review article modulation of micrornas by phytochemicals in … · 2019. 7. 31. · review article...

Review ArticleModulation of MicroRNAs by Phytochemicals in CancerUnderlying Mechanisms and Translational Significance

Sanjeev K Srivastava1 Sumit Arora1 Courey Averett1 Seema Singh1 and Ajay P Singh12

1 Mitchell Cancer Institute University of South Alabama Mobile AL 36604 USA2Department of Biochemistry and Molecular Biology University of South Alabama Mobile AL 36688 USA

Correspondence should be addressed to Ajay P Singh asinghhealthsouthalabamaedu

Received 26 August 2014 Accepted 12 October 2014

Academic Editor Fumitaka Takeshita

Copyright copy 2015 Sanjeev K Srivastava et al 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

MicroRNAs (miRNAs) are small endogenous noncodingRNAs that regulate a variety of biological processes such as differentiationdevelopment and survival Recent studies suggest that miRNAs are dysregulated in cancer and play critical roles in cancerinitiation progression and chemoresistance Therefore exploitation of miRNAs as targets for cancer prevention and therapycould be a promising approach Extensive evidence suggests that many naturally occurring phytochemicals regulate the expressionof numerous miRNAs involved in the pathobiology of cancer Therefore an understanding of the regulation of miRNAs byphytochemicals in cancer their underlying molecular mechanisms and functional consequences on tumor pathophysiology maybe useful in formulating novel strategies to combat this devastating disease These aspects are discussed in this review paper withan objective of highlighting the significance of these observations from the translational standpoint

1 Introduction

MicroRNAs (miRNAs) are endogenous small noncodingRNA molecules that posttranscriptionally regulate geneexpression miRNAs bind to the 31015840-UTRs of target mRNAwith partial or complete complementarity thus causing trans-lational repression or target messenger RNA (mRNA) degra-dation [1] An individual miRNA can regulate the expressionof multiple genes conversely a single mRNA can be targetedby many miRNAs To date about 2469 miRNAs have beenidentified in humans [2] and more than one-third of allhuman genes are potentially regulated bymiRNAs [3] Exten-sive studies have shown thatmiRNAs not only are involved inthe process of cell development and differentiation but alsoplay a critical role in carcinogenesis [4] Emerging data sug-gest that several classes of naturally occurring plant-derivedcompounds (phytochemicals) could potentially regulate theexpression of several miRNAs involved in cancer

Phytochemicals are nonnutritive plant chemicals thathave various applications including anti-inflammatory and

anticancer These phytochemicals are widely distributed invarious fruits vegetables herbs beverages and many otherdietary supplements Numerous studies have demonstratedthat the intake of fruit- and vegetable-rich foods decreasesthe occurrence of cancer [5ndash7] So far more than 10000phytochemicals have been identified [8] and a significantnumber of phytochemicals show anticancer potential with noor minimal toxicity to normal cells [9] Interestingly around47 of FDA approved anticancer drugs are derived fromplants [10 11] Moreover these phytochemicals could be usedas a single chemotherapeutic agent or in association withstandard anticancer drugs Phytochemicals can increase theefficacy of anticancer drugs synergistically while reducingthe toxic side effects of the standard chemotherapeuticdrugs [12 13] These phytochemicals exert their anticancereffects through modulation of multiple molecular targetsaffecting various signaling pathways [8 14 15] In the presentreview paper we focus our attention on the regulation ofmiRNAs by some of the phytochemicals such as resveratrolepigallocatechin-3-gallate (EGCG) curcumin camptothecin

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 848710 9 pageshttpdxdoiorg1011552015848710

2 BioMed Research International

(CPT) and diindolylmethane (DIM) for cancer preventionand therapy

2 Biogenesis of miRNA and Mechanism ofGene Silencing

The biosynthesis of miRNAs begins with gene transcriptionby RNA polymerase II or RNA polymerase III into primarymiRNA (pri-miRNA) transcripts inside the nucleus Thesepri-miRNAs are comprised of either a cluster or single miR-NAs folded into a hairpin stem-like structure [1] This longpri-miRNA is processed by the sequential endonucleolyticcleavage of the transcript by the microprocessor complexcontaining drosha and DGCR8 into a 65ndash70-nucleotideprecursor miRNA (pre-miRNA) This pre-miRNA is thenexported from the nucleus to the cytoplasm by the nuclearexport factor Exportin-5Ran-GTP and cleaved by RNase IIIendonuclease DicerTRBP and argonaute 2 (Ago2) miRNAduplex [16] into an sim22-nucleotide product This duplexmiRNA then unwinds to generate a single-stranded miRNAOne of the strands enters in the RNA-induced silencingcomplex (RISC) along with Ago proteins and directs thecomplex to target mRNA This binding causes either targetmRNA degradation or inhibition of translation [1]

3 Biological Significance of miRNAs inCancer Tumor Suppressors and Oncogenes

Based on in vitro and in vivo studies miRNAs have beencharacterized as tumor suppressors or oncogenes In thissection we will discuss some of the reports from a longlist of tumor suppressoroncogenic miRNAs that have beenexperimentally validated

Numerous studies have shown that the expression of thetumor suppressor Let-7 is significantly downregulated or lostin various cancers [17ndash19] It has been shown that restorationof Let-7 inhibited tumor growth in a K-RAS lung cancermodel [20] Furthermore decreased expression of let-7 corre-lated with shorter survival in non-small-cell lung cancer [21]OthermiRNAs such asmiR-15a andmiR-16 are either deletedor downregulated in most cases of the chronic lymphocyticleukemia and their overexpression induced apoptosis [22]Moreover it has been reported that miR-16 and miR-15were downregulated in multidrug-resistant human gastriccancer cells and restoration of these miRNAs sensitized thecancer cells to chemotherapeutic drugs [23] Takeshita andcoworkers demonstrated the growth inhibitory role of miR-16 in prostate cancer cells [24] The levels of miR-34 aresignificantly decreased in various cancers and its restorationwas reported to inhibit angiogenesis andmalignant behavioryet at the same time it induced apoptosis and cell cycle arrest[25 26] Additionally the role of miR-34 in the inhibition oftumor-initiating cells has also been suggested [27] In mixedlineage leukemia the overexpression of miR-495 inhibitedcell viability and reduced leukemogenesis in vivo [28] Inone of our recent studies we investigated the significanceof miR-150 downregulation in pancreatic cancer [29] Wedemonstrated that the restoration of miR-150 inhibited the

MUC4 oncoprotein Consequently the growth and malig-nant potential of pancreatic cancer cells were suppressed[29 30] The role of miR-451 as a tumor suppressor miRNAby inhibiting cancer cell migration invasion and growthis well known [31ndash33] Further Kovalchuk and coworkersdemonstrated that miR-451 sensitizes MCF-7DOX-resistantcells to doxorubicin cytotoxicity [34] Xu and coworkersdemonstrated that miR-203 overexpression effectively inhib-ited cell proliferation and induced apoptosis and cell cyclearrest Moreover its overexpression also inhibited tumorgrowth in a mouse model [35]

To date several miRNAs have been identified that act asoncogenes [36] miR-17-92 is an oncogenic gene cluster [37]restoration of this cluster in MYC-driven B-cell lymphomassuppressed apoptosis and enhanced tumorigenicity [37] Maet al 2010 demonstrated that miR-27a which is overex-pressed in pancreatic cancer plays an oncogenic role bytargeting tumor suppressor Spry2 [38] Inhibition of miR-27adecreased growth clonogenicity andmigration of pancreaticcancer cells miR-21 is a widely studied oncogenic miRNAwhich is frequently overexpressed in various malignancies[39 40] Inactivation ofmiR-21 results in apoptosis inductioninhibition of growth and malignant progression [39ndash41] Ina transgenic mice model miR-155 induced polyclonal pre-B-cell proliferation resulting in B-cell leukemia [42] miR-373and miR-520c are known to promote migration invasionand metastasis of breast cancer cells by targeting CD44expression [43] Moreover the roles of miR-373 and miR-520c in promoting migration and invasion of prostate cancercells have also been reported [44] In pancreatic cancermiR-424-5p is overexpressed and its high expression hasbeen reported to be associated with enhanced proliferationand apoptosis resistance through downregulating SOCS6[45] miR-10b is overexpressed in various malignancies andpromotes cell migration invasion and metastasis [46ndash48]Moreover a high expression of miR-10b correlated withdisease progression [47 49]miR-221 andmiR-222 are knownto facilitate tumor cell growth malignant potential and EMTinmultiple malignancies such as prostate breast and thyroidcancer [50ndash53]

Moreover overexpression of miR-221 and miR-222 wasshown to impart tamoxifen-resistance in breast cancer cells[54] Altogether these findings indicate that miRNAs playimportant roles as oncogenes in cancer cells

4 Modulation of miRNAs by Phytochemicals

miRNAs are being considered as attractive targets for cancerprevention and therapy due to their oncogenic or tumorsuppressor activities Various studies have suggested that themodulation of miRNAs serves as one of the key mechanismsin the anticancer activities of a variety of phytochemicals(Table 1) Below we describe some of the phytochemicalswhich are known to regulate miRNA expression in cancer

41 Resveratrol Resveratrol is a stilbenoid that has beenshown to have anticancer activities against various cancers

BioMed Research International 3

Table 1 Phytochemical-mediated regulation of miRNAs in cancer Modulation of miRNA expression by certain phytochemical agents andeffect on cancer pathobiology

Phytochemical miRNA Function Reference

Resveratrol uarr miR-141 miR-663 and miR-200c Invasiveness EMT and metastasis [57ndash61 114]darr miR-17 miR-21 miR-25 miR-92a-2 miR-103-1 andmiR-103-2

EGCGuarr miR-16 miR-210 miR-7-1 miR-34a and miR-99a Apoptosis [62ndash66]darr miR-21 miR-98-5p miR-92 miR-93 and miR-106b Proliferation anchorage-independent

growth and drug resistance

Genistein uarr miR-16 Apoptosis [67 68]darr miR-221 and miR-222 Growth

Curcumin uarr miR-15a miR-16 and miR-186lowast Apoptosis [80 82 83]darr miR-21 Metastasis

Quercetin uarr let-7 GrowthApoptosis [88 89]

darr miR-27aCamptothecin darr miR-125b Apoptosis [92]

DIM uarr miR-21 miR-200b miR-200c let-7b let-7c let-7d let-7eand miR-146a

Growth EMT drug resistance invasionand metastasis [95ndash97]

including breast cancer lung cancer glioma prostate can-cer colon cancer and neuroblastoma [55 56] Resveratrolreduced the expression of numerous oncogenic miRNAsnamely miR-17 miR-21 miR-25 miR-92a-2 miR-103-1 andmiR-103-2 in human colon cancer cells [57] Moreoverin the same study tumor suppressor miR-663 levels wereshown to be restored in human colon cancer cells after thetreatment of resveratrol In another study Hagiwara et alreported that resveratrol treatment upregulated miR-141 andresulted in a significant reduction of invasiveness whereasresveratrol-induced miR-200c expression caused reversal ofEMT through downregulation of Zeb1 and upregulation ofE-cadherin [58] It has been demonstrated that the anti-cancer effect of resveratrol on pancreatic cancer cells wasdue to inhibition of oncogenic miR-21 [59] Moreover thesynergistic antitumor activity of resveratrol andmiR-200c hasbeen demonstrated in human lung cancer cells [60] In coloncancer cells resveratrol inhibited the cell growth and inducedapoptosis through upregulating miR-34a expression [61]

42 Epigallocatechin-3-gallate (EGCG) Epigallocatechin-3-gallate is a polyphenol flavonoid that possesses significantantioxidant and anticancer properties It has been shownthat EGCG induces apoptosis in hepatocellular carcinomathrough enhanced expression of miR-16 [62] Increasedexpression of miR-16 resulted in inhibition of its targetantiapoptotic Bcl-2 followed by mitochondrial dysfunctioncytochrome c release and subsequent apoptosis EGCG alsoinhibited the expression of miR-21 followed by repression ofandrogen receptor (AR) signaling and consequently a reduc-tion of prostate cancer cell growth [63] In lung cancer EGCGupregulated the expression of miR-210 which led to the inhi-bition of proliferation and anchorage-independent growth[64] EGCG enhanced the efficacy of cisplatin through down-regulation of miR-98-5p in A549 non-small lung cancer cells[65] A combination of N-(4-hydroxyphenyl) retinamide and

EGCG decreased the expression of oncogenic miRs (miR-92 miR-93 and miR-106b) and enhanced the expressionof tumor suppressor miRs (miR-7-1 miR-34a and miR-99a) which resulted in growth inhibitory effects in humanmalignant neuroblastoma cells [66]

43 Genistein Genistein is another important polyphenolthat showed significant anticancer effects through the regula-tion of miRNAs Genistein treatment was shown to enhanceapoptosis synergistically with miR-16 in human chroniclymphocytic leukemia cells [67] In a study onprostate cancergenistein both downregulated miR-221 and miR-222 andrestored tumor suppressor gene aplasia Ras homologmemberI (ARHI) expression which ultimately resulted in anticancereffects [68] In another study on prostate cancer genisteininhibited the migration and invasion of PC3 and DU145cells through downregulating oncogenic miR-151 [69] Xu etal have shown that treatment of ovarian cancer cells withgenistein caused an inhibition of cell growth and migrationthrough suppression of miR-27a [70] Further genisteinhas been shown to upregulate the tumor suppressor miR-574-3p in prostate cancer cells [71] Moreover it has beenobserved that genistein exerted its antitumor effect in prostatecancer via downregulation of miR-1260b [72] Genisteintreatment downregulated oncogenic miR-1260b and resultedin inhibition ofWnt-signalling in renal cancer cells [72]miR-223 expression was found to be downregulated in pancreaticcancer cells after genistein treatment that correlated with cellgrowth inhibition and induction of apoptosis [73] Genisteinalso plays a tumor suppressor role through inhibition of miR-27a in pancreatic cancer cells [74]

44 Curcumin Curcumin is a constituent of turmeric (Cur-cuma longa) and has been used as an important componentof spice in Indian food and as a traditional medicine in Asian


countries for many decades [75] It possesses chemopreven-tive and chemotherapeutic activities against many tumors[75ndash78] Curcumin exerts its therapeutic effects by regulatingmiRNAs known to play an important role in cancer [79]Yang et al have shown that curcumin upregulated miR-15a and miR-16 in MCF-7 breast cancer cells which causedan induction of apoptosis [80] In another study curcumintreatment resulted in the upregulation of tumor suppressormiR-203 in bladder cancer that led to apoptosis induction anddiminished proliferation migration and invasion [81] Cur-cumin has also been shown to induce tumor suppressor miR-186lowast expression to promote apoptosis in lung cancer [82]Moreover curcumin inhibited the transcriptional regulationof oncogenic miR-21 in colon cancer causing inhibition ofgrowth invasion and metastasis [83] Zhao et al providedevidence that curcumin exerts its cytotoxic effects againstSKOV3 ovarian cancer cells largely through upregulationof miR-9 [84] Another tumor suppressor miR181b hasbeen demonstrated to be induced by curcumin and itinhibited breast cancer metastasis via downregulation of theinflammatory cytokines CXCL1 and CXCL2 [85] High levelsof miR-221 expression have been correlated with shortersurvival in pancreatic cancer patients suggesting that miR-221 could be an oncogenic miRNA [86] In the same studythe synthetic curcumin analogue (CDF) has been foundto suppress the expression of miR-221 and upregulate theexpression of PTEN p27 (kip1) p57 (kip2) and PUMAfollowed by inhibition of cell proliferation and migration ofpancreatic cancer cellsThus altogether these studies provideevidence that curcumin modulates the expression of miRNAsignatures in cancer cells to confer its anticancer activity

45 Quercetin Intake of a quercetin-rich diet has beendemonstrated to modulate the expression of 48 uniquemiRNAs These miRNAs have been reported to decreasetumor metastasis and invasion (miR-146ab 503 and 194)inhibit cell proliferation (miR-125a 155 let-7 family 302c195 26a 503 and 215) induce apoptosis (miR-125a 605 26blet-7g 34a 491 and 16) and upregulate tumor suppressormiRNAs (let-7 family miR-125a 183 146a 98 19b 106a and381) [87] Del Follo-Martinez et al reported that quercetintreatment induced apoptosis in colorectal cancer cells whenused along with resveratrol The underlying mechanism ofapoptosis induction is the downregulation of oncogenicmiR-27a [88] In another study quercetin when used withcatechins was shown to enhance the expression of let-7in pancreatic cancer cells followed by K-ras inhibition andreduction of the advancement of pancreatic cancer [89]

46 Camptothecin (CPT) Camptothecin an alkaloid iso-lated from bark of Camptotheca acuminata is a potentchemotherapeutic agent against a variety of tumors [90ndash92]CPT was demonstrated to reduce the expression of miR-125b significantly which led to the upregulation of Bak1and p53 and resulted in apoptosis of human cervical cancerand myelogenous leukemia cells [92] In a recent studycamptothecin was shown to inhibit HIF-1120572 by enhancing thelevels of miR-155 miR-17-5p and miR-18a in HeLa cells [93]

47 Diindolylmethane (DIM) Diindolylmethane is an activecompound that is generated in the stomach through themetabolic conversion of indole-3-carbinol (I3C) presentin cruciferous vegetables [94] DIM regulates the expres-sion of numerous miRNAs involved in cancer developmentand progression DIM has been demonstrated to inducethe expression of certain miRNAs such as miR-200 and let-7 families that led to the reversal of EMT and enhancedchemosensitivity in gemcitabine-resistant pancreatic cancercells [95] DIM also induced the expression of miR-146awhich resulted in reduced pancreatic cancer cell invasionvia inhibition of metastasis-associated protein 2 (MTA-2) interleukin-1 receptor-associated kinase 1 (IRAK-1) andNF120581B [96] Moreover Jin observed that DIM inhibitedbreast cancer cell growth by enhancing the expression ofmiR-21 which led to the degradation of its target Cdc25A[97] Formulated 331015840-diindolylmethane (BR-DIM) has beenshown to be capable of downregulating miR-221 resulting ingrowth inhibition of pancreatic cancer cells [86]

5 Mechanism of miRNARegulation by Phytochemicals

There have been several aberrantly expressed miRNAs iden-tified in various cancer types Unfortunately the precisemechanisms that regulate the normal expression of miRNAsor their deregulation in cancer remain unclear Growing evi-dence suggests that aberrant transcriptional regulation epi-genetic changes alterations in miRNA biosynthesis machin-ery mutations or DNA copy number could contribute tomiRNA dysregulation in human cancer [98] Experimentalstudies on phytochemicals revealed that the expression ofvarious miRNAs can be regulated by phytochemicals In thefollowing section we provide an overview for the regulationof miRNAs by phytochemicals through various mechanismssuch as epigenetic transcriptional and miRNA processing(Figure 1)

51 Transcriptional Regulation of miRNAs Various studiesindicate the involvement of certain transcription factorsin the regulation of miRNA expression and the subse-quent modulation of pathological conditions in cancerThus transcription factor-mediated miRNA regulation isone critical aspect of study Several groups have observedthat phytochemicals modulate miRNA expression throughtranscriptional regulation (Figure 1) Wang and coworkersdemonstrated that treatment with EGCG results in the tran-scriptional activation ofmiR-210 in lung cancer by promotingthe binding of hypoxia inducible factor-1120572 (HIF-1120572) to thehypoxia response element present in the promoter region ofmiR-210 [64] Transcription factor activator protein (AP-1)an important regulator of genes involved in cell proliferationand extracellular matrix production [99] is an upstreamregulator ofmiR-21 [100]Mudduluru and coworkers demon-strated that curcumin inhibits the transcriptional regulationof miR-21 by downregulating AP-1 to suppress tumor growthinvasion and metastasis of colorectal cancer [83] Anothertranscription factor CCAATenhancer binding protein beta


Pri-miRNA Pri-miRNADGCR8

RNA

Pol

IIII

I

Epigenetic alterations

Nucleus

Ω Exportin Ω

DicerAgo2

RISC

form

atio

n

Target degradation

Translational repression

Ran-GTP

EGCG

Curcumin

Curcumin

Daidzein

miRNA gene

miRNA processing

ΩΩ Ω

Ω Drosha

Cytoplasm

Ago

2

Transcriptionfactors

3998400

3998400

5998400

5998400

3998400

3998400

5998400

5998400

Ω

ResveratrolResveratrol

Genistein

Figure 1 Mechanistic overview of miRNA regulation by phytochemicals Phytochemicals regulate the expression of miRNAs throughmodulation of transcription factors and inducing epigenetic modifications and by interfering with processes associated with miRNAmaturation

(CEBP-120573) negatively regulates tumor suppressormiR-145 bydirectly interacting through the putative CEBP-120573 bindingsite present in the miR-145 promoter It was also shown thatresveratrol treatment resulted in the decreased activationof CEBP-120573 which subsequently induced the expression ofmiR-145 in breast cancer cells [101] Androgen receptor(AR) directly regulates miR-21 by binding to the miR-21promoter in prostate cancer [102] Siddiqui and coworkers(2011) demonstrated that EGCG inhibited prostate cancer cellgrowth by decreasing the level of AR and miR-21 [63] Astudy conducted by Hagiwara and coworkers has shown thatresveratrol transcriptionally upregulated the expression ofseveral tumor suppressor miRNAs such as miR-141 miR-26amiR-195 miR-126 miR-340 miR-34a miR-193b miR-335miR-200c miR-497 miR-196a and miR-125a-3p in MDA-MB-231 breast cancer cells [58] It is known that p53 is a tumorsuppressor gene and a transcription factor which functionsby either causing growth arrest or inducing apoptosis [103]Emerging data suggest that p53 transcriptionally regulatesseveral miRNAs [104] A number of studies have shown thatcurcumin regulates the expression of several miRNAs thatare transcriptional targets of p53 such as miR-22 miR-1516amiR-34 and miR-21 [80 83 105ndash108] Considering all theseobservations it is speculated that curcumin regulates theexpression of p53 which in turn modulates the expression ofseveral miRNAs

52 Epigenetic Regulation of miRNAs Epigenetic regulationis defined asmodifications of the genomewithout any changeto the nucleotide sequence Supporting evidence suggeststhat epigenetic modification like aberrant CpG methylationor histone modifications contributes to the dysregulation ofgene expression in tumor cells Pharmacologic inhibition of

DNAmethyltransferase (DNMT) causesDNAdemethylationandupregulates the expression ofmiRNAs Saini and cowork-ers provided evidence that curcumin treatment resulted inthe hypomethylation of miR-203 promoter and subsequentupregulation of miR-203 which is epigenetically silencedin various malignancies [81] Treatment with a curcuminanalogue difluorinated curcumin restored the expression ofmiR-34a and miR-34c by working as a demethylating agentin colon cancer cells [109] Rabiau and coworkers performedmiRNA expression profiling following the treatment withthe flavonoids genistein and daidzein in prostate cancer cells[110] Their investigation revealed a significant upregulationof miR-548b-5p in PC3 andmiR-15a in LNCaP cells by genis-tein and daidzein through regulation at the epigenetic level[110] Zaman et al demonstrated that miR-145 is inactivatedas a result of its promoter methylation in prostate cancertreatment with genistein demethylated the promoter of miR-145 which resulted in an increased level of miR-145 [111]In a separate study on prostate cancer isoflavone efficientlydemethylated the promoter region of miR-29a and miR-1256and subsequently upregulated their expression [112] All theseobservations suggest the significant role of phytochemicals inthe regulation of miRNAs at the epigenetic level (Figure 1)

53 Regulation of miRNA Processing by PhytochemicalsmiRNA processing can be regulated at various steps andany alteration in processing either increases or decreases thelevel of miRNAs [113] The role of phytochemical-modulatedexpression of miRNAs through the regulation of proteinsinvolved in miRNA processing has been recently investi-gated as shown in Figure 1 Hagiwara and coworkers inves-tigated and reported that resveratrol treatment significantlyincreased the expression of Ago2 and results in enhanced


levels of tumor suppressor miRNAs such as miR-16 miR-141 miR-143 and miR-200c in MDA-MB-231 cells [58]Moreover resveratrol treatment resulted in the enhancedlevel of miR-663 and pre-miR-663 by interfering with thedrosha mediated processing of pri-miR-663 that resulted inthe inhibition of miR-155 which is overexpressed in manycancers [114] These studies provide evidence that phyto-chemicals regulate the expression of miRNAs epigeneticallyand transcriptionally and by controlling miRNA processing

6 Conclusion and Future Perspective

miRNAs are a novel class of gene regulators Thus far wehave only been able to see just a small part of the complexityof cellular regulation by miRNAs with regard to all of thedifferent functions that miRNAs can perform miRNAs areaberrantly expressed in most cancers and this has beencorrelated throughout cancer initiation and progressionhence miRNAs represent very attractive and novel targetsfor cancer therapy Phytochemicals display an inimitableability to alter the level of miRNAs involved in regulation ofcancer pathobiology by modulating the expression of miR-NAs through a variety of mechanisms namely epigenetictranscriptional and miRNA processing In addition phy-tochemicals increase the chemosensitivity of conventionaltherapeutic drugs through modulating miRNAs As a resultphytochemicals can be exploited for designing therapeuticapproaches in combination with conventional therapies toimprove cancer treatment and prevention strategies Despitethe potent anticancer activities of phytochemicals there aresome concerns such as specific targeting and bioavailabilityTo overcome these hurdles in the use of phytochemicalsdifferent approaches are being explored namely chemicalmodification synthetic formulation delivery by nanopar-ticles and so forth Hence there is a wide scope for thedevelopment of phytochemicals into commercial drugs toefficaciously prevent and treat cancer

Conflict of Interests

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

Acknowledgments

Ajay P Singh received Grants nos CA137513 CA167137CA175772 and CA185490 and Seema Singh received Grantno CA169829 by NIHNCI Ajay P Singh received Grantsnos PC110545 and PC0739930 by DODUS Army andinternal funding support from USAMCI

References

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[2] M R Friedlander E Lizano A J S Houben et al ldquoEvidencefor the biogenesis ofmore than 1000 novel humanmicroRNAsrdquoGenome Biology vol 15 no 4 article R57 2014

[3] S Srivastava A Bhardwaj S LeavesleyWGrizzle S Singh andA Singh ldquoMicroRNAs as potential clinical biomarkers emerg-ing approaches for their detectionrdquoBiotechnicampHistochemistryvol 88 no 7 pp 373ndash387 2013

[4] S K Srivastava S Arora S Singh A Bhardwaj C Averett andA P Singh ldquoMicroRNAs in pancreatic malignancy progressand promisesrdquo Cancer Letters vol 347 no 2 pp 167ndash174 2014

[5] G Block B Patterson and A Subar ldquoFruit vegetables andcancer prevention a review of the epidemiological evidencerdquoNutrition and Cancer vol 18 no 1 pp 1ndash29 1992

[6] L Reddy B Odhav and K D Bhoola ldquoNatural products forcancer prevention a global perspectiverdquo Pharmacology andTherapeutics vol 99 no 1 pp 1ndash13 2003

[7] K A Steinmetz and J D Potter ldquoVegetables fruit and cancerprevention a reviewrdquo Journal of the American Dietetic Associa-tion vol 96 no 10 pp 1027ndash1039 1996

[8] M Russo C Spagnuolo I Tedesco and G L Russo ldquoPhyto-chemicals in cancer prevention and therapy truth or darerdquoToxins vol 2 no 4 pp 517ndash551 2010

[9] C V Rao C-X Wang B Simi et al ldquoEnhancement ofexperimental colon cancer by genisteinrdquo Cancer Research vol57 no 17 pp 3717ndash3722 1997

[10] D J Newman and G M Cragg ldquoNatural products as sources ofnew drugs over the last 25 yearsrdquo Journal of Natural Productsvol 70 no 3 pp 461ndash477 2007

[11] G L Russo ldquoIns and outs of dietary phytochemicals in cancerchemopreventionrdquoBiochemical Pharmacology vol 74 no 4 pp533ndash544 2007

[12] Y H Siddique G Ara T Beg J Gupta and M Afzal ldquoAssess-ment of cell viability lipid peroxidation and quantificationof DNA fragmentation after the treatment of anticancerousdrug mitomycin C and curcumin in cultured human bloodlymphocytesrdquo Experimental and Toxicologic Pathology vol 62no 5 pp 503ndash508 2010

[13] W Tan J Lu M Huang et al ldquoAnti-cancer natural productsisolated from chinese medicinal herbsrdquo Chinese Medicine vol6 article 27 2011

[14] N Tyagi and P C Ghosh ldquoFolate receptor mediated targeteddelivery of ricin entrapped into sterically stabilized liposomesto human epidermoid carcinoma (KB) cells effect of monensinintercalated into folate-tagged liposomesrdquo European Journal ofPharmaceutical Sciences vol 43 no 4 pp 343ndash353 2011

[15] N Tyagi S S Rathore and P C Ghosh ldquoEnhanced killingof human epidermoid carcinoma (KB) cells by treatmentwith ricin encapsulated into sterically stabilized liposomes incombination with monensinrdquo Drug Delivery vol 18 no 6 pp394ndash404 2011

[16] J Winter S Jung S Keller R I Gregory and S DiederichsldquoMany roads to maturity microRNA biogenesis pathways andtheir regulationrdquoNature Cell Biology vol 11 no 3 pp 228ndash2342009

[17] SM JohnsonHGrosshans J Shingara et al ldquoRAS is regulatedby the let-7 microRNA familyrdquo Cell vol 120 no 5 pp 635ndash6472005

[18] F Yu H Yao P Zhu et al ldquolet-7 regulates self renewal andtumorigenicity of breast cancer cellsrdquo Cell vol 131 no 6 pp1109ndash1123 2007

[19] B Zhang X Pan G P Cobb and T A Anderson ldquomicroRNAsas oncogenes and tumor suppressorsrdquo Developmental Biologyvol 302 no 1 pp 1ndash12 2007


[20] M S Kumar S J Erkeland R E Pester et al ldquoSuppression ofnon-small cell lung tumor development by the let-7 microRNAfamilyrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 10 pp 3903ndash3908 2008

[21] X-M Xia W-Y Jin R-Z Shi Y-F Zhang and J ChenldquoClinical significance and the correlation of expression betweenlet-7 and K-ras in non-small cell lung cancerrdquo Oncology Lettersvol 1 no 6 pp 1045ndash1047 2010

[22] A Cimmino G A Calin M Fabbri et al ldquomiR-15 and miR-16induce apoptosis by targeting BCL2rdquoProceedings of theNationalAcademy of Sciences of the United States of America vol 102 no39 pp 13944ndash13949 2005

[23] L Xia D Zhang R Du et al ldquomiR-15b and miR-16 modulatemultidrug resistance by targeting BCL2 in human gastric cancercellsrdquo International Journal of Cancer vol 123 no 2 pp 372ndash379 2008

[24] F Takeshita L Patrawala M Osaki et al ldquoSystemic deliveryof synthetic microRNA-16 inhibits the growth of metastaticprostate tumors via downregulation of multiple cell-cyclegenesrdquoMolecular Therapy vol 18 no 1 pp 181ndash187 2010

[25] T-C Chang E A Wentzel O A Kent et al ldquoTransactivationof miR-34a by p53 broadly influences gene expression andpromotes apoptosisrdquoMolecular Cell vol 26 no 5 pp 745ndash7522007

[26] A Javeri M Ghaffarpour M F Taha and M HoushmandldquoDownregulation of miR-34a in breast tumors is not associatedwith either p53 mutations or promoter hypermethylation whileit correlates with metastasisrdquo Medical Oncology vol 30 no 1article 413 2013

[27] Q Ji X Hao M Zhang et al ldquoMicroRNA miR-34 inhibitshumanpancreatic cancer tumor-initiating cellsrdquoPLoSONE vol4 no 8 Article ID e6816 2009

[28] X Jiang H Huang Z Li et al ldquomiR-495 is a tumor-suppressormicroRNA down-regulated inMLL-rearranged leukemiardquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 109 no 47 pp 19397ndash19402 2012

[29] S K Srivastava A Bhardwaj S Singh et al ldquoMicroRNA-150directly targets MUC4 and suppresses growth and malignantbehavior of pancreatic cancer cellsrdquo Carcinogenesis vol 32 no12 pp 1832ndash1839 2011

[30] S Arora S K Swaminathan A Kirtane et al ldquoSynthe-sis characterization and evaluation of poly (DL-lactide-co-glycolide)-based nanoformulation of miRNA-150 potentialimplications for pancreatic cancer therapyrdquo International Jour-nal of Nanomedicine vol 9 pp 2933ndash2942 2014

[31] D Liu C Liu X Wang S Ingvarsson and H ChenldquoMicroRNA-451 suppresses tumor cell growth by down-regulating IL6R gene expressionrdquo Cancer Epidemiology vol 38no 1 pp 85ndash92 2014

[32] X Liu X Zhang J Xiang Y Lv and J Shi ldquomiR-451 potentialrole as tumor suppressor of human hepatoma cell growth andinvasionrdquo International Journal of Oncology vol 45 pp 739ndash745 2014

[33] G Lv Z Hu Y Tie et al ldquoMicroRNA-451 regulates activatingtranscription factor 2 expression and inhibits liver cancer cellmigrationrdquoOncology Reports vol 32 no 3 pp 1021ndash1028 2014

[34] 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

[35] D Xu Q Wang Y An and L Xu ldquoMiR-203 regulates theproliferation apoptosis and cell cycle progression of pancreatic

cancer cells by targeting SurvivinrdquoMolecular Medicine Reportsvol 8 no 2 pp 379ndash384 2013

[36] L Zhang and G Coukos ldquoMicroRNAs a new insight intocancer genomerdquo Cell Cycle vol 5 no 19 pp 2216ndash2219 2006

[37] L He J M Thomson M T Hemann et al ldquoA microRNApolycistron as a potential human oncogenerdquo Nature vol 435no 7043 pp 828ndash833 2005

[38] YMa S YuW Zhao Z Lu and J Chen ldquomiR-27a regulates thegrowth colony formation and migration of pancreatic cancercells by targeting Sprouty2rdquo Cancer Letters vol 298 no 2 pp150ndash158 2010

[39] P P Medina M Nolde and F J Slack ldquoOncomiR addictionin an in vivo model of microRNA-21-induced pre-B-cell lym-phomardquo Nature vol 467 no 7311 pp 86ndash90 2010

[40] F Sicard M Gayral H Lulka L Buscail and P Cordelier ldquoTar-geting miR-21 for the therapy of pancreatic cancerrdquo MolecularTherapy vol 21 no 5 pp 986ndash994 2013

[41] Y Li L Yan W Zhang et al ldquomiR-21 inhibitor suppressesproliferation and migration of nasopharyngeal carcinoma cellsthrough down-regulation of BCL2 expressionrdquo InternationalJournal of Clinical and Experimental Pathology vol 7 pp 3478ndash3487 2014

[42] S Costinean N Zanesi Y Pekarsky et al ldquoPre-B cell prolifera-tion and lymphoblastic leukemiahigh-grade lymphoma in E120583-miR155 transgenic micerdquo Proceedings of the National Academyof Sciences of the United States of America vol 103 no 18 pp7024ndash7029 2006

[43] Q Huang K Gumireddy M Schrier et al ldquoThe microRNAsmiR-373 and miR-520c promote tumour invasion and metasta-sisrdquo Nature Cell Biology vol 10 no 2 pp 202ndash210 2008

[44] K Yang A M Handorean and K A Iczkowski ldquoMicroRNAs373 and 520c are downregulated in prostate cancer suppressCD44 translation and enhance invasion of prostate cancer cellsin vitrordquo International Journal of Clinical and ExperimentalPathology vol 2 no 4 pp 361ndash369 2009

[45] K Wu G Hu X He et al ldquoMicroRNA-424-5p suppresses theexpression of socs6 in pancreatic cancerrdquo Pathology ampOncologyResearch vol 19 no 4 pp 739ndash748 2013

[46] Y Liu M Li G Zhang and Z Pang ldquoMicroRNA-10b overex-pression promotes non-small cell lung cancer cell proliferationand invasionrdquo European Journal of Medical Research vol 18 no1 article 41 2013

[47] L Ma J Teruya-Feldstein and R A Weinberg ldquoTumourinvasion and metastasis initiated by microRNA-10b in breastcancerrdquo Nature vol 449 no 7163 pp 682ndash688 2007

[48] H Xiao H Li G Yu et al ldquoMicroRNA-10b promotesmigrationand invasion through KLF4 and HOXD10 in human bladdercancerrdquo Oncology Reports vol 31 pp 1832ndash1838 2014

[49] A Ahmad S Sethi W Chen R Ali-Fehmi S Mittal and F HSarkar ldquoUp-regulation of microRNA-10b is associated with thedevelopment of breast cancer brain metastasisrdquo The AmericanJournal of Translational Research vol 6 pp 384ndash390 2014

[50] M S Hwang N Yu S Y Stinson et al ldquomiR-221222targets adiponectin receptor 1 to promote the epithelial-to-mesenchymal transition in breast cancerrdquo PLoS ONE vol 8 no6 Article ID e66502 2013

[51] S Mardente E Mari F Consorti et al ldquoHMGB1 induces theoverexpression of miR-222 and miR-221 and increases growthandmotility in papillary thyroid cancer cellsrdquoOncology Reportsvol 28 no 6 pp 2285ndash2289 2012


[52] R Nassirpour P P Mehta S M Baxi and M-J Yin ldquomiR-221promotes tumorigenesis in human triple negative breast cancercellsrdquo PLoS ONE vol 8 no 4 Article ID e62170 2013

[53] X Yang Y Yang R Gan et al ldquoDown-regulation ofmir-221 andmir-222 restrain prostate cancer cell proliferation andmigrationthat is partly mediated by activation of SIRT1rdquo PLoS ONE vol9 no 6 Article ID e98833 2014

[54] T E Miller K Ghoshal B Ramaswamy et al ldquoMicroRNA-221222 confers tamoxifen resistance in breast cancer by target-ing p27Kip1rdquo The Journal of Biological Chemistry vol 283 no44 pp 29897ndash29903 2008

[55] A Bishayee T Politis and A S Darvesh ldquoResveratrol in thechemoprevention and treatment of hepatocellular carcinomardquoCancer Treatment Reviews vol 36 no 1 pp 43ndash53 2010

[56] M Athar J H Back X Tang et al ldquoResveratrol a review ofpreclinical studies for human cancer preventionrdquo Toxicologyand Applied Pharmacology vol 224 no 3 pp 274ndash283 2007

[57] E Tili J J Michaille H Alder et al ldquoResveratrol modulatesthe levels of microRNAs targeting genes encoding tumor-suppressors and effectors of TGF120573 signaling pathway in SW480cellsrdquo Biochemical Pharmacology vol 80 no 12 pp 2057ndash20652010

[58] K Hagiwara N Kosaka Y Yoshioka R U Takahashi FTakeshita and T Ochiya ldquoStilbene derivatives promote Ago2-dependent tumour-suppressive microRNA activityrdquo ScientificReports vol 2 article 314 2012

[59] P Liu H Liang Q Xia et al ldquoResveratrol induces apoptosis ofpancreatic cancers cells by inhibitingmiR-21 regulation of BCL-2 expressionrdquo Clinical and Translational Oncology vol 15 no 9pp 741ndash746 2013

[60] T Bai D-S Dong and L Pei ldquoSynergistic antitumor activityof resveratrol and miR-200c in human lung cancerrdquo OncologyReports vol 31 no 5 pp 2293ndash2297 2014

[61] M Kumazaki S Noguchi Y Yasui et al ldquoAnti-cancer effects ofnaturally occurring compounds through modulation of signaltransduction and miRNA expression in human colon cancercellsrdquo Journal of Nutritional Biochemistry vol 24 no 11 pp1849ndash1858 2013

[62] W P Tsang and T T Kwok ldquoEpigallocatechin gallate up-regulation of miR-16 and induction of apoptosis in humancancer cellsrdquoThe Journal of Nutritional Biochemistry vol 21 no2 pp 140ndash146 2010

[63] I A Siddiqui M Asim B B Hafeez V M Adhami R STarapore andHMukhtar ldquoGreen tea polyphenol EGCGbluntsandrogen receptor function in prostate cancerrdquo The FASEBJournal vol 25 no 4 pp 1198ndash1207 2011

[64] HWang S Bian and C S Yang ldquoGreen tea polyphenol EGCGsuppresses lung cancer cell growth through upregulating miR-210 expression caused by stabilizing HIF-1120572rdquo Carcinogenesisvol 32 no 12 pp 1881ndash1889 2011

[65] D-H Zhou X Wang and Q Feng ldquoEGCG enhances the effi-cacy of cisplatin by downregulating hsa-miR-98-5p in NSCLCA549 cellsrdquo Nutrition and Cancer vol 66 no 4 pp 636ndash6442014

[66] M Chakrabarti W Ai N L Banik and S K Ray ldquoOverexpres-sion of miR-7-1 increases efficacy of green tea polyphenols forinduction of apoptosis in humanmalignant neuroblastoma SH-SY5Y and SK-N-DZ cellsrdquo Neurochemical Research vol 38 no2 pp 420ndash432 2013

[67] E Salerno B J Scaglione F D Coffman et al ldquoCorrectingmiR-15a16 genetic defect inNewZealandBlackmousemodel ofCLL

enhances drug sensitivityrdquo Molecular Cancer Therapeutics vol8 no 9 pp 2684ndash2692 2009

[68] Y Chen M S Zaman G Deng et al ldquoMicroRNAs 221222 andgenistein-mediated regulation of ARHI tumor suppressor genein prostate cancerrdquo Cancer Prevention Research vol 4 no 1 pp76ndash86 2011

[69] T Chiyomaru S YamamuraM S Zaman et al ldquoGenistein sup-presses prostate cancer growth through inhibition of oncogenicmicroRNA-151rdquo PLoS ONE vol 7 no 8 Article ID e43812 2012

[70] L Xu J Xiang J Shen et al ldquoOncogenic microRNA-27a is atarget for genistein in ovarian cancer cellsrdquo Anti-Cancer Agentsin Medicinal Chemistry vol 13 no 7 pp 1126ndash1132 2013

[71] T Chiyomaru S Yamamura S Fukuhara et al ldquoGenisteinup-regulates tumor suppressor microRNA-574-3p in prostatecancerrdquo PLoS ONE vol 8 no 3 Article ID e58929 2013

[72] H Hirata K Ueno K Nakajima et al ldquoGenistein downreg-ulates onco-miR-1260b and inhibits Wnt-signalling in renalcancer cellsrdquo British Journal of Cancer vol 108 no 10 pp 2070ndash2078 2013

[73] J Ma L Cheng H Liu et al ldquoGenistein down-regulates miR-223 expression in pancreatic cancer cellsrdquoCurrent Drug Targetsvol 14 no 10 pp 1150ndash1156 2013

[74] J Xia L Cheng CMei et al ldquoGenistein inhibits cell growth andinvasion through regulation of MiR-27a in pancreatic cancercellsrdquo Current Pharmaceutical Design vol 20 no 33 pp 5348ndash5353 2014

[75] G N Asher and K Spelman ldquoClinical utility of curcuminextractrdquo Alternative Therapies in Health and Medicine vol 19no 2 pp 20ndash22 2013

[76] T O Khor Y-S Keum W Lin et al ldquoCombined inhibitoryeffects of curcumin and phenethyl isothiocyanate on the growthof human PC-3 prostate xenografts in immunodeficient micerdquoCancer Research vol 66 no 2 pp 613ndash621 2006

[77] X-D Sun X-E Liu and D-S Huang ldquoCurcumin reverses theepithelial-mesenchymal transition of pancreatic cancer cells byinhibiting the Hedgehog signaling pathwayrdquo Oncology Reportsvol 29 no 6 pp 2401ndash2407 2013

[78] H K Vyas R Pal R Vishwakarma N K Lohiya and GP Talwar ldquoSelective killing of leukemia and lymphoma cellsectopically expressing hCG120573 by a conjugate of curcumin withan antibody against hCG120573 subunitrdquoOncology vol 76 no 2 pp101ndash111 2009

[79] S Reuter S C Gupta B Park A Goel and B B AggarwalldquoEpigenetic changes induced by curcumin and other naturalcompoundsrdquoGenes and Nutrition vol 6 no 2 pp 93ndash108 2011

[80] J Yang Y Cao J Sun and Y Zhang ldquoCurcumin reduces theexpression of Bcl-2 by upregulating miR-15a and miR-16 inMCF-7 cellsrdquo Medical Oncology vol 27 no 4 pp 1114ndash11182010

[81] S Saini S Arora S Majid et al ldquoCurcumin modulatesmicroRNA-203-mediated regulation of the Src-Akt axis inbladder cancerrdquo Cancer Prevention Research vol 4 no 10 pp1698ndash1709 2011

[82] J Zhang Y Du C Wu et al ldquoCurcumin promotes apoptosis inhuman lung adenocarcinoma cells through miR-186lowast signalingpathwayrdquo Oncology Reports vol 24 no 5 pp 1217ndash1223 2010

[83] G Mudduluru J N George-William S Muppala et al ldquoCur-cumin regulates miR-21 expression and inhibits invasion andmetastasis in colorectal cancerrdquo Bioscience Reports vol 31 no3 pp 185ndash197 2011


[84] S F Zhao X Zhang X J Zhang X Q Shi Z J Yu and QC Kan ldquoInduction of microRNA-9 mediates cytotoxicity ofcurcumin against SKOV3 ovarian cancer cellsrdquo Asian PacificJournal of Cancer Prevention vol 15 pp 3363ndash3368 2014

[85] E KronskiM E Fiori O Barbieri et al ldquoMiR181b is induced bythe chemopreventive polyphenol curcumin and inhibits breastcancer metastasis via down-regulation of the inflammatorycytokines CXCL1 and -2rdquoMolecular Oncology vol 8 no 3 pp581ndash595 2014

[86] S Sarkar H Dubaybo S Ali et al ldquoDown-regulation of miR-221 inhibits proliferation of pancreatic cancer cells throughup-regulation of PTEN p27(kip1) p57(kip2) and PUMArdquoAmerican Journal of Cancer Research vol 3 no 5 pp 465ndash4772013

[87] T K Lam S Shao Y Zhao et al ldquoInfluence of quercetin-richfood intake on microRNA expression in lung cancer tissuesrdquoCancer Epidemiology Biomarkers amp Prevention vol 21 no 12pp 2176ndash2184 2012

[88] A Del Follo-Martinez N Banerjee X Li S Safe and SMertens-Talcott ldquoResveratrol and quercetin in combinationhave anticancer activity in colon cancer cells and repressoncogenic microRNA-27ardquo Nutrition and Cancer vol 65 no3 pp 494ndash504 2013

[89] M Appari K R Babu A Kaczorowski W Gross and IHerr ldquoSulforaphane quercetin and catechins complement eachother in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibitionrdquo International Journal ofOncology vol 45 no 4 pp 1391ndash1400 2014

[90] C G Moertel A J Schutt R J Reitemeier and R G HahnldquoPhase II study of camptothecin (NSC-100880) in the treatmentof advanced gastrointestinal cancerrdquo Cancer ChemotherapyReports vol 56 no 1 pp 95ndash101 1972

[91] H Ulukan and P W Swaan ldquoCamptothecins a review of theirchemotherapeutic potentialrdquo Drugs vol 62 no 14 pp 2039ndash2057 2002

[92] C-W Zeng X-J Zhang K-Y Lin et al ldquoCamptothecininduces apoptosis in cancer cells via microRNA-125b-mediatedmitochondrial pathwaysrdquo Molecular Pharmacology vol 81 no4 pp 578ndash586 2012

[93] D Bertozzi J Marinello S G Manzo F Fornari L Gra-mantieri and G Capranico ldquoThe natural inhibitor of DNAtopoisomerase I camptothecin modulates HIF-1120572 activity bychanging miR expression patterns in human cancer cellsrdquoMolecular Cancer Therapeutics vol 13 no 1 pp 239ndash248 2013

[94] D M Minich and J S Bland ldquoA review of the clinical efficacyand safety of cruciferous vegetable phytochemicalsrdquo NutritionReviews vol 65 no 6 pp 259ndash267 2007

[95] Y Li T G Vandenboom II D Kong et al ldquoUp-regulation ofmiR-200 and let-7 by natural agents leads to the reversal ofepithelial-to-mesenchymal transition in gemcitabine-resistantpancreatic cancer cellsrdquo Cancer Research vol 69 no 16 pp6704ndash6712 2009

[96] Y Li T G VandenBoom Z Wang et al ldquomiR-146a suppressesinvasion of pancreatic cancer cellsrdquoCancer Research vol 70 no4 pp 1486ndash1495 2010

[97] Y Jin ldquo331015840-Diindolylmethane inhibits breast cancer cell growthvia miR-21-mediated Cdc25A degradationrdquoMolecular and Cel-lular Biochemistry vol 358 no 1-2 pp 345ndash354 2011

[98] S Deng G A Calin C M Croce G Coukos and L ZhangldquoMechanisms ofmicroRNAderegulation in human cancerrdquoCellCycle vol 7 no 17 pp 2643ndash2646 2008

[99] B W Ozanne L McGarry H J Spence et al ldquoTranscriptionalregulation of cell invasion AP-1 regulation of a multigenicinvasion programmerdquo European Journal of Cancer vol 36 no13 pp 1640ndash1648 2000

[100] A Misawa R Katayama S Koike A Tomida T Watanabeand N Fujita ldquoAP-1-dependent miR-21 expression contributesto chemoresistance in cancer stem cell-like SP cellsrdquo OncologyResearch vol 19 no 1 pp 23ndash33 2010

[101] M Sachdeva Q Liu J Cao Z Lu and Y-Y Mo ldquoNegativeregulation of miR-145 by CEBP-120573 through the Akt pathway incancer cellsrdquo Nucleic Acids Research vol 40 no 14 pp 6683ndash6692 2012

[102] J Ribas X Ni M Haffner et al ldquomiR-21 an andro-gen receptor-regulated microRNA that promotes hormone-dependent and hormone-independent prostate cancer growthrdquoCancer Research vol 69 no 18 pp 7165ndash7169 2009

[103] L Boominathan ldquoThe tumor suppressors p53 p63 and p73 areregulators of microRNA processing complexrdquo PLoS ONE vol5 no 5 Article ID e10615 2010

[104] M Yamakuchi C D Lotterman C Bao et al ldquoP53-inducedmicroRNA-107 inhibits HIF-1 and tumor angiogenesisrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 107 no 14 pp 6334ndash6339 2010

[105] X Ma S N Choudhury X Hua Z Dai and Y Li ldquoInteractionof the oncogenicmiR-21microRNA and the p53 tumor suppres-sor pathwayrdquo Carcinogenesis vol 34 no 6 pp 1216ndash1223 2013

[106] S Sreenivasan K Thirumalai R Danda and S KrishnakumarldquoEffect of curcumin on miRNA expression in human Y79retinoblastoma cellsrdquo Current Eye Research vol 37 no 5 pp421ndash428 2012

[107] D Subramaniam S Ponnurangam P Ramamoorthy et alldquoCurcumin induces cell death in esophageal cancer cellsthrough modulating Notch signalingrdquo PLoS ONE vol 7 no 2Article ID e30590 2012

[108] M Yamakuchi and C J Lowenstein ldquoMiR-34 SIRT1 and p53the feedback looprdquo Cell Cycle vol 8 no 5 pp 712ndash715 2009

[109] S Roy E Levi A P Majumdar and F H Sarkar ldquoExpressionof miR-34 is lost in colon cancer which can be re-expressed bya novel agent CDFrdquo Journal of Hematology amp Oncology vol 5article 58 2012

[110] N Rabiau H-K TrrafM Adjakly et al ldquomiRNAs differentiallyexpressed in prostate cancer cell lines after soy treatmentrdquo InVivo vol 25 no 6 pp 917ndash921 2011

[111] M S Zaman Y Chen G Deng et al ldquoThe functional signif-icance of microRNA-145 in prostate cancerrdquo British Journal ofCancer vol 103 no 2 pp 256ndash264 2010

[112] Y Li D Kong A Ahmad B Bao G Dyson and F HSarkar ldquoEpigenetic deregulation of miR-29a and miR-1256 byisoflavone contributes to the inhibition of prostate cancer cellgrowth and invasionrdquo Epigenetics vol 7 no 8 pp 940ndash9492012

[113] I Slezak-Prochazka D Selvi B-J Kroesen and A Van DenBerg ldquoMicroRNAs macrocontrol regulation of miRNA pro-cessingrdquo RNA vol 16 no 6 pp 1087ndash1095 2010

[114] E Tili J-J Michaille B Adair et al ldquoResveratrol decreasesthe levels of miR-155 by upregulating miR-663 a microRNAtargeting JunB and JunDrdquoCarcinogenesis vol 31 no 9 pp 1561ndash1566 2010

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


(CPT) and diindolylmethane (DIM) for cancer preventionand therapy

2 Biogenesis of miRNA and Mechanism ofGene Silencing

The biosynthesis of miRNAs begins with gene transcriptionby RNA polymerase II or RNA polymerase III into primarymiRNA (pri-miRNA) transcripts inside the nucleus Thesepri-miRNAs are comprised of either a cluster or single miR-NAs folded into a hairpin stem-like structure [1] This longpri-miRNA is processed by the sequential endonucleolyticcleavage of the transcript by the microprocessor complexcontaining drosha and DGCR8 into a 65ndash70-nucleotideprecursor miRNA (pre-miRNA) This pre-miRNA is thenexported from the nucleus to the cytoplasm by the nuclearexport factor Exportin-5Ran-GTP and cleaved by RNase IIIendonuclease DicerTRBP and argonaute 2 (Ago2) miRNAduplex [16] into an sim22-nucleotide product This duplexmiRNA then unwinds to generate a single-stranded miRNAOne of the strands enters in the RNA-induced silencingcomplex (RISC) along with Ago proteins and directs thecomplex to target mRNA This binding causes either targetmRNA degradation or inhibition of translation [1]

3 Biological Significance of miRNAs inCancer Tumor Suppressors and Oncogenes

Based on in vitro and in vivo studies miRNAs have beencharacterized as tumor suppressors or oncogenes In thissection we will discuss some of the reports from a longlist of tumor suppressoroncogenic miRNAs that have beenexperimentally validated

Numerous studies have shown that the expression of thetumor suppressor Let-7 is significantly downregulated or lostin various cancers [17ndash19] It has been shown that restorationof Let-7 inhibited tumor growth in a K-RAS lung cancermodel [20] Furthermore decreased expression of let-7 corre-lated with shorter survival in non-small-cell lung cancer [21]OthermiRNAs such asmiR-15a andmiR-16 are either deletedor downregulated in most cases of the chronic lymphocyticleukemia and their overexpression induced apoptosis [22]Moreover it has been reported that miR-16 and miR-15were downregulated in multidrug-resistant human gastriccancer cells and restoration of these miRNAs sensitized thecancer cells to chemotherapeutic drugs [23] Takeshita andcoworkers demonstrated the growth inhibitory role of miR-16 in prostate cancer cells [24] The levels of miR-34 aresignificantly decreased in various cancers and its restorationwas reported to inhibit angiogenesis andmalignant behavioryet at the same time it induced apoptosis and cell cycle arrest[25 26] Additionally the role of miR-34 in the inhibition oftumor-initiating cells has also been suggested [27] In mixedlineage leukemia the overexpression of miR-495 inhibitedcell viability and reduced leukemogenesis in vivo [28] Inone of our recent studies we investigated the significanceof miR-150 downregulation in pancreatic cancer [29] Wedemonstrated that the restoration of miR-150 inhibited the

MUC4 oncoprotein Consequently the growth and malig-nant potential of pancreatic cancer cells were suppressed[29 30] The role of miR-451 as a tumor suppressor miRNAby inhibiting cancer cell migration invasion and growthis well known [31ndash33] Further Kovalchuk and coworkersdemonstrated that miR-451 sensitizes MCF-7DOX-resistantcells to doxorubicin cytotoxicity [34] Xu and coworkersdemonstrated that miR-203 overexpression effectively inhib-ited cell proliferation and induced apoptosis and cell cyclearrest Moreover its overexpression also inhibited tumorgrowth in a mouse model [35]

To date several miRNAs have been identified that act asoncogenes [36] miR-17-92 is an oncogenic gene cluster [37]restoration of this cluster in MYC-driven B-cell lymphomassuppressed apoptosis and enhanced tumorigenicity [37] Maet al 2010 demonstrated that miR-27a which is overex-pressed in pancreatic cancer plays an oncogenic role bytargeting tumor suppressor Spry2 [38] Inhibition of miR-27adecreased growth clonogenicity andmigration of pancreaticcancer cells miR-21 is a widely studied oncogenic miRNAwhich is frequently overexpressed in various malignancies[39 40] Inactivation ofmiR-21 results in apoptosis inductioninhibition of growth and malignant progression [39ndash41] Ina transgenic mice model miR-155 induced polyclonal pre-B-cell proliferation resulting in B-cell leukemia [42] miR-373and miR-520c are known to promote migration invasionand metastasis of breast cancer cells by targeting CD44expression [43] Moreover the roles of miR-373 and miR-520c in promoting migration and invasion of prostate cancercells have also been reported [44] In pancreatic cancermiR-424-5p is overexpressed and its high expression hasbeen reported to be associated with enhanced proliferationand apoptosis resistance through downregulating SOCS6[45] miR-10b is overexpressed in various malignancies andpromotes cell migration invasion and metastasis [46ndash48]Moreover a high expression of miR-10b correlated withdisease progression [47 49]miR-221 andmiR-222 are knownto facilitate tumor cell growth malignant potential and EMTinmultiple malignancies such as prostate breast and thyroidcancer [50ndash53]

Moreover overexpression of miR-221 and miR-222 wasshown to impart tamoxifen-resistance in breast cancer cells[54] Altogether these findings indicate that miRNAs playimportant roles as oncogenes in cancer cells

4 Modulation of miRNAs by Phytochemicals

miRNAs are being considered as attractive targets for cancerprevention and therapy due to their oncogenic or tumorsuppressor activities Various studies have suggested that themodulation of miRNAs serves as one of the key mechanismsin the anticancer activities of a variety of phytochemicals(Table 1) Below we describe some of the phytochemicalswhich are known to regulate miRNA expression in cancer

41 Resveratrol Resveratrol is a stilbenoid that has beenshown to have anticancer activities against various cancers




























RNA

Pol

IIII

I


Nucleus

Ω Exportin Ω

DicerAgo2

RISC

form

atio

n

Target degradation


Ran-GTP

EGCG

Curcumin

Curcumin

Daidzein

miRNA gene

miRNA processing

ΩΩ Ω

Ω Drosha

Cytoplasm

Ago

2


3998400

3998400

5998400

5998400

3998400

3998400

5998400

5998400

Ω


Genistein












Acknowledgments


References































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




























RNA

Pol

IIII

I


Nucleus

Ω Exportin Ω

DicerAgo2

RISC

form

atio

n

Target degradation


Ran-GTP

EGCG

Curcumin

Curcumin

Daidzein

miRNA gene

miRNA processing

ΩΩ Ω

Ω Drosha

Cytoplasm

Ago

2


3998400

3998400

5998400

5998400

3998400

3998400

5998400

5998400

Ω


Genistein












Acknowledgments


References































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology







Acknowledgments


References































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology












































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

review article modulation of micrornas by phytochemicals in … · 2019. 7. 31. · review article...

Documents