MicroRNAs, Diet, and Cancer: New Mechanistic
Insights on the Epigenetic Actions of
Mansi A. Parasramka,1* Emily Ho,2David E. Williams,1and Roderick H. Dashwood1*
1Department of Environmental and Molecular Toxicology, and Linus Pauling Institute, Oregon State University, Corvallis, Oregon
2Department of Nutrition and Exercise Sciences, and Linus Pauling Institute, Oregon State University, Corvallis, Oregon
There is growing interest in the epigenetic mechanisms that impact human health and disease, including the role of
microRNAs (miRNAs). These small (18–25 nucleotide), evolutionarily conserved, non-coding RNA molecules regulate
gene expression in a post-transcriptional manner. Several well-orchestered regulatory mechanisms involving miRNAs
have been identified, with the potential to target multiple signaling pathways dysregulated in cancer. Since the initial
discovery of miRNAs, there has been progress towards therapeutic applications, and several natural and synthetic
chemopreventive agents also have been evaluated as modulators of miRNA expression in different cancer types. This
review summarizes the most up-to-date information related to miRNA biogenesis, and critically evaluates proposed
miRNA regulatory mechanisms in relation to cancer signaling pathways, as well as other epigenetic modifications
(DNA methylation patterns, histone marks) and their involvement in drug resistance. We also discuss the mechanisms
by which dietary factors regulate miRNA expression, in the context of chemoprevention versus therapy.
? 2011 Wiley-Liss, Inc.
Key words: microRNA; chemoprevention; epigenetics; natural agents
The discovery of microRNAs (miRNAs) opened a
new era in our understanding of gene regulation.
These small, evolutionarily conserved, non-coding
RNAs were first discovered in Caenorhabditis elegans
more than a decade ago during genetic analyses.
The first miRNA identified, lin-4, was found
to contain complementary sequences in the 30-
untranslated region (UTR) of lin-14 messenger
RNA (mRNA). This exciting finding indicated a reg-
ulatory mechanism by which lin-4 could modulate
mRNA lin-14 translation in C. elegans, thereby me-
diating temporal pattern formation during devel-
opment [1,2]. Regulatory patterns of many other
miRNAs have now been recognized in species rang-
ing from viruses to humans .
The latest version of miRBase (miRBase Version
16.0) has 1048 miRNA sequences annotated in the
human genome, and additional miRNAs are likely
to be validated in the future [4–7]. The literature
indicates that one-third of these miRNAs are locat-
ed in 113 gene clusters and, based on the evidence
from miRNA profiling data in various tissues and
cell lines, these clusters are mostly coexpressed.
This observation leads to questions about cistronic
expression regulatory patterns in gene clusters.
The current understanding is that deregulation of
one member of the cluster is accompanied by simi-
lar deregulations of other miRNAs from the same
cluster. Thus, it would be interesting to ascertain
whether one miRNA in a cluster can be regulated
independently of others, especially those miRNAs
implicated in the pathophysiology of human dis-
eases. MiRNAs are believed to target approximately
one-third of human mRNAs, of several protein-
binding patterns, a single miRNA may target ap-
proximately 200 transcripts simultaneously .
Thus, an in-depth analysis of miRNA regulation
might provide an effective strategy to control nu-
merous genes simultaneously. The present review
focuses on the role of miRNAs in cancer etiology,
and provides a synopisis of the associated epige-
netic pathways of gene regulation. Therapeutic
strategies being implemented to target miRNAs are
discussed, including the use of dietary agents and
synthetic molecules in several cancers.
Abbreviations: miRNAs, microRNAs; UTR, untranslated region;
mRNA, messenger RNA; nt, nucleotides; pri-miRNAs, primary
miRNA transcripts; Ago2, Argonaut 2; SND1, Staphylococcal nucle-
ase homology domain containing 1; EMT, epithelial–mesenchymal
transition; RA, retinoic acid; EGCG, epigallocatechin-3-gallate; I3C,
*Correspondence to: 503 Weniger Hall, Monroe Street, Corvallis,
Received 27 April 2011; Revised 26 May 2011; Accepted 6 June
Published online in Wiley Online Library
? 2011 WILEY-LISS, INC.
BIOGENESIS AND MECHANISM OF ACTION
MiRNAs are naturally occurring, small, non-
coding RNA sequences ?18–25 nucleotides (nt) in
length. The biogenesis and processing of the final
mature miRNA is a highly regulated process (Figure 1).
Long primary miRNA transcripts (pri-miRNAs) con-
taining hundreds to thousands of nt, a 50cap and a
poly(A) tail are produced by RNA Polymerase II
[9,10], with the exception of those within the Alu
repeats that are otherwise transcribed by RNA poly-
merase III  from independent genes, the
introns of protein-coding genes, or polycistronic
regions. The pri-miRNAs contain a single or cluster
of miRNAs in a folded hairpin stem structure
which is processed in the nucleus by the RNAse III
enzyme Drosha, and the double-stranded RNA-
binding domain (dsRBD) protein DiGeorge Critical
Region 8 (DGCR8)/Pasha [12,13]. This duo, com-
monly referred to as the microprocessor complex,
cleaves the pri-miRNA into a ?70 nt hairpin pre-
cursor known as pre-miRNA . Pre-miRNA is
transported to the cytoplasm using a Ran-GTP
dependent mechanism by a nuclear export factor,
through a series of cuts by an RNAse III enzyme
Dicer, in associationwith
response RNA-binding protein (TRBP) and protein
kinase dsRNA-dependent activator (PACT) which,
in human cells, generates a mature ?18–25 nt
miRNA:miRNA?duplex [16,17]. Under the media-
tion of Argonaut 2 (Ago2), the RNA duplex is un-
wound to form two single strands. Ago2, in
association with a glycine-tryptophan protein, acts
as a key factor in the assembly and function of
microRNA-RNA-induced silencing complexes (miR-
RISCs). One strand is the mature miRNA or ‘‘func-
tional’’ strand, and the other strand is the imma-
ture miRNA?or the ‘‘passenger’’ strand which is
degraded [18,19]. The retained, or mature strand,
is the one that has the less stably base-paired 50
end in the duplex. Thus, thermodynamic stability
of the duplex plays a deciding role in the forma-
tion of mature miRNA. The miRNA?of the two
strands in the duplex is not necessarily a by-prod-
uct, and in some circumstances has been found to
be loaded in the RISC assembly to serve as a func-
tional miRNA [20–22]. The mature miRNA strand
is then selectively incorporated into RISC and
directs the complex to target mRNA through a
poorly defined mechanism [23–25]. Most miRNA
genes generate one dominant miRNA species; how-
ever, there are many contributing factors regulat-
ing the final outcome.
Downregulation of target gene expression by
miRNA is mediated by either of two well-studied
mechanisms, dictated by the level of complemen-
tarity between mRNA and miRNA. First, mature
miRNAs with close to perfect complementarity
may bind to the 30UTR of the target mRNA
sequence, inducing cleavage and degradation of
the transcript by deadenylation and decapping of
the mRNA . The second mechanism involves
repression of translation, which is most common,
due to imperfect sequence complementarity be-
tween the miRNA and mRNA . Irrespective of
which of these two events predominate, the over-
all outcome is a reduction in protein encoded by
the respective mRNA targets. Emerging evidence
suggests that only miRNAs in abundance are able
to target a substantial fraction of their available
mRNA target sites and significantly impact mRNA
stability in several diseases [27–29]. However, the
mechanisms controlling mRNA targeting are not
completely understood, as low abundance miRNAs
also have been reported to synergistically regulate
target expression .
Another downstream mechanism is the miRNA-
directed movement of mRNAs and associated RISC
proteins to storage structures such as processing
bodies (p-bodies) or cytoplasmic structures .
This phenomenon is currently believed to be an
outcome of microRNA-based translational repres-
sion, rather than a cause of this event . Inter-
estingly, a recent study reported the reversal of
miR-induced mRNA repression from these storage
bodies and re-entry into polysomes under certain
stress conditions . This protective mechanism
of repressed mRNAs and their subsequent reversal
could be important in several cancer pathways,
influencing aggressive tumor recurrence, drug re-
sistance, and metastatic phenotype. Thus, explor-
ing further the underlying mechanisms of miRNA
biogenesis will be critical in our understanding of
the regulatory patterns of miRNAs, and developing
targeted therapeutic strategies.
Different schools of thought exist concerning
the specific mechanisms involved in miRNA target-
ing. One report suggests that specificity in choos-
ing target transcripts is primarily based on the
principle of Watson–Crick complementarity be-
tween the 30-UTR of the target mRNA and the nu-
cleotide sequence from position 2 to 8 at the 50
end of miRNAs, also referred as the ‘‘seed region’’
. Using advanced computational tools, it has
been found that multiple miRNAs target the 30-
UTR of a single gene . In a recent interesting
finding, researchers reported that some miRNAs
had selective binding affinities for 50-UTR sequence
of target genes, a mechanism that appeared to acti-
vate gene expression [36,37]. Another report by
Wakiyama et al.  demonstrated that efficient
miRNA-dependent translation repression requires
a m7G-cap along with a poly(A) tail. Since the
RISC-miRNA complex plays a major role in direct-
ing miRNA to its target sequence, further in-depth
analyses are required to understand the specific
mechanisms of regulation involved.
PARASRAMKA ET AL.
An alternative biogenesis mechanism was recent-
ly discovered, in which miR-451 was found to
enter the RISC by directly loading its precursor
pre-miRNA after Drosha processing, skipping the
activation steps with Dicer. In this rather unusual
processing mechanism, Ago2 was found to replace
the activity of Dicer . Interestingly, 27% of
tumors across all tissues possess a hemizygous dele-
tion of the Dicer encoding gene. The significance
of Dicer in miRNA processing was evidenced
via knockdown experiments in vitro and in vivo
[40,41]. For example, reduction of Dicer increased
the rate of tumor formation in a K-ras-dependent
lung cancer model, and in an Rb-based retinoblasto-
ma model [41,42]. Recently, Drosha-independent
mechanisms were identified, including mirtrons
and tailed mirtrons that release pre-miRNAs by
splicing and exonuclease trimming. A ‘‘mirtron’’ is
defined as a short hairpin intron that uses splicing
machinery to bypass Drosha cleavage in initial
maturation. Examples include miR-320 and miR-
miRNA biogenesis and regulation is mediated by
Staphylococcal nuclease homology domain contain-
ing 1 (SND1), which is one of the components of
RISC and is proposed to be involved in gene silenc-
ing mechanisms . Johnson et al.  reported
SND1 was an important component of let-7 direct-
ed RISC regulation in RAS signaling. Although the
exact role of SND1 is not fully understood, these
intriguing findings suggest the possible role of
SND1 as a key regulator at both transcriptional
and post-transcriptional levels . Also, ribosome
recruitment to the mRNA and targeting the mRNA
cap structure was found to play a role in inhibition
Figure 1. MicroRNA biogenesis and regulatory pathways. Pri-
miRNAs are transcribed from RNA polymerase II (RNAPII)-specific
miRNA genes, from the intronic region of protein coding genes, or
from polycistronic transcripts. In the first nuclear step, pri-miRNA is
processed into a 70–100 nucleotide precursor hairpin (pre-miRNA)
via the Drosha-DGCR8 complex. Pre-miRNA is transported to the
cytoplasm through export machinery consisting of Exportin 5 and
Ran-GTP. Here, the pre-miRNA is cleaved by another endoribonu-
clease, Dicer, in partnership with TRBP and Ago proteins, forming
a ?20-bp miRNA: miRNA?duplex. After processing, one strand of
the duplex is preferentially incorporated with the help of Ago2 into
the RISC complex (miRISC), whereas the other ‘‘passenger’’ strand
(miRNA?) gets degraded. (A) A few pre-miRNAs are processed
directly from short introns (mirtrons), bypassing the Drosha-DGCR8
step. (B) A dicer-independent mechanism, miRNA being cleaved
by Ago2 to form a mature miRNA. (C) Some miRNAs bind to the
50-UTR of the target mRNA and lead to translational activation.
(D) Full or near-full complementarity between miRNA and mRNA
target facilitates miRISC-directed cleavage of the mRNA target.
(E) With low complementarity, miRNA-mediated regulation is car-
ried out by translational repression (E.1). This can occur pre- and/or
postinitiation of translation leading to gene silencing. (E.2) Target
mRNAs also can be stored in P-bodies, and mechanism reversed by
re-entry into polysomes for translation. (F) In a RISC-independent
decoy activity, miRNAs can directly bind to proteins, particularly
RNA-binding proteins, making them unavailable for binding to
their RNA targets.
MICRORNAS, DIET, AND CANCER
of translational initiation using extracts from
mouse Krebs-2 ascites cells . Kiriakidou et al.
identified a motif within the Ago2 protein that
had significant similarity to a domain of an essen-
tial translation initiation factor, eIF4E. It was
reported that Ago2 protein competes with eIF4E
to bind to the domain and repress initiation of
translation . Thus, the complex mechanistic
intricacy of miRNAs and their biogenesis pathways
should be taken into consideration when design-
MicroRNAs AND MOLECULAR CROSS-TALK IN CANCER
Cancer is the second leading cause of mortality
and is responsible for one in four deaths in the
United States . It is a complex, multi-step dis-
ease characterized by disruption of the homeostat-
ic balance between cell proliferation and cell
death, and uncontrolled clonal expansion leading
to tumor formation. Until recently, protein-coding
genes were the primary focus of cancer research;
however, over the last decade there has been a ma-
jor paradigm shift with the emerging role of miR-
NAs and other ‘‘epigenetic’’ mechanisms [51–53].
MiRNAs interact with an estimated 60% of mRNAs
through one or more evolutionarily conserved
sequences, implicating their role in a wide range
of physiological and pathophysiological processes
MiRNAs have been implicated at all stages of
cancer, from initiation
and progression, influencing cell proliferation,
differentiation, apoptosis, angiogenesis, and metas-
tasis . Various miRNAs are up- or down-regulat-
ed in human neoplasia, with some overlapping
miRNA profiles depending on tissue origin (Table 1).
Previous reports suggested that miRNA expression
patterns are tissue-specific and might be a useful
tool for classifyinghuman
[56,57]. However, recent reports indicate that
miRNA expression levels, rather than specific
miRNA identity, characterize normal versus tumor
miRNA expression and intensity levels in various
tumor tissues. Aberrant miRNA expression patterns
are often attributed to the presence of miRNAs in
regions of chromosomal instability, due to amplifi-
cation, translocation or deletion events, represent-
ing ?52.5% of miRNA genes in cancer-associated
regions or fragile sites . Some examples include
amplification of the miR-17-92 cluster in lympho-
mas or its translocation in T cell acute lymphoblas-
tic leukemia [59,60], amplification of miR-26a in
glioblastoma , and deletion of an miR-15a/16-1
cluster in a putative tumor suppressor-containing
region in B cell lymphoblastic leukemia . There
are certain miRNAs that have emerged as prime
regulators of key cellular and physiological states
in human tumor tissues. For example, miR-21 was
found to be consistently upregulated in cancers of
the breast, colon, lung, pancreas and stomach, as
well as in chronic lymphocytic leukemia (CLL),
acute myeloid leukemia (AML), glioblastoma, and
myeloma . Members of the let-7 family were
Table 1. Common Cancer-Associated miRNAs
miRNA Nature Common targetsMalignancy
miRNA-21 ONC PTEN, TPMI, PDCD4, Maspin,
NFIB, Timp3, RECK
RAS, PRDMI, HMGA2, E2F,
c-Myc, cyclin D2
Tsp I, E2F I, TGFBR2, AIB I,
CTGF, BIM, PTEN, CDKN1A
E2F3, Notch1, CDK 4, CDK 5
Colon, prostate, lung, pancreatic, breast, liver,
Colon, lung, ovarian, breast cancerslet-7 familyTS
miR-17-92 familyONC Lung, colon, breast, pancreatic cancers,
Breast, colon, pancreatic cancers
Ovarian, medulloblastoma, and breast cancers
Gastric, colon and prostate cancers
Lung, breast cancers, CLL, AML
Breast, bladder, gastric, ovarian, and renal
Breast and liver cancer, CLL
CLL, lymphoma, liver, lung, and breast cancers
TP53INPI, ATIR, SHIP1, CEBPB
KIT, p27(Kip1), p57, PTEN
MCL-1, CDK6, TCL1,
Bcl-2, Wt-1, MCL1
TCL 1, E2F5, eIF5A
Lung and gastric cancers
Early and late stage colorectal cancer
MicroRNAs deregulated in cancers target multiple genes simultaneously. Certain miRNA expression profiles overlap in cancers of
different tissues. Please refer to the text and references listed for further details. TS, tumor suppressor-like activity; ONC, oncogenic
PARASRAMKA ET AL.
found to be downregulated in colon, breast, lung,
ovarian, and gastric cancers, suggesting that resto-
ration of let-7 members may be a useful therapeu-
tic approach in these cancers [64–69]. These
observations suggested that miRNAs mimic onco-
genes or tumor suppressors (Figure 2), due to their
respective up- or down-regulated expression pat-
terns in different cancers .
Profiling differential expression patterns of miR-
NAs suggests potential ‘‘molecular signatures’’ that
can distinguish histopathologic features in various
tissues. For instance, differential miRNA expression
profiles clearly defined colon cancer and rectal
cancer as two quite distinct pathologies, emphasiz-
ing that ‘‘associations can be masked when study-
ing them as one disease’’ . Aberrant expression
of 15 miRNAs distinguished tumor from normal
tissue in breast cancer patients. Of these, miR-10b,
miR-125b, let-7, and miR-145 were consistently
downregulated, whereas miR-21 and miR-155 were
upregulated in malignant tissue . In another
study, metastatic miRNA biomarkers were identi-
fied in breast cancer. Reduced metastasis from
breast to lung or bone in mice was associated with
overexpression of miR-335, miR-126, and miR-206,
indicating a possible breast cancer-specific miRNA
signature pattern .
screening, several studies have reported deregula-
tion of specific miRNA expression in pancreatic
cancer as compared to other tumors. For example,
expression levels of miR-375 and miR-376 were sig-
nificantly higher in mouse pancreas and pancreatic
islet cells as compared to brain, heart, and liver tis-
sue . One of the most significantly upregulated
miRNAs in pancreatic cancer is miR-21, which is
considered an ‘‘oncogenic’’ miRNA that may be re-
sponsible for chemotherapeutic (gemcitabine) re-
sistance in pancreatic cancer cells [74–76]. The
QuantiMir system was used to examine differential
expression patterns of 95 miRNAs in 10 pancreatic
cancer cell lines and 17 pairs of pancreatic/normal
adjacent tissues . This study reported a signifi-
cant upregulation of miR-196a, miR-190, miR-186,
miR-221, miR-222, miR-200b, miR-15b, and miR-
95 in most pancreatic cancer tissues and cell lines.
Interestingly, upregulation of these eight miRNAs
ranged from 70% to 100% between normal and
tumor cells or tissues. MiRNA profiling may be
Figure 2. MicroRNAs impacting oncogenic and tumor suppressor pathways. (A) The reduction or deletion of
a ‘‘tumor suppressor miRNA’’ due to mutation, deletion, epigenetic modification, or irregularities in miRNA
processing cause inappropriate elevation of miRNA-target oncoproteins, ultimately leading to tumor formation.
(B) Amplification or overexpression of an ‘‘oncogenic miRNA’’ inhibits miRNA-targets of vital tumor suppressor
genes. The overall outcome is to increase cell proliferation, angiogenesis, and metastasis, or augment chromo-
somal instability and apoptosis.
MICRORNAS, DIET, AND CANCER
important in determining an effective treatment
strategy to deal with this fatal disease, which
is otherwise deadly due to its late diagnosis and
limited therapeutic options.
Similarly, miRNA signature profiles can be de-
fined in non-small-cell lung cancers (NSCLC) that
are useful in distinguishing clinical phenotypes. In
a study by Yanaihara et al.  five miRNAs (miR-
155, miR-17-3p, let-7a-2, miR-145, and miR-21)
were found to be differentially expressed in tumor
versus normal tissue in lung cancer patients. Im-
portantly, let-7 members were commonly downre-
gulated in lung cancers and appear to serve as a
marker of survival in lung cancer patients [78–80].
Taken together, the results imply a pivotal role of
miRNAs in the pathogenesis of various human
Furthermore, miRNA profiles can provide infor-
mation regarding tumor differentiation and clini-
cal subtypes. For example, certain miRNAs were
implicated in late stages of carcinogenesis, and sev-
eral pro- and anti-angiogenic miRNAs have been
(VEGF), an angiogenesis mediator, is known to
be regulated by miR-15a-16-1 [81,82], miR-126
[83,84], and miR-378  via indirect targeting of
various intermediary upstream signaling mole-
cules. Several miRNAs also inhibit cancer cell inva-
sion, adhesion and migration, including miR-122,
miR-126, miR-128, miR-146 a/b, miR-31, miR-29c,
and the miR-200 family. Conversely, miRNAs that
are known to promote metastatic mechanisms in-
clude miR-21, miR-10b, miR-155, miR-373, and
miR-520c . MiR-29c and let-7g target expres-
sion of components of the extra-cellular matrix
(ECM) involved in cell adhesion and migration.
For example let-7g, a tumor suppressor miRNA,
was reported to be poorly expressed in a metastatic
hepatocellular carcinoma cell line when compared
to normal cells. Forced overexpression of let-7g
inhibited cell migration by targeting type I colla-
gen a2 . Overexpression of miR-17 resulted in
growth retardation along with reduced cell adhe-
sion, migration, and proliferation in the same can-
cer cell line . Other important regulators of
ECM are matrix metalloproteinases (MMPs) that
are upregulated by miR-21, miR-221, miR-222
[89,90] or downregulated by miR-181b, miR-146b
[91,92]. These miRNAs modulate the expression of
various genes that regulate invasiveness of cancer
Much is being learned about the downstream
targets of miRNAs. However, recent evidence indi-
cates that miRNAs themselves are subject to higher
levels of control that regulate both miRNA metab-
olism and function. One mode of action is the
ability to self-regulate. Due to their ability to di-
rectly base-pair with various mRNAs, coding for
factors involvedin biogenesis
mechanisms, miRNAs can participate in their own
transcription mechanisms through feedback loops
with specific transcription factors. For example, a
regulatory loop between miR-133b and the tran-
scription factor PITX3 controls neuronal differenti-
ation . Another example is provided by let-7, a
suppressor of proliferation that can target Dicer
mRNA, thereby preventing the upregulation of
growth stimulatory miRNAs involved in cancer
. Accumulating evidence suggests a role for var-
ious oncogenic or tumor suppressor transcription
factors such as ras, myc, and p53 in regulating
miRNA expression, in a tissue-specific manner.
Examples of such regulatory mechanisms include
expression of miR-34 and miR-107 families being
stimulated by p53 [95,96], miR-21 regulation mod-
ulated by ras , and regulation of the miR-17-92
cluster and miR-9 by myc and mycn in lymphoma
cells  and neuroblastoma cells , respect-
ively. SMAD, signal transducer of transforming
growth factor-b (TGF-b), and bone morphogenetic
factor (BMP), control Drosha-mediated miRNA
processing. A SMAD-p68 complex with Drosha is
reported to enhance processing and accumulation
MicroRNA AND DRUG RESISTANCE
Cancer therapeutics is an important research
area. However, there is room for improvement
when viewed in the context of current patient sur-
vival rates, and persistent concerns such as intrin-
sic or acquired drug resistance. Accumulating
evidence supports a role for miRNAs in the forma-
tion of cancer stem cells, and in the acquisition of
an epithelial–mesenchymal transition (EMT) phe-
notype [102–104]. The mechanisms regulating
EMT are known to be closely associated with drug
resistance and metastasis. Recent studies have
revealed that miRNAs are involved in the develop-
ment of anti-cancer drug resistance [105,106]. For
example, miR-200, which was earlier reported to
be downregulated in various cancers, was also
found to be involved in EMT and drug resistance
inpancreatic cancer .
miRNA-200 downregulated EMT markers such as
ZEB1, slug, and vimentin, and enhanced sensitivi-
ty to gemcitabine. Similar results were obtained
with the suppressor miRNA family, let-7. MiR-200
also was reported to be involved in drug resistance
mechanisms in bladder, endometrial, breast, and
ovarian cancers [107,108]. Conversely, oncogenic
miR-21 increased chemoresistance by targeting the
tumor suppressor protein programmed cell death 4
(PDCD4), thereby causing an upregulation of
inhibitors of apoptosis proteins (IAPs) and multi-
drug-resistant protein-1 (MDR1) in breast cancer
cells . MiR-21 has been reported to modulate
PARASRAMKA ET AL.
drug resistance in various other cancers, such as
glioblastoma , prostate , and pancreatic
According to Garofalo et al.  transfecting
NSCLC with anti-miR-221 and -222 resulted in en-
hanced sensitivity to TRAIL, by modulating p27kip1
and Kit. Similarly, knockdown of miR-221 and
-222 in breast cancer cells resulted in enhanced
sensitivity to tamoxifen . However, in anoth-
er report, miR-221 and miR-128b were downregu-
lated in MLL-AF4 ALL and re-expression of these
two miRNAs resulted in sensitization of MLL-AF4
ALL cells to glucocorticoids . This suggests
the possibility of tissue specificity and synergistic
effects modulated by certain miRNAs. In yet
another study, transfection of miR-205 in breast
cancer cells increased the responsiveness to tyro-
sine kinase inhibitors of EGFR (gefitinib) and
EGFR/HER2 (lapatinib), thereby reducing HER3-
mediated drug resistance . Thus, targeted
therapy aimed at critical miRNAs involved in drug
resistance may help restore efficacy in various
MicroRNA CROSSTALK WITH
OTHER EPIGENETIC MECHANISMS
Epigenetics is the study of changes in gene
expression that are not associated with alterations
in DNA sequence. Two important areas of epige-
netics focus on histone modifications and DNA
methylation . These mechanisms individually
or cooperatively regulate cancer signaling path-
ways, some involving miRNAs . Examples in-
clude hypermethylation of CpG islands near the
transcriptional start site of miR-34, thereby modu-
lating p53 expression in cancer cells ; silenc-
ing by methylation of miR-9 loci, which correlates
with cancer metastasis [118,120]; and downregula-
tion of miR-449a, which, in prostate cancer cells,
causes overexpression of histone deacetylase 1
(HDAC1) . Conversely, several miRNAs modu-
late gene expression by altering the methylation
machinery or chromatin remodeling factors in
cancer cells [122,123]. Thus, it is intriguing to pon-
der the complex integrated mechanisms involving
One of the earlier reports on epigenetic regula-
tion of miRNAs was from studies of bladder cancer
. Saito et al. evaluated the effect of simulta-
neous treatment with 5-Aza-CdR, a potent DNA
methylation inhibitor, and 4-phenylbutyric acid
(PBA), an HDAC inhibitor. Interestingly, among 17
of 313 miRNAs upregulated, miR-127 was overex-
pressed almost 50-fold in bladder cancer cells as
compared to normal human fibroblasts. Upregula-
tion of miR-127 resulted in downregulation of
proto-oncogene BCL6. These and other studies
suggest that epigenetic mechanisms can activate
tumor suppressor miRNAs (Figure 3).
The effect of DNA methylation on miRNA
expression has been investigated by several groups.
Lujambio et al.  identified miR-148a, miR-
34b/c, and miR-9 as commonly silenced in colon
cancer cells as compared to normal tissues. Early
reports identified miRNA-34a as a target of the
tumor suppressor p53 [95,125,126], and miR-34a
was found to be regulated by DNA methylation,
with the silencing mechanism dominating over
transactivation by p53. In prostate and pancreatic
carcinoma cell lines, silencing of miR-34a by CpG
methylation also was observed .
Another important silencing mechanism was
identified when methylation of miR-148 promoted
cancer metastasis in melanoma and breast cancer
by upregulating its target gene, TGIF2 . MiR-
148-mediated repression of DNMT3b identified
high homology binding near the 30-UTR regions
and poly(A) tail, but the exact repressive mecha-
nism remains unclear . Similarly, an inverse
correlation was observed between the miR-29
family (especially miR-29a-c) and DNMT3A and
DNMT3B in lung cancer cells. Overexpression of
miR-29 resulted in re-expression of methylation-si-
lenced tumor suppressor genes such as FHIT and
WWOX . Using Dnmt1 and Dnmt3b knock-
out HCT116 colorectal cancer cells, 18 miRNAs
were upregulated >3-fold in knockout cells, sug-
gesting a CpG island hypermethylation mecha-
nism to silence tumor suppressor miRNAs. One
correlation between miR-124a and a bona fide
oncogene, cyclin D kinase 6 [129,130]. In yet
another study, let-7a-3 was found to be heavily
methylated in normal human tissues as compared
to the hypomethylated profile in lung adenocarci-
paradigm that promoter regions
might in some circumstances aid in reactivation of
let-7a-3 in human lung cancer cells. Interestingly,
DNA methylation enzymes such as DNMT1, 3a,
and 3b are anticipated to be miRNA targets and
vice versa [132,133]. In a recent study, miR-34b
and miR-129-2 were dramatically silenced in gas-
tric carcinogenesis. Epigenetic regulation was im-
plicated by cotreatment with the demethylating
agent 5-Aza-dC and the HDAC inhibitor trichosta-
tin A, suggesting a strong association of these miR-
NAs with poor clinical outcome in gastric cancer
Epigenetic regulations are also mediated by
histone modifications. The effect of a hydroxamic
acid HDAC inhibitor, LAQ824, was evaluated in
breast cancer cells. On treatment with LAQ824,
a dramatic alteration in miRNA profiles was
MICRORNAS, DIET, AND CANCER
observed, with 22 miRNAs being upregulated and
5 miRNAs being downregulated . The HDAC
inhibitor vorinostat (suberoylanilide hydroxamic
acid, SAHA) altered markedly the expression of 31
miRNAs in HCT116 colon cancer cells, as well as
downstream targets affecting cell cycle, apoptosis,
and differentiation . By comparing HCT116
cells that were p53 wild-type versus p53 null, miR-
NAs were identified that responded to p53 status
in cancer cells, including miR-7-1, miR-9, miR-22,
miR-30c, miR-32, miR-221, and miR-222 .
Other miRNAs associated with specific compo-
nents of histone modification mechanisms have
been identified. For example, miR-449 regulates
HDAC1 levels inprostate
HDAC4 is a validated target of miR-1 in hepatocel-
lular carcinomas . These initial studies pro-
unexplored aspects of epigenetics and miRNAs in
thepath toas yet
DIETARY REGULATORS OF MicroRNAs—POTENTIAL
ROLES IN CHEMOPREVENTION
In the temporal progression to malignancy,
cells accumulate alterations in multiple cellular
signaling pathways. Previous attempts to treat can-
cer often failed due to a ‘‘one gene-one target’’ ap-
proach, sometimes referred to as mono-modal
therapy. At the same time, the benefits associated
with a healthy diet and life style strongly support a
multi-modal disease prevention strategy. Various
natural dietary chemopreventive agents have been
identified, some with well characterized pleiotropic
actions in cancer cells. This has led to studies of
natural agents that might modulate gene expres-
sion by targeting miRNAs, via direct or indirect
chemopreventive mechanisms [103,106,138–140].
Although there are relatively few such studies at
present, this is likely to gain significant attention
in the future. Some examples are presented below
of dietary or nutritional factors known to impact
Figure 3. Epigenetic modifications and miRNA regulation. MiRNAs can impact the epigenetic machinery
by regulating key players involved in DNA methylation and chromatin remodeling. (A) Demethylated tumor
suppressor miR-29 (open red dots) inhibits translation of cancer-promoting DNMT3s in lung cancer, (B) hyper-
methylation of let-7a-3 (closed red dots) in normal cells results in repression of cancer-promoting genes in lung,
(C) an integrated loop is becoming apparent between miRNAs, and chromatin remodeling via HATs and HDACs,
which influence miRNA expression in the cell.
PARASRAMKA ET AL.
miRNAs involved in various stages of carcinogene-
sis, including early chemoprevention versus late-
stage therapeutic effects.
MicroRNAs and Essential Nutritional Factors
Vitamin A is an essential dietary factor involved
in vision, reproduction, immune function, cell
growth, and differentiation. All-trans-retinoic acid
(RA), the most biologically active form of Vitamin
A, acts as a tumor suppressor in lung, prostate,
bladder, liver, breast, and pancreatic cancer models
. In a recent report , 243 miRNAs were
examined using microarray analyses in RA-treated
human acute promyelocytic leukemia (APL) cells.
Interestingly, previously known deregulated miR-
NAs were differentially expressed upon treatment
with RA. In another study using microarrays, sever-
al tumor suppressor miRNAs were upregulated
upon RA treatment in human APL cells . In
the latter study, putative NFkB consensus elements
were identified in the upstream genomic region of
let-7 cluster following RA treatment.
hydroxyvitamin D3 (25(OH)D3), regulate miRNA
profiles in different cancers. Treatment of human
myeloid leukemia cells with 1,25D3led to downre-
gulation of miR-181a and miR-181b, resulting
in enhanced expression of p27Kip1and p21Cip1,
causing G1cell cycle arrest . 25(OH)D3con-
ferred a protective role against cellular stress in
breast epithelial cells by modulating p53 and
PCNA levels, along with alteration in miR-182
expression . Cancer chemopreventive effects
of vitamin D and its metabolites are mediated via
binding with its receptor (VDR). MiR-125b was
identified as having a potential sequence match in
the 30-UTR region of human VDR mRNA, suggest-
ing a pathway for targeted therapy via VDR down-
regulation in human cancers .
Deficiency of vitamin E in rats resulted in signifi-
cant downregulation of tumor suppressor miRNAs
in liver. Vitamin E modulated lipid metabolism,
inflammation, and other cancer-associated path-
ways by altering the expression of miR-122 and
Folate is a water-soluble B-vitamin. Hepatocellu-
lar carcinoma in rats fed a folate-deficient diet for
54 wk was associated with increased expression of
several miRNAs in tumors, including miR-21, and
reduced expression of liver-specific miR-122. Folate
levels, and was associated with inhibition of tu-
morigenesis, suggesting a potential chemopreven-
tion paradigm affecting miRNAs . A similar
trend was observed in an in vitro study in which
adequate folate in the culture media restored
miRNA levels in human lymphoblastoid cells. One
of the key miRNAs upregulated in human periph-
eral blood cells from individuals with low folate
intake was miR-222 .
Selenium deficiency is associated with increased
cancer risk. Sodium selenite, an inorganic form of
selenium, activates p53 and increases its targets in
the miR-34 family . Specific members of miR-
34 family, miR-34b and miR-34c, but not miR-34a,
were increased significantly in prostate cancer cells
treated with sodium selenite. Because of toxicity
concerns associated with inorganic and some or-
ganic forms of selenium, it will be important for
future miRNA studies to examine these com-
pounds on a case-by-case basis, including their
n-3-Polyunsaturated fatty acids (n-3 PUFAs) are
found in walnuts, fish-oil, soybeans, green leafy
vegetables, and seed oils. Protective roles of PUFAs
have been documented in various human disease
conditions, including cancer [154,155]. A recent
study evaluated the chemopreventive effects of
PUFAs on azoxymethane-induced colon cancer in
rats. Carcinogen treatment resulted in significant
downregulation of five known tumor suppressor
miRNAs, which were reversed upon exposure to
fish oil. Based on transfection experiments in vitro,
tumor suppressor PTEN was found to be targeted
by oncogenic miR-21 in human colon cancer cells.
Similarly, beta site amyloid precursor protein-
cleaving enzyme (BACE-1) was reported as a func-
tional target of tumor suppressor miR-107 and
was downregulated in carcinogen-induced tumor
tissues versus normal colonic mucosa . This
study demonstrated the chemoprotective role of
dietary n-3 PUFAs in colon by modulating the
miRNA expression pattern in carcinogen-induced
rat colon cancer. Short-chain fatty acids which
inhibit HDAC activity, such as butyrate, also alter
miRNA patterns regulating endodermal differentia-
tion mechanisms, as studied in human embryonic
stem cells .
MicroRNAs AND PHYTOCHEMICALS
Curcumin, a bioactive ingredient in turmeric,
anti-carcinogenic properties, although such effects
MICRORNAS, DIET, AND CANCER
are not always realized in vivo [158,159]. An initial
study evaluated miRNA profiles in curcumin-
treated pancreatic cancer cells, with evidence for
upregulation of 11 miRNAs and downregulation of
18 miRNAs. MiR-22 was upregulated upon curcu-
min treatment, and the predicted targets were ERa
and transcription factor Sp1. MiR-196, an onco-
genic miRNA in gastric cancers, was significantly
downregulated after curcumin treatment .
Due to the low bioavailability of curcumin in vivo,
a synthetic analogue (CDF-diflourinated-curcumin)
was evaluated in a chemopreventive pancreatic
cancer model . Curcumin and its CDF analog,
alone or in combination, attenuated expression of
miR-200 and miR-21 leading to induction of tumor
suppressor PTEN. The CDF analog inhibited sphere
forming ability (pancreatospheres) by attenuating
cancer stem cell markers and other signaling mole-
cules, via changes in miR-21 and miR-200. These
findings suggested a role for certain miRNAs in tu-
mor recurrence in pancreatic cancer, and the effec-
tiveness of the CDF analog as an alternative
therapeutic strategy to curcumin parent com-
pound . In a recent study of curcumin and
multi-drug resistance, alterations were detected in
342 miRNAs . Significant changes (>2.5-fold)
in various oncogenic and tumor suppressor miR-
NAs were reported after curcumin treatment. A key
target was miR-186?, which promoted apoptosis in
cancer cells. Overall, these studies provided sup-
port for the idea that diet-induced miRNAs play a
role in overcoming drug resistance in cancers.
Resveratrol is a chemopreventive agent from
grapes, mulberries, wine, and peanuts. Effects of
resveratrol on colon cancer cells were examined by
Tili et al. . Several ‘‘signature’’ miRNAs for co-
lon cancer such as miR-21, miR-196a, miR-25,
miR-17, and miR-92a-2 were significantly downre-
gulated by resveratrol. Simultaneously, miR-663-
mediated regulation of Dicer, PDCD4, PTEN, and
TGFb signaling through the SMAD promoter was
observed. This study provided the first insights
into resveratrol-mediated miR-663 regulation in
colon cancer cells. A resveratrol-induced, miR-663-
dependent effect was observed in monocytic cells
used to evaluate adaptive and innate immune
responses . MiR-663 was reported to target ac-
tivator protein-1 (AP-1) through the Jun signaling
pathway. Interestingly, resveratrol also impaired
the upregulation of oncogenic miR-155 in a miR-
Chemopreventive effects of epigallocatechin-3-
gallate (EGCG) and other tea catechins have been
described in preclinical models for all major sites
of cancer development, including colon, prostate,
EGCG and related catechins target various cancer
signaling pathways in a pleiotropic manner; how-
ever, clinical efficacyis
Recently, miRNAs were included among the mo-
lecular targets of EGCG. In human hepatocellular
carcinoma cells, one of the 13 miRNAs that was
upregulated on EGCG treatment was miR-16, a tu-
mor suppressor miRNA that mediated apoptosis
via downregulation of Bcl-2. This mechanistic tar-
get was identified based on transfection studies
. Further work is needed to elucidate the de-
tailed miRNA ‘‘target map’’ following treatment
with EGCG and, equally importantly, by potential
chemopreventive metabolites such as the glucuro-
nide and O-methylated forms which constitute
the major fractions found in plasma after oral
lung, liver,andskin. Mechanistically,
Ellagitannins are polymeric polyphenols found
in abundance in strawberries, raspberries, almonds,
walnuts, and various other fruits and nuts. They
were initially characterized for their anti-oxidant
and free radical scavenging activity. Anti-inflam-
matory, anti-tumor promoting, anti-proliferative,
and apoptosis-inducing properties also have been
identified . A plant grown in Japan and
China, Balanophora Japonica MAKINO, contains
This ellagitannin was examined for anti-prolifer-
ative effects in human liver cancer cells, along
with profiling of miRNAs . Using a dose- and
time-dependent strategy, 17 miRNAs were found
to be upregulated and 8 miRNAs were downregu-
lated following treatment of HepG2 cells, includ-
ing let-7 family members, miR-370, miR-373, and
miR-526b. Prediction software and functional anal-
yses identified likely targets with roles in cell pro-
liferation and differentiation; however, the precise
mechanisms await further study.
Soy isoflavones, including genistein, daidzein,
and glycitein, have been implicated in anti-carci-
nogenic mechanisms, via the modulation of estro-
gen receptor binding in target tissues. Genistein is
currently undergoing clinical trials for chemo-
preventive and therapeutic effects in breast, pros-
tate, bladder, and kidney cancers . Li et al.
miRNA profiles in pancreatic cancer, and noted a
differential effect in gemcitabine-resistant versus
gemcitabine-sensitive cancer cells. For example,
miRNAs belonging to miR-200 and let-7 families
were downregulated in gemcitabine-resistant cells
versus gemcitabine-sensitive cells. However, isofla-
vone treatment increased both miR-200 and let-7
family miRNAs by modulating EMT transcription
PARASRAMKA ET AL.
factors, such as vimentin, slug, and ZEB1. Genis-
tein also upregulated miR-146a in pancreatic can-
cer cells, inhibiting their invasive potential by
downregulating EGFR, NFkB, IRAK-1, and MTA-2
Another study  examined minichromosome
maintenance (MCM) genes involved in DNA repli-
cation, which are commonly dysregulated in can-
cer cells. In prostate cancer cells treated with
genistein, MCM2 was downregulated by miR-1296.
Genistein induced the expression of miR-1296 by
up to fivefold, along with cell cycle arrest in S-
phase. Chemopreventive effects of genistein on
the temporal changes during ovarian cancer pro-
gression were assessed using microarray analyses
. This was a descriptive study that focused on
significant alterations in miRNAs, and awaits fur-
ther validation of potential targets. Genistein also
was investigated in other cancer models, such as
human uveal melanoma cells ; using both in
vitro and in vivo models, miR-27a was found to be
downregulated with concomitant upregulation of
its target gene, ZBTB10.
considerable attention due to the chemopreventive
properties of the whole food or isolated com-
pounds, such as sulforaphane and indole-3-carbi-
nol (I3C) . Upon ingestion, I3C undergoes
acid condensation reactions in the stomach pro-
ducing a number of oligomers including dimers,
trimers, and tetramers. The major compound
found in vivo in human plasma is 3,30-diindolyl-
methane (DIM) which has been examined for che-
prostate, pancreatic and cervical cancer . In a
well-designed study by Izzotti et al. , altered
miRNA profiles in lung tissue were observed in rats
exposed to environmental cigarette smoke. Resto-
ration of miRNAs targeting p53 functions (miR-
34b), TGF-b expression (miR-26a), ERBB2 activa-
tion (miR-125a), and angiogenesis (miR-10a) was
recorded on treatment with five dietary agents, in-
cluding I3C. Also, as discussed in the studies by Li
et al. [103,173], along with soy isoflavones, DIM
influenced EMT via differentially expressed miR-
NAs in pancreatic cancer cells. Based on these ini-
tial reports with I3C and DIM in cancer models,
miRNAs appear to be promising molecular targets
of dietary indoles, awaiting further mechanistic
Isothiocyanates derived from cruciferous vegeta-
bles modulate carcinogen metabolism in different
tissues, but likely exert numerous other chemopro-
tective mechanisms [177–180]. The effect of phe-
nethyl isothiocyanate(PEITC) onmiRNA
alterations induced by smoking in rat lung tissue
was evaluated by Izzotti et al. . Of the five die-
tary agents tested, PEITC intervention alone, or in
combination with I3C, was the most effective in
restoring miRNAs downregulated by exposure to
cigarette smoke. Major PEITC-induced miRNA tar-
gets were miR-192 (Ras activation); let-7a, let-7c
(cell proliferation, angiogenesis, Ras activation);
miR-146 (NFkB activation); miR-123, miR-222, (an-
giogenesis, cell proliferation), and miR-99b (apo-
ptosis). In another study by the same group,
miRNA alterations upon exposure to cigarette
smoke were investigated in mouse lung and liver
tissues . PEITC-induced changes in miRNA
expression profiles were more robust in mouse
liver (significant >2-fold downregulation of 9
oncogenic miRNAs and upregulation of 3 tumor
suppressor miRNAs) as compared to lung tissue. It
would be interesting to evaluate the effect of other
dietary isothiocyanates on miRNA expression pro-
files in cancer models.
Collectively, these studies support a growing
interest in the chemopreventive role of dietary
agents such as vitamins, fatty acids, trace elements,
polyphenols, indoles, and isothiocyanates as mod-
ulators of miRNA profiles in cancer etiology and
prevention (Figure 4). The latter work will likely
dovetail with ongoing research on the therapeutic
aspects of miRNAs, as described below.
MicroRNA-BASED CANCER THERAPEUTICS
Over the past decade, evidence has accrued on
the possibility of using miRNA profiling in the
diagnosisof human pathological
including cancer . Through the ‘‘fine tuning’’
of multiple signaling pathways, miRNA-based ther-
apy might restore homeostasis and provide an
effective means of regulating the transcriptome or
proteome. High-throughput technologies, such as
microarrays and genome-wide association studies
with deep sequencing, are moving rapidly to en-
hance miRNA detection. Various therapeutic strat-
egies have thus evolved concurrently with the
increased understanding of miRNA regulation and
functionality. Most of the strategies are based on
the principle of gain- or loss-of-function.
Inhibiting Oncogenic miRNAs
The observation that certain miRNAs are com-
monly upregulated in tumor development provid-
competitive inhibitors for cancer therapy. These
‘‘designer’’ miRNAs often have good bioavailability
and stability, but there are limitations in terms of
effects [183,184]. Another approach is the use of
locked nucleic acid (LNA) constructs. These nucle-
MICRORNAS, DIET, AND CANCER
secured by a methylene bridge connecting the 20-O
atom and the 40-C atom, leading to successful
knockdown of specific miRNAs [185,186]. Al-
though this strategy was found to be effective,
again there are concerns regarding potential toxici-
ty and off-target effects. Small molecule inhibitors,
such as diazobenzene-1, also have been investigat-
ed for their ability to influence oncogenic miRNAs
in different cancers . Chemotherapeutic drugs
are currently under investigation for their ability
to restore miRNAs to a normal phenotype in
cancer cells [124,143].
Another therapeutic strategy is the ‘‘miR-mask,’’
designed to be completely complementary to a
miRNA binding site in the 30-UTR region of the
mRNA being targeted . Despite its apparent
specificity, this approach has limited scope due to
an inability to target multiple cancer signaling
pathways. A slightly more sophisticated approach
uses miRNA ‘‘sponges,’’ which contain multiple
tandem binding sites corresponding to a miRNA of
interest, and exhibit competitive binding with des-
ignated targets for a particular miRNA . In a
recent study, sponges containing heptameric seed
sequences effectively blocked an entire miRNA
family, due to their common seed sequence recog-
nition . Despite targeting an entire family of
miRNAs, further research is needed to improve de-
livery and enhance specificity. In a similar vein, li-
posome-based oligonucleotide-mimics of miRNAs
resulted in improved stability and delivery, but
had impaired biological activity and enhanced tox-
icity due to formation of cationic lipids [191–193].
Polymers and nanoparticle-based strategies are
generating more promising results in terms of de-
livery, stability, and reduced toxicity [194,195].
Upregulating Tumor Suppressor miRNAs
In most cancers, tumor suppressor miRNAs are
repressed or completely absent; thus, reinstating
these miRNAs could be therapeutically beneficial
[196–198]. Several miRNA mimics have been devel-
oped to restore tumor suppressor activity, with
successful induction of cell death and inhibition of
cell proliferation. So far, these ‘‘miR-mimics’’ have
been evaluated in vitro and await experimental
validation in vivo. Another approach involves
the use of adenovirus-associated vectors, some of
which have entered Phase I and II clinical trials
[199,200]. This strategy seeks to upregulate the
expression of tumor suppressor miRNAs without
integration into the genome and avoiding toxicity.
In addition, DNA demethylating agents, HDAC
Figure 4. MicroRNA regulation by dietary agents. Dietary agents such as curcumin, resveratrol, DIM, I3C,
EGCG, and ellagitannin modulate miRNAs that regulate cancer signaling pathways.
PARASRAMKA ET AL.
possible means of restoring expression of suppres-
sor miRNAs in cancers.
CONCLUSIONS AND FUTURE PERSPECTIVES
There is a pressing need for clinical translation
of novel breakthroughs in cancer biology. Enthusi-
asm abounds for miRNAs as novel gene regulators,
with the potential to fine tune physiological pro-
cesses involved in cellular differentiation and me-
tabolism. Given that the deregulation of miRNA
expression is implicated in numerous facets of can-
cer pathology, we anticipate further interest in
miRNAs as novel targets for cancer chemopreven-
tion and therapy.
This review summarized key mechanisms of
miRNA biogenesis and the regulatory functions
specific to oncogenesis. The emerging role of miR-
NAs as oncogenic and/or tumor suppressor factors
has opened a new avenue for therapeutics, but
much work is needed to clarify the mechanisms by
which miRNAs regulate their own expression and
other signaling pathways. A modest change in the
expression of a single miRNA can provoke a cas-
cade that activates several feedback pathways, in-
volving various other miRNAs. Though still in a
preliminary stage, several examples exist of the in-
ter-regulatory patterns between promoter regions
of miRNAs and various other genes. Profiling stud-
ies have provided insights into the complex roles
of miRNAs in different clinical situations. For
example, miR-195 is upregulated in cardiovascular
highlighting the need for careful therapeutic strat-
egies that alleviate one condition without simulta-
neously exacerbating others.
This review also summarized the broader interest
in epigenetics and miRNA regulation, involving
cross-talk with DNA methylation patterns and his-
tone modifications. As more studies target miRNAs
as a therapeutic strategy, we will gain greater
insights into their ability to affect drug resistance
mechanisms associated with standard chemothera-
peutic drugs. Several therapeutic strategies also
have been proposed based on synthetic analogs of
miRNAs; however, this field is still in its infancy.
Various dietary agents are now under investiga-
tion as modulators of miRNA profiles in cancer,
and there is much promise in this area from a
chemoprevention standpoint. Effects of natural
agents on temporal changes in miRNA profiles dur-
ing cancer initiation and progression could pro-
vide new insights into early biomarkers for cancer
chemoprevention. However, issues such as in vivo
bioavailability, selective targeting, and the genera-
tion of appropriate bioactive metabolites await
further examination. Alternative approaches are
being investigated, such as synthetic formulations
of natural products with enhanced bioavailability,
or encapsulation via nanoparticles and liposomes.
As a closing comment, many of the published
studies on dietary agents and miRNAs are highly
descriptive, and there now exists a clear need to
move the research into more detailed, mechanistic
areas. This is somewhat analogous to the situation
in the 1970s and 1980s in screening antimutagens
in vitro—leading journals elected to no longer ac-
cept descriptive data without experiments on the
associated mechanisms. Such an approach would
likely move the field forward in the context of
miRNAs involved in cancer chemoprevention. This
is important given the growing awareness of the
complex regulation of miRNAs and their targets
during different stages of cancer development. As
we continue to clarify the mechanisms of these in-
teresting gene regulators, there is much optimism
that new chemopreventive and therapeutic modal-
ities will be developed along the way.
We thank Mr. Animesh Koya for assistance with
the art work. Studies in the authors’ laboratories
are supported by National Cancer Institute grants
CA090890, CA122959, CA65525, CA122906, and
CA80176, and by Award T32 ES007060 from the
National Institute of Environmental Health Scien-
ces. The content of this review is solely the respon-
sibility of the authors and does not necessarily
represent the official views of the National Insti-
tutes of Health.
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