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Role of miRs in Polyphenol-Mediated Anticancer: History
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Contributor: Sumio Hayakawa , Tomokazu Ohishi ,
Yumiko Oishi
, Mamoru Isemura , Noriyuki Miyoshi

The anticancer effects of daily consumption of polyphenols. These dietary polyphenols include chlorogenic acid, curcumin, epigallocatechin-3-O-gallate, genistein, quercetin, and resveratrol. These polyphenols have similar chemical and biological properties in that they can act as antioxidants and exert the anticancer effects via cell signaling pathways involving their reactive oxygen species (ROS)-scavenging activity. These polyphenols may also act as pro-oxidants under certain conditions, especially at high concentrations. Epigenetic modifications, including dysregulation of noncoding RNAs (ncRNAs) such as microRNAs, long noncoding RNAs, and circular RNAs are now known to be involved in the anticancer effects of polyphenols. These polyphenols can modulate the expression/activity of the component molecules in ROS-scavenger-triggered anticancer pathways (RSTAPs) by increasing the expression of tumor-suppressive ncRNAs and decreasing the expression of oncogenic ncRNAs in general. Multiple ncRNAs are similarly modulated by multiple polyphenols. Many of the targets of ncRNAs affected by these polyphenols are components of RSTAPs. Therefore, ncRNA modulation may enhance the anticancer effects of polyphenols via RSTAPs in an additive or synergistic manner, although other mechanisms may be operating as well.

  • anticancer
  • ROS
  • polyphenols

1. Introduction

A number of epidemiological studies have provided evidence for the anticancer effects of daily polyphenol intake [1][2][3][4][5][6]. These dietary polyphenols include chlorogenic acid (CGA), curcumin (CUR), epigallocatechin-3-O-gallate (EGCG), genistein (GEN), quercetin (QUE) and resveratrol (RES), which are six major polyphenols in our dietary life and are found in vegetables, fruits, and beverages. Preclinical and cell-based studies have supported their anticancer effects and provided a mechanism of action for these polyphenols [1][2][3][5]. Recent studies have shown involvement of epigenetic modifications including dysregulation of noncoding RNAs (ncRNAs) such as micro RNAs (miRs), long noncoding RNAs (lncRs), and circular RNAs (circRs).
Researchers have provided updated information from human studies supporting the anticancer effects of consumption of green tea, coffee, red wine, soybeans, and curry and discussed the involvement of miRs in polyphenol action mechanisms (Table 1 and Table 2). Previous data have shown that the six major dietary polyphenols, chlorogenic acid (CGA), curcumin (CUR), epigallocatechin-3-O-gallate (EGCG), genistein (GEN), genistein (QUE), and resveratrol (RES), have similar properties since they can act as antioxidants and exert the anticancer effects via reactive oxygen species (ROS)-scavenger-triggered anticancer pathways (RSTAPs) (Figure 1) [7][8]. These dietary polyphenols are also known to act as pro-oxidants and reactive oxygen species (ROS) generated can activate AMP-activated protein kinase (AMPK) which will result in polyphenols’ anticancer effects (Figure 1). Moreover, data indicated that at least three of the six polyphenols can commonly modulate several miRs associated with RSTAPs [7][8].
Antioxidants 11 02352 g001 550
Figure 1. ROS-scavenger-triggered anticancer pathways (RSTAPs) and contribution of ncRNAs. lncRs upregulated and downregulated by polyphenols are in red and blue, respectively, on a yellow background. miRs upregulated and downregulated by polyphenols are in red and blue, respectively, on a green background.
Table 1. Modulation of molecular targets of tumor-suppressor miRs upregulated by three to five CUR, EGCG, QUE, RES and GEN.
miRs miR-16 miR-22 miR-34a miR-141 miR-145 miR-146a miR-200c
Polyphenols CUR
Yang et al. [9]
EGCG 
Tsang et al.[10] 
QUE          Sonoki et al. [11];
Zhao et al. [12]
RES
Hagiwara et al. [13];
Azimi et al. [14]		 CUR
Sun et al. [15];
Sreenivasan et al.
[16];
Sibbesen et al. [17]
EGCG
Li et al. [18]
QUE
Zhang et al. [19]		 CUR
Guo et al. [20]; Sun et al. [21];
Toden et al. [22]; Sun et al. [15]
EGCG
Chakrabarti et al. [23]; Li et al. [18];
Chakrabarti et al. [24]; Toden et al. [25]; Mostafa et al. [26]
GEN
Hsieh et al. [27]; Xia et al. [28];
Chiyomaru et al. [29]
RES
Hagiwara et al. [13]; Otsuka et al. [30];
Kumazaki et al. [31]; Yao et al. [32]		 CUR
Toden et al. [33]
EGCG
Gordon et al. [34]
GEN
Chiyomaru et al. [35]
RES
Hagiwara et al. [13]		 CUR
Mirgani et al. [36];
Liu et al. [37]
EGCG
Toden et al. [25]
GEN
Wei et al. [38]
QUE
Zhou et al. [39]
RES
Sachdeva et al. [40]		 CUR
Wu et al. [41]
GEN
Li et al. [42]
QUE
Tao et al. [43]		 CUR
Toden et al. [33];
Soubani et al. [44]
EGCG
Toden et al. [25]
RES
Hagiwara et al. [13];
Dermani et al. [45]
Targets * Bcl-2↓
CUR: Yang et al. [9];
EGCG: Tsang et al. [10]
HOXA10↓
QUE: Zhao et al. [12]		 SP1↓, ESR1↓
CUR: Sun et al. [15]
Erbb3↓
CUR: Sreenivasan et al. [16]
NCoA1↓, HDAC6↓, MYCBP↓, PTEN↓,
CUR: Sibbesen et al. [17]
Wnt1/β-catenin↓
QUE: Zhang et al. [19]		 Bcl-2↓, Bmi-1↓
CUR: Guo et al. [20]
Bcl-2↓, CDK4↓, Cyclin D1↓
CUR: Sun et al. [21]
Cyclin D↓, c-Myc↓, CDK6↓, Bcl-2↓
CUR: Toden et al. [22]
miR-92↓, miR-93↓, miR-106b↓, miR-7-1↑, miR-34a↑, miR-99a↑
EGCG: Chakrabarti et al. [23]
EMT↓, RTCB↓, ROS↑
GEN: Hsieh et al. [27]
HOTAIR↓
GEN: Chiyomaru et al. [29]
Notch-1↓
GEN: Xia et al. [28]
Sirt1↓ via E2F3
RES: Kumazaki et al. [31]
HNRNPA1↓
RES: Otsuka et al. [30]
Bcl-2↓
RES: Yao et al. [32]		 EMT↓
CUR: Toden et al. [33]
HOTAIR↓
GEN: Chiyomaru et al. [35]
Cancer stemness↓
RES: Hagiwara et al. [13]		 Oct4↓, SOX-2↓, Oct4B1↓,
CUR: Mirgani et al. [36]
Oct4↓, CD44↓, CD133↓, Cyclin D1↓, Cdk4↓
CUR: Liu et al. [37]
c-Myc↓
EGCG: Toden et al. [25]
ABCE1↓
GEN: Wei et al. [38]
Caspase 3↑
QUE: Zhou et al. [39]		 NF-κB↓
CUR: Wu et al. [41]
EGFR↓
MTA-2↓, IRAK-1↓, NF-κB↓
GEN: 
Li et al. [42]
Caspase 3↑, Bax↑, EGFR↓
QUE: Tao et al. [43]		 EMT↓
CUR: Toden et al. [33]
PTEN↑,
MT1-MMP↓
CUR: Soubani et al. [44]
Cancer stemness↓
EGCG: Toden et al. [25]
Cancer stemness↓
RES: Hagiwara et al. [13]
EMT↓ via vimentin, ZEB1↑, E-cadherin↓
RES: Dermani et al. [45]
* Targets upregulated and downregulated by polyphenols through upregulation of miRs are indicated by ↑ and ↓, respectively. Bcl-2; B-cell lymphoma 2, HOXA10; homeobox A10, SP1; specificity protein 1, ESR1; estrogen receptor alpha 1, Erbb3; Erb-b2 receptor tyrosine kinase 3, NCoA1; nuclear receptor coactivator 1, HDAC6; histone deacetylase 6, MYCBP; Myc binding protein, PTEN; phosphatase and tensin homolog deleted on chromosome 10, Wnt1; wingless and int-1, EMT; epithelial-mesenchymal transition, RTCB; RNA 2′,3′-cyclic phosphate and 5′-OH ligase, ROS; reactive oxygen species, HOTAIR; HOX transcript antisense RNA, Notch-1; Notch homolog protein 1, Sirt1; sirtuin 1, ABCE1; ATP-binding cassette E1, NF-κB; nuclear factor-κB, EGFR; epidermal growth factor receptor, MTA-2; metastasis-associated 2, Bax; Bcl2-associated X protein, MT1-MMP; membrane type 1-matrix metalloproteinase, Bmi-1; B-cell-specific Moloney murine leukemia virus integration site 1, CDK; cyclin-dependent kinase, E2F3; E2F transcription factor 3, HNRNPA1; heterogeneous nuclear ribonucleoprotein A1, Oct4; octamer-binding transcription factor 4, SOX-2; SRY [sex determining region Y]-box 2, ZEB1; zinc finger E-box binding homeobox 1.
Table 2. Modulation of molecular targets of oncogenic miRs downregulated by three to five CGA, CUR, EGCG, QUE, RES and GEN.
miRs miR-20a miR-21 miR-25 miR-27a miR-93 miR-106b miR-155 miR-221
Polyphenols CGA
Huang et al. [46]
CUR
Gandhy et al. [47]
EGCG
Mirzaaghaei et al. [48]
RES
Dhar et al. [49];
Dhar et al. [50]		 CGA
Wang et al. [51]
CUR
Mudduluru et al. [52];
Subramaniam et al. [53];
Zhang et al. [54];
Taverna et al. [55];
Yallapu et al. [56]
EGCG
Fix et al. [57] **;
Siddiqui et al. [58]
GEN
Zaman et al. [59]
RES
Tili et al. [60]; Sheth et al. [61]; Liu et al. [62]; Li et al. [63]; Zhou et al. [64]		 CUR
Sun et al. [15]
EGCG
Fix et al. [57] **;
Gordon et al. [34];
Zan et al. [65]
RES
Tili et al. [60]		 CUR
Toden et al. [22];
Noratto et al. [66]
EGCG
Fix et al. [57] **
GEN
Xia et al. [67];
Xu et al. [68];
Sun et al. [69]		 CGA
Huang et al. [46]
EGCG Chakrabarti et al. [23];
Chakrabarti et al. [24]
RES
Singh et al. [70]		 CGA
Huang et al. [46]
EGCG
Chakrabarti et al. [23]
RES
Dhar et al. [50];
Dhar et al. [49]		 CGA
Zeng et al. [71]
CUR
Ma et al. [72]
GEN
de la Parra et al. [73]
QUE
Boesch-Saadatmandi et al. [74]
RES
Tili et al. [75]		 CUR
Zhang et al. [76];
Allegri et al. [77]
EGCG
Allegri et al. [77]
GEN
Chen et al. [78]
Targets * p21↑
CGA: Huang et al. [46]
PTEN↑
RES: Dhar et al. [49]		 Smad7↑
CGA: Wang et al. [51]
PDCD4↑
CUR: Mudduluru et al. [52]
PTEN↑
CUR: Zhang et al. [54]
PTEN↑
CUR: Taverna et al. [55]
p21↑, p38 MAPK↑, Cyclin E2↓
GEN: Zaman et al. [59]
PDCD4↑
RES: Sheth et al. [61]
Bcl-2↓
RES: Liu et al. [62]
NF-κB↓
RES: Liu et al. [63]
AKT↓, Bcl-2↓
RES: Zhou et al. [64]		 p53↑
EGCG: Gordon et al. [34]
PARP1↑, Caspase 3↑,
Caspase 9↑
EGCG: Zan et al. [65]		 Cyclin E1↓, c-Myc↓ via FBXW7
CUR: Toden et al. [22]
ZBTB10-Sp↑
CUR: Noratto et al. [66]
Sp1↓, Sp3↓ Sp4↓, EGFR↓, hepatocyte growth factor receptor↓, survivin↓, Bcl-2↓, Cyclin D1↓, NFκB↓, ZBTB4↑
CUR: Grandhy et al. [47]
Spry2↑
GEN: Xu et al. [68]		 p21↑
CGA: Huang et al. [46]
Caspase 8↑, tBid↑, Calpain↑, Caspase 3↑
EGCG: Chakrabarti et al. [23]		 p21↑
CGA: Huang et al. [46]
PTEN↑
RES: Dhar et al. [50];
Dhar et al. [49]		 Inflammation↓ via NF-κB/NLRP3
CGA: Zeng et al. [71]
SOCS1↓, IL-6↓,
CUR: Ma et al. [72]
PTEN↑, FOXO3a↑
GEN: de la Parra et al. [73]
AP-1↓ via miR-663
RES: Tili et al. [75]		 PTEN↑, p27↑, p57↑, PUMA↑
CUR: Sarkar et al. [79]
FGF2↓, MMP2↓, VEGF↓, HGF↓,
CUR: Zhang et al. [76]
miR-21↓, miR-146b↓, miR-221↓, miR-222↓
CUR: Allegri et al. [77]
miR-221↓,
EGCG: Allegri et al. [77]
ARHI↑
GEN:Chen et al. [78]
* Targets upregulated and downregulated by polyphenols through downregulation of miRs are indicated by ↑ and ↓, respectively. ** EGCG-rich Polyphenon-E. PTEN; phosphatase and tensin homolog deleted on chromosome 10, Smad; Small mother against decapentaplegic, PDCD; programmed cell death, Bcl-2; B-cell lymphoma 2, NF-κB; nuclear factor-κB, AKT; AKT serine/threonine kinase 1, PARP; poly(ADP-ribose) polymerase 1, FBXW7; F-Box And WD Repeat Domain Containing 7, ZBTB10; Zinc finger and BTB domain containing 10, Sp1; specificity protein 1, EGFR; epidermal growth factor receptor, Spry2; Sprouty RTK signaling antagonist 2, tBid; truncated BH3 interacting domain death agonist, NLRP3; NLR family, pyrin domain containing 3, SOCS1; suppressor of cytokine signal 1, IL-6; interleukin-6, FOXO3a; forkhead Box O3, AP-1; Activator protein 1, PUMA; p53-upregulated modulator of apoptosis, ARHI; age-related hearing impairment, FGF2; fibroblast growth factor 2, MMP; matrix metalloproteinase, VEGF; vascular endothelial growth factor, HGF; hepatocyte growth factor.
Researchers further discuss the miR-modulating effects of polyphenols, which have been reported in studies using one or two of the six dietary polyphenols (Table 3 and Table 4). Furthermore, based on recent evidence on involvement of lncRs and circRs in anticancer mechanisms of these polyphenols, researchers summarize the modulatory effects of six dietary polyphenols on lncRs and circRs in relation to their anticancer effects.
Table 3. miRs upregulated by one of five dietary polyphenols and their proposed targets *.
CUR   EGCG GEN QUE RES
miR-7
SET8↓, Bcl-2↓, p53↑ [80];
Skp2↓, p57↑, p21↑ [81]
miR-9
AKT↓, FOXO1↓ [82];
GSK-3β↑, β-catenin↑, Cyclin D1↓ [83]
miR-15a
Bcl-2↓ [9]; WT1↓ [84]
miR-16-1
WT1↓ [84]
miR-28-5p
BECN1↓ [85]
miR-29a
DNMT1↓, 3A↓, 3B↓ [86]
miR-30c-5p
MTA1↓ [87]
miR-33b
HMGA2↓ [88]; XIAP↓ [89]
miR-98
LIN28A↓, MMP2↓, MMP9↓ [90]
miR-99a
JAK1↓, STAT1↓, STAT3↓ [91]
miR-101
EZH2↓, EpCAM↓ [92];
Notch1↓ [93]; EZH2↓ [94]
miR-124
Midkine↓ [95]		 miR-125a
ERRα↓ [96]
miR-138
Smad4↓, NF-kB↓, Cyclin D3↓ [97]
miR-143
NF-kB↓ [98]; PGK1↓ [99];
Autophagy via ATG2B↓ [100]
miR-181b
CXCL1↓ [101]
miR-185
DNMT1↓, 3A↓, 3B↓ [86]
miR-192-5p
XIAP↓ [102]; PI3K↓, AKT↓ [103];
Wnt/β-catenin↓ [104]
miR-196b **
BCR-ABL↓ [55]
miR-206
mTOR↓, AKT↓ [105]
miR-215
XIAP↓ [102]
miR-340
XIAP↓ [106]
miR-384
circ-PRKCA↓ [107]
miR-491
PEG10↓ [108]
miR-593
MDR1↓ [109]		 miR-15b
STIM2↓, Orai1↓ [110]
miR-29b
KDM2A↓ [111]
miR-485-5p
RXRα↓ [112]
let-7b
HMGA2↓ [113]		 miR-574-3p
RAC1↓, EGFR↓, EP300↓ [114]
miR-1469
Mcl1↓ [115]
let-7d
THBS1↓ [116]		 miR-1-3p
TAGLN2↓ [117]
miR-16-5p
WEE1↓ [118]
miR-22
Wnt1↓ [19]
miR-34a-5p
SNHG7↓ [119]
miR-142-3p
HSP70 ↓ [120]
miR-197
IGFBP5↓ [121]
miR-200b-3p
Notch1↓ [122]
miR-217
KRAS↓ [123]
miR-503-5p
Cyclin D1↓ [124]
miR-1254
CD36↓ [125]
miR-1275
IGF2BP1↓, IGF2BP3↓ [126]
let7-a
KRAS↓ [127]
let-7c
Numbl/Notch1↑ [128]		 miR-424-3p
Galectin-3↓ [129]
* Upregulation (↑) and downregulation (↓) of miR targets by polyphenols are indicated. ** Downregulation by RES is reported [130]. SET8; SET domain-containing lysine methyltransferase 8, Bcl-2; B-cell lymphoma 2, Skp2; S-phase kinase-associated protein 2, AKT; AKT serine/threonine kinase 1, FOXO1; forkhead Box O1, GSK-3β; glycogen synthase kinase-3 beta, WT1; Wilms’ tumor-1, BECN1; beclin 1, DNMT; DNA methyltransferase, MTA1; metastasis-associated 1, HMGA2; high mobility group A2, XIAP; X-linked inhibitor of apoptosis, LIN28A; Lin-28 homolog A, MMP; matrix metalloproteinase, JAK1; Janus kinase 1; STAT; signal transducer and activator of transcription, EZH2; enhancer of zeste homolog 2, EpCAM; epithelial cell adhesion molecule, Notch1; neurogenic locus notch homolog protein 1, ERRα; estrogen-related receptor alpha, PGK1; phosphoglycerate kinase 1, ATG2B; autophagy-related 2B, CXCL1; chemokine (C-X-C motif) ligand 1, PI3K; phosphoinositide-3 kinase, Wnt; wingless and int-1, BCR-ABL; BCR-ABL fusion gene, mTOR; mammalian target of rapamycin, circ-PRKCA; circ_0007580, PEG10; paternally expressed gene 10, MDR1; multidrug resistance mutation1, STIM2; Stromal interaction molecule 2, Orai1; ORAI calcium release-activated calcium modulator 1, KDM2A; lysine demethylase 2A, RXRα; retinoid X receptor alpha, RAC1; ras-related C3 botulinum toxin substrate 1, EGFR; epidermal growth factor receptor, EP300; E1A-associated protein P300, THBS1; thrombospondin 1, TAGLN2; transgelin 2, WEE1; WEE1 G2 checkpoint kinase, SNHG7; small nucleolar RNA host gene 7, HSP; heat shock protein, IGFBP; insulin-like growth factor binding protein, KRAS; KRAS proto-oncogene, GTPase, Numbl; NUMB like endocytic adaptor protein, Mcl1; myeloid cell leukemia 1, IGF2BP; insulin-like growth factor 2 mRNA binding protein.
Table 4. miRs downregulated by one of six dietary polyphenols and their targets *.
CGA CUR EGCG GEN QUE RES
miR-17
p21↑, G0/G1 arrest↑ [46]		 miR-19a,b
PTEN↑ [131]
miR-125a-5p
TP53↑ [132]
miR-130a
Nkd2↑ [133]
miR-7641
p16↑ [134]		 miR-98-5p
CTR1↑ [135]		 miR-23b-3p
PTEN↑ [136]
miR-151a-5p
CASZ1↑, IL1RAPL1↑, SOX17↑, N4BP1↑, ARHGDIA↑ [137]
miR-155
PTEN↑ [73]
miR-221
miR-222
ARHI↑ [78]
miR-223
Fbw7↑ [138]
miR-223
E-cadherin↑ [139]
miR-873-5p
FOXM1↓ [140]
miR-1260b
sFRP1↑, Smad4↑, Dkk2↑ [141][142]		 miR-30d-5p
Notch↓ Wnt↓ [143]		 miR-196b **
miR-1290
IGFBP3↑ [130]
* Upregulation (↑) and downregulation (↓) of miR targets by polyphenols are indicated. ** Upregulation by CUR is also reported [55]. PTEN; phosphatase and tensin homolog deleted on chromosome 10, Nkd2; naked cuticle homolog 2, CTR1; copper transporter 1, CASZ1; castor zinc finger 1, IL1RAPL1; interleukin 1 receptor accessory protein like 1, SOX17; SRY-box transcription factor 17, N4BP1; NEDD4-binding protein 1, ARHGDIA; rho-GDP dissociation inhibitor-alpha, ARHI; age-related hearing impairment, Fbw7; F-Box and WD repeat domain-containing 7, FOXM1; forkhead box M1, sFRP1; secreted frizzled-related protein 1, Smad; small mother against decapentaplegic, Dkk2; Dickkopf-related protein 2, Wnt; wingless and int-1, IGFBP; insulin-like growth factor binding protein.

2. Involvements of miRs in Polyphenol-Mediated Anticancer Mechanisms

miRs are defined as small single-stranded molecules (approximately 20 to 25 nucleotides) and can regulate gene expression at the transcriptional and post-transcriptional levels, leading to modulation of beneficial health effects exerted by these polyphenols in diseases including cancer [7][8].
Table 1 and Table 2 summarize miRs modulated by at least three of six dietary polyphenols. Four of six dietary polyphenols upregulate miR-16, 34a and 141, and downregulate miR-20a and 221; five of six dietary polyphenols upregulate miR-145 and downregulate miR-21 and 155. Table 1 and Table 2 also list the molecular targets of miRs that are modulated by these polyphenols; targets associated with RSTAPs (Figure 1) are also shown in these tables. Thus, it appears that six dietary polyphenols can exert their anticancer effects not only by directly involving RSTAPs, but also by miR-mediated regulation of the molecular targets associated with RSTAPs.
One or two of the miRs up- and down-regulated by six polyphenols for which studies have been reported are listed in Table 3 and Table 4, respectively, together with determined or proposed targets of these miRs. Many miRs can target components of RSTAPs, but some contribute to other mechanisms that are not depicted in these pathways (Figure 1). Based on previous findings on positive crosstalk between NF-κB and Wnt/β-catenin signaling [144][145], the Wnt/β-catenin signaling is connected in Figure 1. Furthermore, previous findings are incorporated to show that TNF-α activates Wnt/β-catenin pathway, leading to increases in cancer stemness and epithelial-to-mesenchymal transition (EMT) which are involved in cancer cell renewals and tumorigenesis [146][147][148].

This entry is adapted from the peer-reviewed paper 10.3390/antiox11122352

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