIT1 [59]EGFR-ERK12-MMP29

miR-483-3p mdash API5 BRIC5 and RAN [94]miR-196a Up MAMDC2 [95]miR-26ab Down TMEM184B [96]

miRNA the miR-21 has been shown to be overexpressedand to regulate several biological functions in OSCC [1618ndash20] Overexpression of miR-21 has also been observedin oral premalignant lesions (oral leukoplakia) comparedto normal oral mucosa indicating that alteration in miR-21 could be an earlier event in OSCC progression [21] Anumber of in vitro and in vivo experimental data have demon-strated an oncogenic role of miR-21 in OSCC by promoting

cell proliferation [22] invasion [18 23] antiapoptosis [16]and chemoresistance [24] These oncogenic functions wereshown to be regulated by miR-21-mediated downregulationof several established tumor suppressor molecules includ-ing PTEN [25] programmed cell death 4 (PDCD4) [23]tropomyosin [16] reversion-inducing cysteine-rich proteinwith kazal motifs (RECK) [26] and dickkopf 2 (DKK2) [18]In addition to the functional roles in OSCC cells a growing


body of evidence suggests that miR-21 might be importantin the regulation of carcinoma associated fibroblasts (CAFs)induction and their activity [20 27] miR-21 was shown tobe predominately localized in OSCC stroma and colocalizedwith 120572-smooth muscle actin positive CAFs Additionallyhigher stromal expression ofmiR-21 was associatedwith poorprognosis in OSCC [20]

miR-31 and its passenger strand miRNA (miR-31lowast) havebeen shown to be upregulated in oral leukoplakia (OLP) andOSCC and to have an oncogenic role in OSCC tumorigenesis[28ndash31] Liu et al demonstrated that ectopic expressionof miR-31 repressed its target factor-inhibiting hypoxia-inducible factor (FIH) expression to activate hypoxia-inducible factor (HIF) under normoxic conditions bothin vitro and in vivo Additionally miR-31-FIH-HIF-VEGFregulatory cascade was found to affect several biologicalprocesses such as cell proliferation migration and epithelial-mesenchymal transition (EMT) in OSCC cells [28] More-over miR-31 was shown to collaborate with human telom-erase reverse transcriptase (hTERT) to immortalize normaloral keratinocytes (NOKs) indicating that itmight contributeto early stage oral carcinogenesis [31] Similarly miR-31lowast reg-ulated apoptosis cell proliferationmigration and invasion inOSCC cells [29] These miR-31lowast regulated functional effectswere mediated by the regulation of fibroblast growth factor 3(FGF3) [29] and RhoA [32] expression levels

miR-146a has been demonstrated to be overexpressedin OSCC and to enhance OSCC tumorigenesis both in thein vitro and in vivo mouse xenograft model [33 34] Theoncogenic functions of miR-146a were found to be associatedwith concomitant downregulation of IL-1 receptor-associatedkinase 1 (IRAK1) TNF receptor-associated factor 6 (TRAF6)and NUMB [33] A previous study from the same groupsuggested an association between a higher OSCC miR-146a expression and nodal involvement in patients carryingC polymorphism (rs2910164) [34] However findings fromPalmieri et al indicated that the rs2910164 polymorphism isnot associated with OSCC progression [35] Further investi-gations are needed to clarify a possible role of the variant alleleor rs2910164 in OSCC progression

miR-134 expression was upregulated in HNSCC tissuespecimens and cells (HSC-3 OECM-1 and SAS cell-lines)compared to the corresponding normal controls Functionalanalysis revealed thatmiR-134 expression enhanced the onco-genicity of HNSCC cells in vitro as well as tumor growth andmetastasis of HNSCC cells in vivo via targetingWWdomain-containing oxidoreductase (WWOX) [36] In another studymiR-155 was found to be overexpressed in OSCC cells andtissues compared to the controls [37 38] Oncogenic effectsof miR-155 were suggested to be due to downregulation ofa tumor suppressor CDC73 in OSCC [39] Similarly miR-27a was shown to downregulate expression of and to inhibittumor suppressor function of microcephalin 1 (MCPH1) inOSCC cells [40]

4 miRNAs as Tumor Suppressors in OSCC

Several miRNAs have been shown to be downregulated inOSCC Accordingly functional studies have demonstrated

tumor suppressive roles for these miRNAs in OSCC tumori-genesis miR-320 was downregulated in OSCC-derived cell-lines and tissue specimens with its expression correlatinginversely with the vascularity Hypoxia suppressed miR-320expression through HIF-1120572 and increased the expression ofneuropilin 1 (NRP1) and promoted the motility and tubeformation ability of endothelial cells via vascular endothelialgrowth factor (VEGF) signaling pathway resulting in tumorangiogenesis [41]

The function of miR-7 has been characterized as a tumorsuppressor in several human cancers including glioblas-toma breast cancer and OSCC among others A numberof protooncogenes were experimentally confirmed as itstarget genes including insulin receptor substrate 1 (IRS1)insulin receptor substrate 2 (IRS2) epidermal growth factorreceptor (EGFR) v-raf-1 murine leukaemia viral oncogenehomologue 1 (RAF1) and p21CDC42RAC1-activated kinase1 (PAK1) [42ndash44] Jiang et al showed that miR-7 regulatedIGF1RIRSPI3KAkt signaling pathway by posttranscrip-tional regulation of insulin-like growth factor 1 receptor(IGF1R) in cells derived from tongue squamous cell carci-noma (TSCC the most common subtype of OSCC) cells[45] Similarly studies have demonstrated that IGF1R andmammalian target of rapamycin (mTOR) components ofIGF1R signaling pathway are target genes of another tumorsuppressor miRNA the miR-99a [46 47] Downregulationof miR-99a was observed in OSCC patient specimens andcell-lines [46 47] especially in OSCC patients with lym-phovascular invasion [46] suggesting a role for miR-99ain lymphovascular invasion In addition miR-99a inducedapoptosis and inhibited OSCC cell proliferation migrationand invasion in vitro as well as lung colonization in vivo[46 47]

miR-218 has been shown to be epigenetically (DNAhypermethylation) silenced in OSCC tissue specimens andto have a tumor suppressive function by regulating theexpression of rapamycin-insensitive component of mTORRictor [48] DNA hypermethylation has been suggested asone of the mechanisms for the downregulation of miR-9in OSCC and oropharyngeal carcinoma [49] Lentivirus-mediated miR-9 overexpression in highly aggressive tumorcells led to significant inhibition of proliferation in vitro andin vivo These tumor suppressive functions were suggestedto be mediated via targeting CXC chemokine receptor 4(CXCR4) gene and Wnt120573-catenin signaling pathway [50]

Accumulating evidence suggests a critical role for EMT intumor progression invasion and metastasis and acquisitionof stem-like phenotype [51] Findings from a number ofstudies point towards a role of miRNAs in the regulation ofEMT and EMT-related malignant phenotypes in OSCC cellsDifferent studies have shown a role for miR-138 in the sup-pression of EMT cell proliferation migration and invasioninHNSCC-derived cells At themolecular level miR-138 reg-ulated the expression of key EMT-related molecules like Fos-like antigen 1 (FOSL1) vimentin (VIM) zinc finger E-box-binding homeobox 2 (ZEB2) enhancer of zeste homologue2 (EZH2) RhoC and ROCK2 [52ndash54] Furthermore miR-138 was suggested to suppress the expression of prometastaticRhoC and other downstream signaling molecules FAK Src


and Erk12 in HNSCC-derived cells [55] Likewise miR-181a was shown to inhibit Twist1 mediated EMT metastaticpotential and cisplatin induced chemoresistance in TSCCcells [56]

Recent studies have shown that miRNAs play a crucialrole in the regulation of extracellular matrix (ECM) compo-nents such as matrix metalloproteinases (MMPs) and inte-grins Lu and coworkers reported that miR-29a was under-expressed in OSCC tissues and inhibited the expression ofMMP2 by directly binding to the MMP2 31015840-UTR Function-ally miR-29a inhibited invasion and antiapoptosis of OSCC-derived cells [57] Further functional studies revealed thattransfection with miRNA-29a mimics attenuated invasivepotential increased apoptosis rate and enhanced chemosen-sitivity of OSCC cell-lines to cis-platinum (CDDP) [57]miR-124 was found to be downregulated in OSCC andits forced expression suppressed OSCC cell migration andinvasion through downregulation of ITGB1 expression [58]Furthermore miR-491-5p was shown to suppress invasionand metastatic potential of OSCC cells in vitro and in vivoby targeting the expression of G-protein-coupled receptorkinase-interacting protein 1 (GIT1) which further regulatedthe expression of focal adhesions steady-state levels of pax-illin phospho-paxillin phospho-FAK EGFEGFR-mediatedextracellular signal-regulated kinase (ERK12) activation andMMP29 levels and activities [59]

A miRNA cluster miR-17-92 including miR-17 miR-19b miR-20a and miR-92a was found to be significantlydownregulated in a more migratory OSCC-derived TW26MS-10 cells as compared to the less migratory TW26 cellsOverexpression of this cluster was found to decrease themigratory ability of OSCC cell-linesThrough a bioinformat-ics screening analysis and 31015840-UTR reporter assay integrin(ITG) 1205738 was identified to be a direct target of miR-1720ain OSCC cells [60] Likewise miR-375 was shown to bedownregulated in HNSCC and to function as a tumorsuppressor by regulating the expression of AEG-1MTDHCIP2A (cancerous inhibitor of protein phosphatase 2A)Transient transfection of miR-375 in HNSCC-derived cellsreduced the expression of CIP2A (cancerous inhibitor ofprotein phosphatase 2A) [61 62] FurthermoremiR375 sensi-tized TNF-120572-induced apoptosis probably through inhibitingNF-120581B activation in vitro [63] Previous studies have sug-gested miR-34a which was frequently downregulated in anumber of tumor types to function as a tumor suppressorEctopic expression of miR-34a suppressed proliferation andcolony formation of HNSCC cells by downregulation of E2Ftranscription factor 3 (E2F3) and survivin in the in vitro andin vivo models [64] miR-34a further led to the inhibition oftumor angiogenesis by blocking VEGF production as well asby directly inhibiting endothelial cell functions [64] miR-125b another downregulated miRNA in OSCC was ableto inhibit proliferation rate and to enhance radiosensitivityto X-ray irradiation via downregulation of ICAM2 mRNAexpression in OSCC-derived cells [65] Likewise miR-145was found to be frequently downregulated in OSCCs [66]and to inhibit OSCC cell proliferation and colony formation[67]

5 Diagnostic and Prognostic Value ofmiRNAs in OSCC

Distinct expression profile of miRNA in OSCC and oralprelalignant tissue specimens compared to the normal con-trols offers the use of specific miRNA(s) signature for earlystage diagnosis and prediction of OSCC prognosis [16 17]In addition miRNAs possess the following unique propertieswhichmake them attractive diagnostic and prognostic tool inOSCC Firstly they are abundantly expressed in OSCC andcontrol tissues and hence their isolation and quantificationare convenient and reproducible Secondly several OSCC-related miRNAs are secreted in bodily fluids such as serumplasma and saliva [68] making them very useful for nonin-vasive clinical application Candidate miRNAs reported to berelevant forOSCCdiagnostics and prognosis are summarizedin Table 2

51 miRNA as Diagnostic Biomarkers The use of a specificmiRNA signature as a diagnostic tool in OSCC has beensuggested by a number of recent studies miR-16 and let-7bwere highly upregulated in sera frompatients withOSCC andoral carcinoma in situ while miR-338-3p miR-223 and miR-29a were highly downregulated as compared to the matchedcontrols ROC analysis indicated that the signature of fivemiRNAs (miR-16 let-7b miR-338-3p miR-223 and miR-29a) might be useful as a biomarker for oral cancer detection(AUC gt 08) [69] Lin et al showed that the plasma levelsof miR-24 in OSCC patients were significantly higher thanin the control individuals [70] Likewise the elevated plasmalevels of miR-21 and miR-146a were suggested to have adiagnostic value in OSCC [33 71] Expression level of miR-31 in saliva was found to be significantly increased in patientswith OSCC of all clinical stages as compared to that of thehealthy controls The high salivary level was significantlyreduced after excision of OSCC lesion indicating that themain contributor for miR-31 upregulation was OSCC lesion[72] In addition increased expression of miR-27b in salivaof OSCC patients was suggested as a valuable biomarkerto identify OSCC patients by ROC curve analyses [73]However another study showed a downregulated expressionof miR-27b in both the tumor tissues and the plasma ofOSCC patients [74] Further research is therefore requiredto validate the above findings and elucidate the molecularmechanismof different levels ofmiR-27b in saliva and plasmain OSCC

In addition to their potential use in OSCC diagnosisseveral miRNAs were suggested to be important in the earlierdiagnosis and prediction of malignant transformation oforal premalignant lesionsconditions Dang et al showeda significantly higher methylation frequency of miR-137promotor in patients with oral lichen planus (35) andOSCC(583) as compared to the absence of methylation in normalcontrols suggesting that the methylation status of miR-137might be a valuable biomarker in the prediction of malignanttransformation of OLP [75] In saliva significantly differentexpressions of miR-10b miR-145 miR-99b miR-708 andmiR-181c were observed in progressive low grade dysplasia


Table 2 miRNA deregulation and relevance to OSCC diagnosis and prognosis

miRNA(s) Source Updownregulation (OSCCversus normal control) Diagnosticprognostic relevance Ref

miR-16 Let-7b Serum Up YesND [69]a

miR-223 miR-29a Serum Downand miR-338-3pmiR-24 Plasma Up YesND [70]miR-146a Tissueplasma Up YesND [33]

miR-21

Tissue Up YesND [71]b

Plasma Up YesyesTissue Up NDyes [16]c

Tissue Up NDyes [26]Tissue Up Yesyes [17 80]b

Tissue Up NDyes [20]d

miR-31 Saliva Up YesND [72]miR-27b Saliva Up YesND [73]miR-125b Tissue Down NDyes [65]miR-491-5p Tissue Down NDyes [59]miR-181 Plasmatissue Up Yesyes [77]miR-375 Tissue Down NDyes [78]b

miR-205 and Let-7d Tissue Down NDyes [79]b

miR-155 Tissue Up NDyes [38]Tissue Up Yesyes [37]

miR-21-3p Tissue Up NDyes [97]miR-141-3pmiR-96-5pmiR-130b-3pmiR-196ab Tissue Up Yesyes [98]miR-196a Plasma Up YesyesmiR-211 Tissue Down NDyes [99]aOSCC group also consists of lesions with carcinoma in situ bHNSCC specimens cTSCC dexpression examined in the tumor stroma Ref references NDnot determined

(LGD) as compared to nonprogressive LGD leukoplakiapatients [76]

52 miRNA as Prognostic Biomarkers The expression pat-terns of certain miRNAs have been found to correlate withclinical stage lymph node metastasis and patient survivalindicating that thesemiRNAs can act as prognostic predictorsin OSCC Higher expression levels of miR-21 in TSCC corre-lated with advanced clinical stage poor differentiation andlymph node metastasis [16] Moreover multivariate analysisshowed that expression level of miR-21 could be used as anindependent prognostic factor for TSCC patientsrsquo survival[16] Similarly prognostic value of miR-21 in OSCCHNSCCwas reported in another study [26] miR-31 miR-1720amiR-125b miR-155 miR-181 miR-375 and miR-491-5p miR-205and miR-let7d were found to be associated with lymph nodemetastasis and poor OSCC patient survival [38 59 60 65 7277ndash80]

53 miRNA as Target for OSCC Therapy The ability tomanipulate miRNAs expression and function by local andsystemic delivery ofmiRNA inhibitors (anti-miRNAoligonu-cleotides or miRNA sponges [81 82]) or miRNAmimics [82]has recently gained immense interest as novel therapeuticapproach This treatment approach came into light after thefirst successful anti-miRNA oligonucleotides based humanclinical trial in 2011 for the treatment of hepatitis C virusinfection (reviewed in [83]) Recent identification of keymiRNAs with either oncogenic or tumor suppressive func-tions in OSCC has opened up new possibilities for miRNAbased OSCC therapy The advantage of miRNA based cancertherapy lies in the ability of miRNAs to concurrently targetmultiple effectors of pathways involved in cell proliferationdifferentiation and survival [82] Accordingly several invitro and in vivo studies employing strategies to suppressthe function of oncogenic miRNA andor restore the tumorsuppressive miRNAs have reported significant inhibition ofaggressiveOSCCphenotypes For example inhibitingmiR-21


by anti-miRNA oligonucleotides has been shown to inhibitsurvival anchorage-independent growth [16] and invasion[18] of OSCC cells Likewise restoration of miR-99a level bymiR mimic transfection markedly suppressed proliferationand induced apoptosis of TSCC cells [47]

Resistance to chemotherapy and resistance to radio-therapy are major challenges in the management of OSCCpatients as significantly high proportions of OSCC lesions failto respond to these treatment modalities Recent studies havelinked resistance to chemotherapy and radiotherapy inOSCCto altered miRNA expression and function Dai et al havecorrelated a miRNA signature (downregulation of miR-100miR-130a and miR-197 and upregulation of miR-181b miR-181d miR-101 and miR-195) in HNSCC cells with multipledrug resistance phenotypes in vitro [84] In another study lowexpression ofmiR-200b andmiR-15b in TSCCwas associatedwith chemotherapeutic resistance and poor patient prognosis[85] Similarly higher expression ofmiR-196awas reported tobe associated with recurrent disease and resistance to radio-therapy in HNSCC [86] The miRNA signature(s) related totherapeutic resistance has also been used experimentally torevert the resistance phenotypes For example inhibition ofmiR-21 by anti-miRNA oligonucleotides has been shown toinhibit chemoresistance in OSCC cells [24 87] Likewiseforced expression of miR-125b has been reported to enhanceradiosensitivity in OSCC cells [65] Recently nanoparticlebased delivery of miRNAs was suggested as a promisingapproach in the treatment of HNSCC [88] Despite thesepromising results more in-depth studies are necessary tobetter understand the effective delivery system for optimaluptake and to minimize degradation of miRNA based drugsin the in vivo situation

6 Conclusions

Alteration in the expression pattern of miRNA is a commonfinding in OSCC tumorigenesis Several altered miRNAsseem to play critical roles in the initiation and progression ofOSCC by functioning either as oncogenes or as tumor sup-pressors Specific miRNA signatures identified from tumorspecimens serumplasma or saliva from OSCC patientshave a potential to be clinically useful in the diagnosisprognosis and therapeutic targets in OSCC Neverthelessit will be a big challenge ahead to translate these promisingfindings to clinic before the following issues will be fullyaddressed Firstly findings from several studies are based onlimited number of patient materials from different subloca-tions of oral cavity which lead to more heterogeneous dataand reduced statistical power Additionally use of differentexpression profiling platforms (such as microarray or PCR)with different normalizing strategies leads to inconsistentmiRNA expression results Hence a comprehensive miRNAprofiling including larger number of paired tissue specimensof oral premalignant lesionsconditions primary OSCC andmetastasis will enable us to identify miRNAs involved instepwise tumorigenesis and metastatic process of OSCCThe identified miRNAs will pave the way for their futureclinical use in the diagnosis prognosis and therapy ofOSCC

Conflict of Interests

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

Acknowledgments

The authors would like to thank Professor Anne ChristineJohannessen for her assistance during the revision processof this paper This work was supported by the Grants fromNational Natural Science Foundation for young scholar ofChina (no 81102045) Clinical Key Subject Foundation ofHealthMinistry of China BergenMedical Research Founda-tion (20102011 DEC)TheWestern Norway Regional HealthAuthority Norway (no 911902) and University of Bergen(postdoctoral fund DS)

References

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[2] R Siegel DNaishadham andA Jemal ldquoCancer statistics 2013rdquoCA Cancer Journal for Clinicians vol 63 no 1 pp 11ndash30 2013

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[4] K D C B Ribeiro L P Kowalski andMD R D D O LatorreldquoPerioperative complications comorbidities and survival inoral or oropharyngeal cancerrdquo Archives of OtolaryngologymdashHead amp Neck Surgery vol 129 no 2 pp 219ndash228 2003

[5] T Hunter ldquoCooperation between oncogenesrdquo Cell vol 64 no2 pp 249ndash270 1991

[6] J M Bishop ldquoMolecular themes in oncogenesisrdquo Cell vol 64no 2 pp 235ndash248 1991

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[8] V Ambros ldquoThe functions of animal microRNAsrdquo Nature vol431 no 7006 pp 350ndash355 2004

[9] A E Pasquinelli S Hunter and J Bracht ldquoMicroRNAs a devel-oping storyrdquo Current Opinion in Genetics and Development vol15 no 2 pp 200ndash205 2005

[10] L P LimNC Lau PGarrett-Engele et al ldquoMicroarray analysisshows that some microRNAs downregulate large numbers of-target mRNAsrdquo Nature vol 433 no 7027 pp 769ndash773 2005

[11] B D Harfe ldquoMicroRNAs in vertebrate developmentrdquo CurrentOpinion in Genetics amp Development vol 15 no 4 pp 410ndash4152005

[12] D P Bartel and C-Z Chen ldquoMicromanagers of gene expres-sion the potentially widespread influence of metazoanmicroR-NAsrdquo Nature Reviews Genetics vol 5 no 5 pp 396ndash400 2004

[13] N Rajewsky ldquomicroRNA target predictions in animalsrdquoNatureGenetics vol 38 pp S8ndashS13 2006

[14] N Tran C J OrsquoBrien J Clark and B Rose ldquoPotential role ofmicro-RNAs in head and neck tumorigenesisrdquo Head amp Neckvol 32 no 8 pp 1099ndash1111 2010

[15] N Sethi AWright HWood and P Rabbitts ldquoMicroRNAs andhead and neck cancer reviewing the first decade of researchrdquoEuropean Journal of Cancer vol 50 no 15 pp 2619ndash2635 2014


[16] J Li H Huang L Sun et al ldquoMiR-21 indicates poor prognosisin tongue squamous cell carcinomas as an apoptosis inhibitorrdquoClinical Cancer Research vol 15 no 12 pp 3998ndash4008 2009

[17] M Avissar B C Christensen K T Kelsey and C J MarsitldquoMicroRNA expression ratio is predictive of head and necksquamous cell carcinomardquo Clinical Cancer Research vol 15 no8 pp 2850ndash2855 2009

[18] A Kawakita S Yanamoto S-I Yamada et al ldquoMicroRNA-21promotes oral cancer invasion via the wnt120573-catenin pathwayby targeting DKK2rdquo Pathology ampOncology Research vol 20 no2 pp 253ndash261 2014

[19] D Chen R J Cabay Y Jin et al ldquoMicroRNA deregulations inhead and neck squamous cell carcinomasrdquo Journal of Oral ampMaxillofacial Research vol 4 no 1 article e2 2013

[20] N Hedback D H Jensen L Specht et al ldquomiR-21 expressionin the tumor stroma of oral squamous cell carcinoma anindependent biomarker of disease free survivalrdquo PLoSONE vol9 no 4 Article ID e95193 2014

[21] J A R Brito C C Gomes A L S Guimaraes K Camposand R S Gomez ldquoRelationship between microRNA expressionlevels and histopathological features of dysplasia in oral leuko-plakiardquo Journal of Oral Pathology and Medicine vol 43 no 3pp 211ndash216 2014

[22] W Mydlarz M Uemura S Ahn et al ldquoClusterin is a gene-specific target of microRNA-21 in head and neck squamous cellcarcinomardquoClinical Cancer Research vol 20 no 4 pp 868ndash8772014

[23] P P Reis M Tomenson N K Cervigne et al ldquoProgrammedcell death 4 loss increases tumor cell invasion and is regulatedby miR-21 in oral squamous cell carcinomardquoMolecular Cancervol 9 article 238 2010

[24] L Y W Bourguignon C Earle G Wong C C Spevakand K Krueger ldquoStem cell marker (Nanog) and Stat-3 sig-naling promote MicroRNA-21 expression and chemoresistancein hyaluronanCD44-activated head and neck squamous cellcarcinoma cellsrdquo Oncogene vol 31 no 2 pp 149ndash160 2012

[25] F Meng R Henson H Wehbe-Janek K Ghoshal S TJacob and T Patel ldquoMicroRNA-21 regulates expression of thePTEN tumor suppressor gene in human hepatocellular cancerrdquoGastroenterology vol 133 no 2 pp 647ndash658 2007

[26] H M Jung B L Phillips R S Patel et al ldquoKeratinization-associated miR-7 and miR-21 regulate tumor suppressorreversion-inducing cysteine-rich protein with kazal motifs(RECK) in oral cancerrdquoThe Journal of Biological Chemistry vol287 no 35 pp 29261ndash29272 2012

[27] Q Li D Zhang Y Wang et al ldquoMiR-21Smad 7 signalingdetermines TGF-1205731-inducedCAF formationrdquo Scientific Reportsvol 3 article 2038 2013

[28] C-J Liu M-M Tsai P-S Hung et al ldquomiR-31 ablates expres-sion of the HIF regulatory factor FIH to activate the HIFpathway in head and neck carcinomardquo Cancer Research vol 70no 4 pp 1635ndash1644 2010

[29] W Xiao Z-X Bao C-Y Zhang et al ldquoUpregulation of miR-31 is negatively associated with recurrentnewly formed oralleukoplakiardquo PLoS ONE vol 7 no 6 Article ID e38648 2012

[30] S-B Ouyang J Wang Z-K Huang and L Liao ldquoExpressionof microRNA-31 and its clinicopathologic significance in oralsquamous cell carcinomardquo Zhonghua Kou Qiang Yi Xue Za Zhivol 48 no 8 pp 481ndash484 2013

[31] P-S Hung H-F Tu S-Y Kao et al ldquomiR-31 is upregulated inoral premalignant epithelium and contributes to the immortal-ization of normal oral keratinocytesrdquoCarcinogenesis vol 35 no5 pp 1162ndash1171 2014

[32] K-W Chang S-Y Kao Y-H Wu et al ldquoPassenger strandmiRNAmiR-31 regulates the phenotypes of oral cancer cells bytargeting RhoArdquo Oral Oncology vol 49 no 1 pp 27ndash33 2013

[33] P-S Hung C-J Liu C-S Chou et al ldquomiR-146a enhances theoncogenicity of oral carcinoma by concomitant targeting of theIRAK1 TRAF6 and NUMB genesrdquo PLoS ONE vol 8 no 11Article ID e79926 2013

[34] P-S Hung K-W Chang S-Y Kao T-H Chu C-J Liu andS-C Lin ldquoAssociation between the rs2910164 polymorphism inpre-mir-146a and oral carcinoma progressionrdquo Oral Oncologyvol 48 no 5 pp 404ndash408 2012

[35] A Palmieri F Carinci M Martinelli et al ldquoRole of theMIR146A polymorphism in the origin and progression of oralsquamous cell carcinomardquo European Journal of Oral Sciencesvol 122 no 3 pp 198ndash201 2014

[36] C-J Liu W G Shen S-Y Peng et al ldquoMiR-134 induces onco-genicity and metastasis in head and neck carcinoma throughtargeting WWOX generdquo International Journal of Cancer vol134 no 4 pp 811ndash821 2014

[37] Y-H Ni X-F Huang Z-Y Wang et al ldquoUpregulation of apotential prognostic biomarker miR-155 enhances cell prolif-eration in patients with oral squamous cell carcinomardquo OralSurgery Oral Medicine Oral Pathology and Oral Radiology vol117 no 2 pp 227ndash233 2014

[38] L J Shi C Y Zhang Z T Zhou et al ldquoMicroRNA-155 inoral squamous cell carcinoma overexpression localization andprognostic potentialrdquo Head amp Neck 2014

[39] M I Rather M N Nagashri S S Swamy K S Gopinath andA Kumar ldquoOncogenic microRNA-155 down-regulates tumorsuppressor CDC73 and promotes oral squamous cell carcinomacell proliferation implications for cancer therapeuticsrdquo Journalof Biological Chemistry vol 288 no 1 pp 608ndash618 2013

[40] T Venkatesh M N Nagashri S S Swamy S M A Mohiyud-din K S Gopinath andAKumar ldquoPrimarymicrocephaly geneMCPH1 shows signatures of tumor suppressors and is regulatedby miR-27a in oral squamous cell carcinomardquo PLoS ONE vol8 no 3 Article ID e54643 2013

[41] Y-Y Wu Y-L Chen Y-C Jao I-S Hsieh K-C Chang andT-M Hong ldquoMiR-320 regulates tumor angiogenesis driven byvascular endothelial cells in oral cancer by silencing neuropilin1rdquo Angiogenesis vol 17 no 1 pp 247ndash260 2014

[42] B Kefas J Godlewski L Comeau et al ldquomicroRNA-7 inhibitsthe epidermal growth factor receptor and the akt pathway and isdown-regulated in glioblastomardquo Cancer Research vol 68 no10 pp 3566ndash3572 2008

[43] S D N Reddy K Ohshiro S K Rayala and R KumarldquoMicroRNA-7 a homeobox D10 target inhibits p21-activatedkinase 1 and regulates its functionsrdquo Cancer Research vol 68no 20 pp 8195ndash8200 2008

[44] R J Webster K M Giles K J Price P M Zhang J S Mattickand P J Leedman ldquoRegulation of epidermal growth factorreceptor signaling in human cancer cells by MicroRNA-7rdquo TheJournal of Biological Chemistry vol 284 no 9 pp 5731ndash57412009

[45] L Jiang X Liu Z Chen et al ldquoMicroRNA-7 targets IGF1R(insulin-like growth factor 1 receptor) in tongue squamous cellcarcinoma cellsrdquo Biochemical Journal vol 432 no 1 pp 199ndash205 2010


[46] Y-C Yen S-G Shiah H-C Chu et al ldquoReciprocal regulationof MicroRNA-99a and insulin-like growth factor I receptorsignaling in oral squamous cell carcinoma cellsrdquo MolecularCancer vol 13 no 1 article 6 2014

[47] B Yan Q Fu L Lai et al ldquoDownregulation of microRNA 99ain oral squamous cell carcinomas contributes to the growth andsurvival of oral cancer cellsrdquoMolecular Medicine Reports vol 6no 3 pp 675ndash681 2012

[48] AUesugi K-I Kozaki T Tsuruta et al ldquoThe tumor suppressivemicroRNA miR-218 targets the mTOR component rictor andinhibits AKT phosphorylation in oral cancerrdquo Cancer Researchvol 71 no 17 pp 5765ndash5778 2011

[49] J Minor XWang F Zhang et al ldquoMethylation of microRNA-9is a specific and sensitive biomarker for oral and oropharyngealsquamous cell carcinomasrdquoOral Oncology vol 48 no 1 pp 73ndash78 2012

[50] T Yu K Liu Y Wu et al ldquoMicroRNA-9 inhibits the prolif-eration of oral squamous cell carcinoma cells by suppressingexpression of CXCR4 via theWnt120573-catenin signaling pathwayrdquoOncogene vol 33 pp 5017ndash5027 2013

[51] J P Their ldquoEpithelial-mesenchymal transitions in tumor pro-gressionrdquo Nature Reviews Cancer vol 2 no 6 pp 442ndash4542002

[52] Y Jin C Wang X Liu et al ldquoMolecular characterizationof the MicroRNA-138-Fos-like antigen 1 (FOSL1) regulatorymodule in squamous cell carcinomardquo The Journal of BiologicalChemistry vol 286 no 46 pp 40104ndash40109 2011

[53] X Liu C Wang Z Chen et al ldquoMicroRNA-138 suppressesepithelial-mesenchymal transition in squamous cell carcinomacell linesrdquo Biochemical Journal vol 440 no 1 pp 23ndash31 2011

[54] L Jiang X Liu A Kolokythas et al ldquoDownregulation of theRho GTPase signaling pathway is involved in the microRNA-138-mediated inhibition of cell migration and invasion intongue squamous cell carcinomardquo International Journal ofCancer vol 127 no 3 pp 505ndash512 2010

[55] M Islam J Datta J C Lang and T N Teknos ldquoDownregulation of RhoC by microRNA-138 results in de-activationof FAK Src and Erk12 signaling pathway in head and necksquamous cell carcinomardquo Oral Oncology vol 50 no 5 pp448ndash456 2014

[56] M Liu J Wang H Huang J Hou B Zhang and AWang ldquoMiR-181a-Twist1 pathway in the chemoresistance oftongue squamous cell carcinomardquo Biochemical and BiophysicalResearch Communications vol 441 no 2 pp 364ndash370 2013

[57] L Lu X Xue J Lan et al ldquoMicroRNA-29a upregulates MMP2in oral squamous cell carcinoma to promote cancer invasionand anti-apoptosisrdquo Biomedicine and Pharmacotherapy vol 68no 1 pp 13ndash19 2014

[58] S Hunt A V Jones E E Hinsley S A Whawell and DW Lambert ldquoMicroRNA-124 suppresses oral squamous cellcarcinoma motility by targeting ITGB1rdquo FEBS Letters vol 585no 1 pp 187ndash192 2011

[59] W-C Huang S-H Chan T-H Jang et al ldquoMiRNA-491-5p andGIT1 serve as modulators and biomarkers for oral squamouscell carcinoma invasion and metastasisrdquo Cancer Research vol74 no 3 pp 751ndash764 2014

[60] C-C Chang Y-J Yang Y-J Li et al ldquoMicroRNA-1720afunctions to inhibit cell migration and can be used a prognosticmarker in oral squamous cell carcinomardquo Oral Oncology vol49 no 9 pp 923ndash931 2013

[61] H M Jung R S Patel B L Phillips et al ldquoTumor suppressormiR-375 regulates MYC expression via repression of CIP2A

coding sequence through multiple miRNA-mRNA interac-tionsrdquoMolecular Biology of theCell vol 24 no 11 pp 1638ndash16482013

[62] N Nohata T Hanazawa N Kikkawa et al ldquoTumor suppressivemicroRNA-375 regulates oncogene AEG-1MTDH in head andneck squamous cell carcinoma (HNSCC)rdquo Journal of HumanGenetics vol 56 no 8 pp 595ndash601 2011

[63] J Wang H Huang C Wang X Liu F Hu and M LiuldquoMicroRNA-375 sensitizes tumour necrosis factor-alpha (TNF-120572)-induced apoptosis in head and neck squamous cell carci-noma in vitrordquo International Journal of Oral and MaxillofacialSurgery vol 42 no 8 pp 949ndash955 2013

[64] B Kumar A Yadav J Lang T N Teknos and P KumarldquoDysregulation of microRNA-34a expression in head and necksquamous cell carcinoma promotes tumor growth and tumorangiogenesisrdquo PLoS ONE vol 7 no 5 Article ID e37601 2012

[65] M Shiiba K Shinozuka K Saito et al ldquoMicroRNA-125bregulates proliferation and radioresistance of oral squamous cellcarcinomardquo British Journal of Cancer vol 108 no 9 pp 1817ndash1821 2013

[66] L Gao W Ren S Chang et al ldquoDownregulation of miR-145expression in oral squamous cell carcinomas and its clinicalsignificancerdquo Onkologie vol 36 no 4 pp 194ndash199 2013

[67] Y Shao Y Qu S Dang B Yao andM Ji ldquoMiR-145 inhibits oralsquamous cell carcinoma (OSCC) cell growth by targeting c-Myc and Cdk6rdquo Cancer Cell International vol 13 no 1 article51 2013

[68] N J Park H Zhou D Elashoff et al ldquoSalivary microRNAdiscovery characterization and clinical utility for oral cancerdetectionrdquo Clinical Cancer Research vol 15 no 17 pp 5473ndash5477 2009

[69] S A MacLellan J Lawson J Baik M Guillaud C F Poh andC Garnis ldquoDifferential expression of miRNAs in the serum ofpatients with high-risk oral lesionsrdquo Cancer Medicine vol 1 no2 pp 268ndash274 2012

[70] S-C Lin C-J Liu J-A Lin W-F Chiang P-S Hung and K-W Chang ldquomiR-24 up-regulation in oral carcinoma positiveassociation from clinical and in vitro analysisrdquo Oral Oncologyvol 46 no 3 pp 204ndash208 2010

[71] C-M Hsu P-M Lin Y-M Wang Z-J Chen S-F Lin andM-Y Yang ldquoCirculatingmiRNA is a novel marker for head andneck squamous cell carcinomardquo Tumour Biology vol 33 no 6pp 1933ndash1942 2012

[72] C-J Liu S-C Lin C-C Yang H-W Cheng and K-W ChangldquoExploiting salivary miR-31 as a clinical biomarker of oralsquamous cell carcinomardquo Head and Neck vol 34 no 2 pp219ndash224 2012

[73] F Momen-Heravi A J Trachtenberg W P Kuo and Y SCheng ldquoGenomewide study of salivary microRNAs for detec-tion of oral cancerrdquo Journal of Dental Research vol 93 no 7supplement pp 86Sndash93S 2014

[74] W-Y Lo H-J Wang C-W Chiu and S-F Chen ldquomiR-27b-regulated TCTP as a novel plasma biomarker for oral cancerfrom quantitative proteomics to post-transcriptional studyrdquoJournal of Proteomics vol 77 pp 154ndash166 2012

[75] J Dang Y-Q Bian J Y Sun et al ldquoMicroRNA-137 promotermethylation in oral lichen planus and oral squamous cellcarcinomardquo Journal of Oral Pathology amp Medicine vol 42 no4 pp 315ndash321 2013

[76] Y Yang Y-X Li X Yang L Jiang Z-J Zhou and Y-Q ZhuldquoProgress risk assessment of oral premalignant lesions withsaliva miRNA analysisrdquo BMC Cancer vol 13 article 129 2013


[77] C-C Yang P-S Hung P-WWang et al ldquomiR-181 as a putativebiomarker for lymph-node metastasis of oral squamous cellcarcinomardquo Journal of Oral Pathology andMedicine vol 40 no5 pp 397ndash404 2011

[78] T Harris L Jimenez N Kawachi et al ldquoLow-level expressionof miR-375 correlates with poor outcome and metastasis whilealtering the invasive properties of head and neck squamous cellcarcinomasrdquoThe American Journal of Pathology vol 180 no 3pp 917ndash928 2012

[79] G Childs M Fazzari G Kung et al ldquoLow-level expression ofmicroRNAs let-7d andmiR-205 are prognostic markers of headand neck squamous cell carcinomardquo The American Journal ofPathology vol 174 no 3 pp 736ndash745 2009

[80] M Avissar M D McClean K T Kelsey and C J MarsitldquoMicroRNA expression in head and neck cancer associates withalcohol consumption and survivalrdquo Carcinogenesis vol 30 no12 pp 2059ndash2063 2009

[81] M S Ebert J R Neilson and P A Sharp ldquoMicroRNA spongescompetitive inhibitors of small RNAs in mammalian cellsrdquoNature Methods vol 4 no 9 pp 721ndash726 2007

[82] R Garzon G Marcucci and C M Croce ldquoTargeting microR-NAs in cancer rationale strategies and challengesrdquo NatureReviews Drug Discovery vol 9 no 10 pp 775ndash789 2010

[83] E van Rooij and E N Olson ldquoMicroRNA therapeutics forcardiovascular disease opportunities and obstaclesrdquo NatureReviews Drug Discovery vol 11 no 11 pp 860ndash872 2012

[84] Y Dai C-H Xie J P Neis C-Y Fan E Vural and PM SpringldquoMicroRNA expression profiles of head and neck squamous cellcarcinoma with docetaxel-induced multidrug resistancerdquoHeadand Neck vol 33 no 6 pp 786ndash791 2011

[85] L Sun Y Yao B Liu et al ldquoMiR-200b and miR-15b regulatechemotherapy-induced epithelial-mesenchymal transition inhuman tongue cancer cells by targeting BMI1rdquo Oncogene vol31 no 4 pp 432ndash445 2012

[86] Y-E Suh N Raulf J Gaken et al ldquomicroRNA-196a promotesan oncogenic effect in head and neck cancer cells by suppressingannexin A1 and enhancing radioresistancerdquo International Jour-nal of Cancer 2015

[87] W Ren XWang L Gao et al ldquoMiR-21 modulates chemosensi-tivity of tongue squamous cell carcinoma cells to cisplatin bytargeting PDCD4rdquo Molecular and Cellular Biochemistry vol390 no 1-2 pp 253ndash262 2014

[88] L Piao M Zhang J Datta et al ldquoLipid-based nanoparticledelivery of pre-miR-107 inhibits the tumorigenicity of head andneck squamous cell carcinomardquoMolecular Therapy vol 20 no6 pp 1261ndash1269 2012

[89] K Lefort Y Brooks P Ostano et al ldquoA miR-34a-SIRT6 axis inthe squamous cell differentiation networkrdquoThe EMBO Journalvol 32 no 16 pp 2248ndash2263 2013

[90] Y Kai W Peng W Ling H Jiebing and B Zhuan ldquoRecipro-cal effects between microRNA-140-5p and ADAM10 suppressmigration and invasion of human tongue cancer cellsrdquoBiochem-ical and Biophysical Research Communications vol 448 no 3pp 308ndash314 2014

[91] K-H Shin S D Bae H S Hong R H Kim M K Kangand N-H Park ldquomiR-181a shows tumor suppressive effectagainst oral squamous cell carcinoma cells by downregulatingK-rasrdquo Biochemical and Biophysical Research Communicationsvol 404 no 4 pp 896ndash902 2011

[92] J-S Kim S-K Yu M-H Lee et al ldquoMicroRNA-205 directlyregulates the tumor suppressor interleukin-24 in human KB

oral cancer cellsrdquo Molecules and Cells vol 35 no 1 pp 17ndash242013

[93] J-S Kim S-Y Park S A Lee et al ldquoMicroRNA-205 suppressesthe oral carcinoma oncogenic activity via down-regulation ofAxin-2 in KB human oral cancer cellrdquo Molecular and CellularBiochemistry vol 387 no 1-2 pp 71ndash79 2014

[94] T Bertero I Bourget-Ponzio A Puissant et al ldquoTumor sup-pressor function of miR-483-3p on squamous cell carcinomasdue to its pro-apoptotic propertiesrdquo Cell Cycle vol 12 no 14pp 2183ndash2193 2013

[95] L Darda F Hakami R Morgan et al ldquoThe role of HOXB9 andmiR-196a in head and neck squamous cell carcinomardquo PLOSONE vol 10 no 4 Article ID e0122285 2015

[96] I Fukumoto T Hanazawa T Kinoshita et al ldquoMicroRNAexpression signature of oral squamous cell carcinoma func-tional role of microRNA-26ab in the modulation of novelcancer pathwaysrdquo British Journal of Cancer vol 112 no 5 pp891ndash900 2015

[97] F Ganci A Sacconi V Manciocco et al ldquomicroRNAs expres-sion predicts local recurrence risk in oral squamous cell carci-nomardquo Head amp Neck 2014

[98] C-J Liu M-M Tsai H-F Tu M-T Lui H-W Chengand S-C Lin ldquoMiR-196a overexpression and mir-196a2 genepolymorphism are prognostic predictors of oral carcinomasrdquoAnnals of Surgical Oncology vol 20 no 3 pp S406ndashS414 2013

[99] K-W Chang C-J Liu T-H Chu et al ldquoAssociation betweenhigh miR-211 microRNA expression and the poor prognosis oforal carcinomardquo Journal of Dental Research vol 87 no 11 pp1063ndash1068 2008

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


RISC

miRNA gene

Transcription

NucleusDrosha

Exportin 5

Dicer

Cytoplasm

Unwinding

Translationalrepression

mRNAdegradation

Regulation of geneexpression

miRNAmiRNAlowast duplex

Activation of oncogenesandor suppression of

tumor suppressor genes

Invasive OSCCgrowth

uarrProliferation and survival

metastatic potential of oralkeratinocytes

darrapoptosis and uarrinvasion andor

Figure 1 Schematic illustration demonstrating biogenesis and function of miRNA miRNA genes are transcribed into primary miRNA (pri-miRNA) by RNA polymerase IIIThese miRNAs are further converted into second precursors (pre-miRNA) by Drosha and are exported intocytoplasm by Exportin 5 Additional processing by Dicer produces miRNAmiRNAlowast duplex Only one strand of miRNAmiRNAlowast duplex ispreferentially assembled into the RNA-induced silencing complex (RISC) RISC acts on target mRNA(s) and leads to either translationalrepression or mRNA cleavage Suppression of tumor suppressive genes andor activation of oncogenes by miRNA lead to excessive cellproliferation and survival increased antiapoptosis and enhanced invasive and metastatic potential of oral keratinocytes resulting intoinvasive cancerous growth

Among them miRNAs 18ndash25 nucleotides long noncod-ing RNA molecules [7ndash9] have recently gained significantattention as potential regulators and biomarkers for humancarcinogenesis At the molecular level miRNA binds to31015840-untranslated region (31015840-UTR) of target mRNA(s) andsuppresses its expression by either translational repression ormRNA cleavage [10] (Figure 1) A single miRNA can regulateexpression andor function of hundreds of targetmRNAs andproteins and regulates several biological processes (eg cellproliferation differentiationmigration apoptosis and signaltransduction) important for cancer development [8 11ndash13](Figure 1)

Many recent studies have shown deregulated expressionof miRNAs in OSCC and OSCC-derived cell-lines comparedto their normal counterparts indicating their potential role inoral cancer development Accordingly several miRNAs havebeen shown to function either as tumor suppressors or astumor promoters in OSCCs (reviewed in [14 15]) In additionto their key biological functions in OSCC tumorigenesisexpression levels of several of miRNAs have been shown tocorrelate with clinicopathological variables [16] and to have adiagnostic and prognostic value in OSCC [15 17] For thesereasons miRNA has been a hot topic in cancer research forthe last few years and several studies about miRNAs in OSCC

have been published recently as summarized in Table 1 Thecurrent review aims to highlight the oncogenic and tumorsuppressive roles of miRNAs in OSCC development anddiscusses their potential value as diagnostic and prognosticmarkers for OSCC management

2 Methods

Literature search was performed by using the PubMeddatabase Following key words were used for the litera-ture search ldquooral cancer and miRNArdquo ldquooral cancer andmicroRNArdquo ldquooral squamous cell carcinoma andmiRNArdquo andldquooral squamous cell carcinoma and microRNArdquo Exclusioncriteria were articles not related to OSCCHNSCC andormiRNA purely descriptive articles articles lacking clinicalpathological correlation andor articles for which full textswere not available in English Only clinically relevant articlespublished within April 2015 were included in this reviewAdditionally individual articles retrieved manually from thereference list of the relevant papers were also included

3 miRNAs as Oncogenes in OSCC

A number of miRNAs have been shown to be upregulatedin OSCC and to function as oncogenes A well-studied




miR-21 Up











































miR-21















6 Conclusions




Acknowledgments


References














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















miR-21 Up











































miR-21















6 Conclusions




Acknowledgments


References














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of








































miR-21















6 Conclusions




Acknowledgments


References














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















6 Conclusions




Acknowledgments


References














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article micrornas as important players and...

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