The p53/microRNA connection in gastrointestinal cancer

Abstract

The protein encoded by the TP53 gene is one of the most important suppressors of tumor formation, which is also frequently inactivated in gastrointestinal cancer. MicroRNAs (miRNAs) are small noncoding RNAs that inhibit translation and/or promote degradation of their target messenger RNAs. In recent years, several miRNAs have been identified as mediators and regulators of p53's tumor suppressing functions. p53 induces expression and/or maturation of several miRNAs, which leads to the repression of critical effector proteins. Furthermore, certain miRNAs regulate the expression and activity of p53 through direct repression of p53 or its regulators. Experimental findings indicate that miRNAs are important components of the p53 network. In addition, the frequent genetic and epigenetic alterations of p53-regulated miRNAs in tumors indicate that they play an important role in cancer initiation and/or progression. Therefore, p53-regulated miRNAs may represent attractive diagnostic and/or prognostic biomarkers. Moreover, restoration of p53-induced miRNAs results in suppression of tumor growth and metastasis in mouse models of cancer. Thus, miRNA-based therapeutics may represent a feasible strategy for future cancer treatment. Here we summarize the current published state-of-the-art on the role of the p53-miRNA connection in gastrointestinal cancer.

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Clinical and Experimental Gastroenterology 2014:7 395–413
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http://dx.doi.org/10.2147/CEG.S43738
The p53/microRNA connection
in gastrointestinal cancer
Matjaz Rokavec
Huihui Li
Longchang Jiang
Heiko Hermeking
Experimental and Molecular
Pathology, Institute of Pathology,
Ludwig-Maximilians-Universität
München, Munich, Germany
Correspondence: Heiko Hermeking
Experimental and Molecular Pathology,
Institute of Pathology,
Ludwig-Maximilians-University Munich,
Thalkirchner Strasse 36,
D-80337 Munich, Germany
Tel +49 89 2180 73 685
Fax +49 89 2180 73 697
Email heiko.hermeking@med.uni-
muenchen.de
Abstract: The protein encoded by the TP53 gene is one of the most important suppressors of
tumor formation, which is also frequently inactivated in gastrointestinal cancer. MicroRNAs
(miRNAs) are small noncoding RNAs that inhibit translation and/or promote degradation
of their target messenger RNAs. In recent years, several miRNAs have been identified as
mediators and regulators of p53’s tumor suppressing functions. p53 induces expression and/
or maturation of several miRNAs, which leads to the repression of critical effector proteins.
Furthermore, certain miRNAs regulate the expression and activity of p53 through direct
repression of p53 or its regulators. Experimental findings indicate that miRNAs are important
components of the p53 network. In addition, the frequent genetic and epigenetic alterations of
p53-regulated miRNAs in tumors indicate that they play an important role in cancer initiation
and/or progression. Therefore, p53-regulated miRNAs may represent attractive diagnostic and/
or prognostic biomarkers. Moreover, restoration of p53-induced miRNAs results in suppression
of tumor growth and metastasis in mouse models of cancer. Thus, miRNA-based therapeutics
may represent a feasible strategy for future cancer treatment. Here we summarize the current
published state-of-the-art on the role of the p53-miRNA connection in gastrointestinal cancer.
Keywords: p53, microRNA, cancer, gastrointestinal tract
Introduction
Gastrointestinal (GI) cancers represent malignant tumors of the GI tract and accessory
organs of digestion. They include carcinomas arising in the oral cavity, esophagus,
stomach, liver, gallbladder, pancreas, small intestine, large intestine, rectum, and anus.
GI cancer represents about 30% of all tumor incidences and is responsible for approxi-
mately 40% of tumor-related mortality worldwide (Figure 1A and B).1 Tumors of the
GI tract harbor mutations in the p53 tumor suppressor gene (TP53) with a prevalence
ranging from 31% to 45% (Figure 1C).2 The p53 protein functions as a transcription
factor that mediates the response to many cellular stresses, most prominently the
DNA damage response. p53 suppresses a variety of malignant processes, thereby
representing one of the most important cancer suppressing proteins.3 p53 protects
against cancer by inducing cellular processes such as apoptosis or cell cycle arrest,
thereby preventing the propagation of damaged cells that potentially could give rise to
tumors.4,5 Moreover, p53 inhibits epithelial to mesenchymal transition (EMT), stem-
ness, and metabolic adaptations, which are typically found in tumors.6 In addition,
p53 promotes DNA repair, antioxidant defense, and differentiation. On the molecular
level, p53 exerts its tumor suppressive functions by regulating the expression of numer-
ous target genes, mainly by direct binding to specific DNA motifs located in target
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gene promoters.7 Besides p53-regulated protein expression,
p53-induced microRNAs (miRNAs) have emerged as impor-
tant effectors of p53.8,9 The generation of mature miRNAs
is a multistage process (see Figure 2) starting with the tran-
scription of miRNA encoding genes to yield the primary
miRNA (pri-miRNA).10 Next, the pri-miRNA is cleaved by
the RNAse III enzyme Drosha, resulting in a ∼70 nucleotide
stem-loop-structured miRNA precursor molecule (pre-
miRNA).11 The pre-miRNA is transported to the cytoplasm
by Exportin 5, where it is cleaved further by the RNAse
Dicer. The resulting 20 to 25 bp mature miRNA is incorpo-
rated into the miRNA-induced silencing complex (miRISC),
which mediates miRNA-induced silencing of target mes-
senger RNAs (mRNAs).12 miRNAs bind to 3′-untranslated
regions (3′-UTR) of mRNAs via their seed sequences, which
are conserved seven nucleotide regions in their 5′ region. The
association of the miRISC with seed-matching sequences
in target mRNAs results in the inhibition of translation and
degradation of the target mRNAs.10 It has been estimated
that .60% of human protein coding genes are subject to
regulation by miRNAs.13 Not surprisingly, miRNA-mediated
regulation has been implicated in almost all physiological
and pathophysiological processes.10 Interestingly, several
miRNAs may also be of use for diagnostic, prognostic,
and therapeutic applications in GI-cancers.14–18 Extracel-
lular miRNAs have been detected in blood serum. These
miRNAs are either secreted by living cells via exosomes or
microvesicles, or they originate from dying cells.19 Interest-
ingly, these circulating miRNAs are extremely stable, both in
blood and after isolation. Numerous studies have shown their
potential usefulness as noninvasive diagnostic and prognos-
tic markers in GI cancers.20 Seven years ago it was shown
that p53 also regulates the expression of miRNA-encoding
genes.8 The p53-regulated miRNAs have been implicated
Figure 1 Incidence (A) and mortality (B) of indicated gastrointestinal (GI) cancers worldwide. (C) Prevalence of mutations in the TP53 gene in the indicated GI cancers.

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The p53/microRNA axis in GI cancer
in the control of various cancer-related processes, such
as proliferation, apoptosis, EMT, migration, invasion, and
metastasis. Therefore, they may represent important media-
tors of the tumor suppressive function of p53. In addition,
a number of miRNAs can regulate expression and activity
of the p53 protein, either negatively through direct repres-
sion of p53 expression, or positively through the repression
of negative regulators of p53. In this review we summarize
the current knowledge about the p53/miRNA network and
its role in GI cancers.
Figure 2 Effects of p53 on miRNA biogenesis.
Notes: Wild-type p53 (green) regulates miRNA transcription, processing, and target selection. In contrast, mutant p53 (blue) is unable to induce the expression of miRNAs
and additionally inhibits the p63-mediated activation of the miRNA processing protein Dicer.
Abbreviations: mRNA, messenger RNA; miRNA, microRNA; pre-microRNA, miRNA precursor molecule; pri-microRNA, primary miRNA; miRISC, miRNA-induced
silencing complex; mut, mutant; RE, response element.

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Table 1 Summary of changes in expression of p53-pathway-related miRNAs in GI cancers
Notes: For a more detailed description of the single miRNAs and references see Tables 2 and 3. Green box with : downregulated in indicated GI tumor type; Red box
with ∆: upregulated in indicated GI tumor type; Yellow box with /∆: down- or upregulated in indicated GI tumors.
Abbreviations: CRC, colorectal cancer; EC, esophageal cancer; GC, gastric cancer; GI, gastrointestinal; HCC, hepatocellular cancer; miRNA, microRNA; PaC, pancreatic cancer.
p53 regulated miRNAs
In 2007, we and other groups identified several miRNAs as
direct transcriptional targets of p53.21–27 Since then, many of
these miRNAs have been validated as important mediators of
p53 functions (Table 1 and 2).9 p53 regulates the expression
of its target miRNAs either on the transcriptional level by
direct binding to the promoters of the corresponding genes,
or by regulating miRNA processing (Figure 2). It was shown
that p53 interacts with the DEAD-box RNA helicase p68
(also known as DDX5) and enhances its interaction with the
Drosha complex. As a result, p53 promotes the processing of
specific pri-miRNAs to pre-miRNAs, leading to elevated lev-
els of the respective miRNAs.28 Another link between p53 and
miRNA-processing has been observed in conditional Dicer
knockout mice.29 Dicer deficiency, and therefore incomplete
miRNA maturation, induces p53, which leads to

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The p53/microRNA axis in GI cancer
Table 2 Compilation of p53-regulated miRNAs and their alterations in GI cancers
miRNA Validated by Clinical and pathological associations in GI cancers
miRNAs induced by p53
miR-34a Luc reporter (mut), qPCR, ChIP24 CRC: downregulated in tumors38 and serum;162 Downregulation in metastatic tumors;70,163 CpG
methylation66,67 in metastatic tumors70
EC, HCC: downregulated in tumors;39,41 CpG methylation39,41,164
GC: downregulated in tumors40
PaC: downregulation associated with poor OS;165 CpG methylation66,67
miR-34b/c Luc reporter (mut), qPCR, ChIP24 CRC, GC, PaC: CpG methylation67,69
EC: upregulation associated with advanced tumor stage;166 CpG methylation164
HCC: downregulated in tumors41
miR-15a/16-1 qPCR, ChIP33 CRC: miR-16-1 down-regulated in tumors;77 Downregulation of miR-16-1 associated with pN,
TNM stage, and poor OS77
EC: miR-15a upregulated in tumors167
miR-200c/141 Luc reporter (mut), qPCR, ChIP32 CRC: downregulation of miR-200c is associated with poor OS;168 miR-200c is downregulated
in metastatic CRC;169 miR-200c is upregulated in patient serum;112,170 Upregulation in serum is
associated with tumor stage, pN, metastasis, and prognosis;109 CpG methylation171
EC: miR-200c is upregulated in patient serum;108 Upregulation in serum associated with poor RFS108
GC: miR-141 is downregulated in tumors172
HCC: miR-200c is downregulated in tumors;173 Downregulation associated with poor RFS174
miR-200a/
200b/429
Luc reporter (mut), qPCR, ChIP32 CRC: miR-429 is downregulated in tumors175; downregulation of miR-200a/429 is associated
with poor OS;168 CpG methylation171
EC: miR-200a/b are upregulated in tumors167,176
GC: miR-200a is downregulated in tumors176
PaC: CpG hypomethylation and overexpression in tumors177
miR-107 Luc reporter (mut), qPCR, ChIP36 CRC: upregulation associated with metastasis and poor OS117
EC: downregulated in tumors and serum178
GC: upregulated in tumors; Upregulation associated with tumor invasion, stage, pN, and poor
DFS and OS119
PaC: CpG methylation179
miR-145 Luc reporter (mut), qPCR, ChIP35 CRC: downregulated in tumors180,181 and patient stool samples;182 Downregulation associated
with tumor size91
EC, GC, HCC, PaC: downregulated in tumors88–90,173,183,184
miR-192/
194/215
qPCR, ChIP34 CRC: downregulation of miR-192/194/215 in tumors;34,185,186 Downregulation of miR-192/215
associated with stage, grade, pN;103,186 Downregulation of miR-215 associated with poor RFS;101
Upregulation of miR-194 associated with poor RFS and OS187
GC: downregulation of miR-194 associated with higher tumor size and stage;188 miR-215
upregulated in tumors189
miR-29 Luc reporter, qPCR149 CRC: upregulated in serum;190 Upregulation associated with metastasis and OS191
GC: downregulated in tumors; Downregulation associated with metastasis152,192
HCC: downregulated in tumors; Downregulation associated with poor RFS and OS153,154
miR-605 Luc reporter (mut), qPCR, ChIP193 NA
miR-149 Luc reporter (mut), qPCR, ChIP194 CRC: downregulated in tumors;195 CpG methylation;196 Downregulation associated with
invasion and poor OS196
GC: downregulated in tumors197
miR-22 Luc reporter (mut), qPCR, ChIP198 CRC: downregulated in tumors and liver metastases; Downregulation associated with poor OS199
EC, PaC: upregulated in serum200,201
GC: downregulated in tumors;202 Downregulation associated with tumor stage, pN, metastasis,
poor OS203
HCC: downregulated in tumors, Downregulation associated with pN, grade, and poor OS204,205
miR-23b Luc reporter (mut), ChIP206 EC: downregulation associated with poor prognosis207
CRC, HCC: downregulated in tumors208,209
miR-205 Luc reporter (mut), qPCR, ChIP210 EC: downregulated in tumors,211,212 Down-regulation associated with poor prognosis207
HCC: downregulated in tumors213
miR-1246 Luc reporter (mut), qPCR, ChIP214 CRC: downregulated in tumors215; Upregulated in patient serum216
EC: upregulated in tumors217 and patient serum218
miR-1204 qPCR, ChIP219 NA
(Continued)

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reduced proliferation and premature senescence. Therefore,
p53 may operate as a checkpoint to monitor proper miRNA
processing. Moreover, expression of Dicer1 is regulated by the
p53 family member p63, which can be inhibited by associa-
tion with mutant p53.30 Finally, p53 also affects miRNA target
gene selection by regulating mRNA-binding proteins, such as
RNA-binding-motif protein 38, which competes with miR-
NAs for binding to 3′-UTRs of mRNAs.31 miRNAs transcrip-
tionally induced by p53 include the miR-34,21–26 miR-200,32
miR-15a/16-1,33 and miR-192/194/21534 clusters, as well as
miR-14535 and miR-107.36 Yet some of these miRNAs, such as
miR-16-1, miR-145, and miR- 199a-3p, are also regulated on
the post-transcriptional level by p53.28,37 The expression of the
majority of these miRNAs is frequently altered in GI tumors
and has been associated with clinical and pathological param-
eters of various types of GI cancer (Tables 1 and 2).
The miR-34 family
The miR-34 family includes three members – miR-34a,
miR-34b, and miR-34c – which show a marked induc-
tion by p53.8 MiR-34a is encoded by its own host gene,
whereas miR-34b and miR-34c share a common precursor.
Both miR-34 genes contain several p53-responsive
elements, which are occupied by p53 and mediate activa-
tion of miR- 34a/b/c after DNA damage.25,26 Expression of
miR-34a/b/c is frequently downregulated in colorectal,38
esophageal,39 gastric,40 and hepatocellular cancers (HCCs).41
Consistently, all members of the miR-34 family were shown
to suppress tumor growth and metastasis by inhibiting pro-
cesses that promote cancer, including cell cycle progression,
EMT, metastasis, and stemness and by promoting tumor
suppressive processes, such as apoptosis and senescence.42
MiR-34s regulate these processes through suppressing the
expression of their target mRNAs, such as SNAIL, c-Myc,
Bcl2, c-Met, and Axl.43 The miR-34/p53 axis and its targets
are often connected through positive or negative feedback
loops that either reinforce the miR-34/p53 signaling or
suppress it. For example, a positive feedback loop connects
miR-34a and p53 via MDM4 (Figure 3A). MDM4 and
its human counterpart HDM4 bind to p53 and inhibit its
transcriptional activity. At the same time MDM4/HDM4
are targets of miR-34a.44,45 Therefore, the repression of
MDM4/HDM4 by miR-34a leads to stabilization of p53 and
enhanced expression of miR-34a. Recently, it was shown that
in addition to full-length HDM4 that is targeted by miR-34a,
a short isoform of HDM4 also exists, which lacks seed-
matching sites for miR-34a, thereby evading suppression
by miR-34a.45 Consistently, this short HDM4 isoform was
highly expressed in tumors, where it presumably inhibits
the miR-34a/p53 axis.
Furthermore, SIRT1 was shown to mediate activation
of p53 by miR-34a.46 SIRT1 is an nicotinamide adenine
dinucleotide (NAD+)-dependent deacetylase, which represses
p53 activity by deacetylation of p53 protein. Yamakuchi
et al showed that SIRT1 is a miR-34 target and that miR-34
induces the activity of p53 by repressing SIRT1 in colorectal
cancer (CRC) cell lines (Figure 3B). Moreover, miR-34 not
only represses the expression of SIRT1, but also suppresses
SIRT1 activity by downregulating nicotinamide phospho-
ribosyltransferase (NAMPT), the rate-limiting enzyme of
NAD+ biosynthesis.47 Furthermore, SIRT1 and MYC regulate
each other via a positive feedback loop.48,49 By repressing
both SIRT1 and MYC, miR-34a may therefore efficiently
suppress this circuitry.
Another double-negative feedback loop involving miR-
34a was discovered by Siemens et al,50 who demonstrated that
miR-34a directly targets and suppresses the EMT-inducing
transcription factor (EMT-TF) SNAIL, whereas SNAIL
represses the miR-34a and miR-34b/c genes by directly
binding to their promoters in CRC cell lines (Figure 3C).
By utilizing HCC and CRC cells, Kim et al showed that
p53 regulates EMT by inducing members of the miR-200
Table 2 (Continued)
miRNA Validated by Clinical and pathological associations in GI cancers
miRNAs repressed by p53
miR-17-92 Luc reporter (mut), qPCR, ChIP126 CRC,220,221 EC,222,223 GC,224,225 HCC,226 PaC;227 Upregulated in tumors
miR-224 Luc reporter (mut), qPCR, ChIP124 CRC: upregulated in tumors;228,229 Upregulation associated with poor RFS and OS;228,229
Downregulation associated with poor OS;230 Upregulation associated with tumor size, stage,
and metastasis229
HCC: upregulated in tumors231,232
miR-502 Luc reporter125 CRC: downregulated in tumors125
Abbreviations: ChIP, chromatin immunoprecipitation; CRC, colorectal cancer; DFS, disease-free survival; EC, esophageal cancer; GC, gastric cancer; GI, gastrointestinal;
HCC, hepatocellular cancer; Luc reporter, Luciferase miRNA promoter reporter assay; miRNA, microRNA; mut, mutation in the p53 binding site; NA, not
applicable or not analyzed; OS, overall survival; PaC, pancreatic cancer; pN, nodal status; qPCR, quantitative real-time polymerase chain reaction; RFS, relapse-free
survival; TNM, tumor, node, metastasis status based classication.

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The p53/microRNA axis in GI cancer
Figure 3 The role of p53/miRNA axis in (A) p53 autoregulation, (B) cancer cell metabolism, (C) invasion, and metastasis, as a result of the regulation of EMT/MET (D)
cancer-associated inammatory signaling.
Notes: Color code: p53/green; miRNAs/yellow; miRNA-targets/red; green arrow/activation; red arrow/inhibition.
Abbreviations: EMT, epithelial–mesenchymal transition; IL-6, interleukin 6; IL-6R, interleukin 6 receptor; MET, mesenchymal–epithelial transition; miRNA, microRNA;
NAD+, nicotinamide adenine dinucleotide; NAMPT, nicotinamide phosphoribosyltransferase.
family,32 which also represent EMT-regulating miRNAs that
suppress EMT by a similar double-negative feedback loop
involving the EMT-TFs ZEB1 and ZEB2.51,52 Thus, p53 is a
key regulator of cellular plasticity by controlling EMT and
its counterpart mesenchymal–epithelial transition (MET)
through inducing the miRNAs of the miR-34 and miR-200
family (Figure 3C). These miRNAs form two double-
negative feedback loops with their targets SNAIL, ZEB1,
and ZEB2 that act as bimodal switches to stabilize either
the epithelial or the mesenchymal state. Moreover, ZEB1

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was also shown to repress miR-34a expression by binding
to the same E-boxes in the miR-34 promoters as SNAIL,
thereby further interconnecting the miR-34/SNAIL and
miR-200/ZEB loops.50,53 In addition, we recently showed
that the zinc-finger 281 (ZNF281) protein is an important
miR-34 target with respect to EMT.54 We found that the
expression of ZNF281 is controlled by miR-34 and SNAIL
in a coherent feed-forward-loop, whereby SNAIL and
ZNF281 induce each other, whereas miR-34 can directly
repress both SNAIL and ZNF281 (Figure 3C). Accord-
ingly, ectopic SNAIL induced EMT by directly activating
ZNF281 and concomitantly repressing miR-34a expres-
sion, which leads to a further increase in ZNF281 levels.
Notably, the induction of ZNF281 by SNAIL was required
for SNAIL-induced EMT.
Recently, we demonstrated that inflammation can
suppress the expression of miR-34a.55 We showed that
exposure to the proinflammatory cytokine interleukin-6
(IL-6) results in repression of miR-34a via direct binding
of the IL-6 effector STAT3 to the first intron of the miR-
34a gene. Furthermore, we identified the IL-6 receptor
(IL-6R) as a direct target of miR-34a. Further functional
analysis revealed the existence of an IL-6R/STAT3/miR-
34a feedback loop (Figure 3D). The activation of this loop
was required for EMT, invasion, and metastasis of CRC
cell lines and was associated with nodal and distant metas-
tasis in CRC patients. Moreover, in miR-34a-deficient
mice, colitis-associated intestinal tumors displayed acti-
vation of the loop and, in contrast to tumors in wild-type
mice, progressed to invasive carcinomas. Our findings
suggest that the activation of the IL-6R/STAT3/miR-34a
loop by IL-6 drives cancer cells toward a mesenchymal
and invasive phenotype, whereas suppression of the loop
by p53 shifts cancer cells toward an epithelial state and
prevents EMT and invasion.55
Reintroduction of miR-34 into tumors, which lost
miR-34 expression, may represent an attractive alterna-
tive for cancer treatment. The most common approach for
miRNA delivery relies on lipid-based nanoparticles, which
contain vectors expressing miRNAs, or ∼19–23-nt double-
stranded mimics of mature miRNAs. These can be admin-
istered systemically by intravenous injection or locally into
tumors. Several studies have shown that systemic miR-34a
delivery suppresses tumor growth in vivo. Using xenograft
or genetically engineered mouse models of melanoma,
lymphoma, multiple myeloma, breast, prostate, pancreatic,
and non-small-cell lung cancer, the authors observed an
inhibition of tumor growth by 20% to 83% after reintroduc-
tion of miR-34a.56 Importantly, no severe toxicity caused by
systemic miR-34a delivery has been observed in mice.57,58
Likewise, no unwanted immune response has been detected,
based on serum cytokine levels in immune-competent mice.59
Recently, the company Mirna Therapeutics has initiated a
clinical Phase I trial of nanoparticle-based delivery of miR-
34a in patients with non-resectable primary liver cancer or
metastatic cancer with liver involvement.60 Therefore, miR-
34a may be one of the first miRNA mimics to reach the clinic.
Conventional anticancer therapies, such as chemotherapy
and treatment with radiation, induce miR-34 expression in
human cancer cells with wild-type p53.27 However, since the
majority of human tumors lack normal p53 function, replace-
ment of miR-34 may enhance the efficacy of standard cancer
therapies. Indeed, in prostate, colorectal, and bladder cancer
cells, reintroduction of miR-34a precursors enhanced the
sensitivity toward camptothecin, paclitaxel, 5-fluorouracil,
and cisplatin.61–65 Furthermore, lentiviral transduction of
miR-34a sensitized gastric and pancreatic cancer cells to
radiation and to the chemotherapeutic drugs docetaxel,
gemcitabine, cisplatin, and doxorubicin.63,64 Moreover, we
recently showed that c-Kit is an important miR-34a target
that mediates, at least in part, chemosensitization by miR-
34a in CRC cell lines.65 Thus, these results suggest that
combined treatment with miR-34 mimics may enhance the
beneficial effects of conventional cancer therapies.
Downregulation of miR-34 expression in tumors has
been frequently attributed to methylation of the CpG islands
present in promoters of miR-34a and miR-34b/c.66–69 CpG
methylation is causally involved in repression of miR-34-
a/b/c, since treatment of CRC cell lines with the demethylat-
ing agent 5-aza-2′-deoxycytidine leads to re-expression of
miR-34a/b/c.66,68,69 Moreover, a significant inverse correlation
between miR-34a methylation and expression has been
observed in colon tumors.70,71 Therefore, miRNA cancer
treatment strategies may rely not only on delivery of syn-
thetic miRNA mimics corresponding to miR-34a/b/c into
tumors, but also on re-expression of these miRNAs using
demethylating agents. Indeed, treatment with BioResponse
3,3′-Diindolylmethane, an experimental anti-androgen pros-
tate cancer drug, resulted in demethylation and re-expression
of miR-34a in prostate cancer cells.72 In a Phase II clinical
trial, treatment of prostate cancer patients with BioResponse
3,3′-Diindolylmethane prior to radical prostatectomy led
to the re-expression of miR-34a as well as repression and
nuclear exclusion of its target, the androgen receptor.72,73
Several reports showed that miR-34 methylation may also
have prognostic value. In our study, miR-34a methylation

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The p53/microRNA axis in GI cancer
in primary CRC was significantly associated with increased
formation of lymph node and liver metastases.70 Recently,
Wu et al analyzed miR-34a/b/c methylation in stool samples
of 82 CRC patients and 40 controls.74 They demonstrated
that detection of miR-34a and miR-34b/c methylation could
identify CRC with a remarkable sensitivity of 76.8% or 95%
and a specificity of 93.6% or 100%, respectively. Therefore,
the detection of miR-34 miRNAs and CpG methylation of
miR-34 promoter regions in body fluids or stool represent
potential biomarkers which may be utilized for noninvasive
screening and diagnosis of cancer in the future.
miR-15a and miR-16-1
Mir-15a and miR-16-1 were the first miRNAs genetically
linked to cancer: In 2002, Calin et al showed that miR-15a and
miR-16-1, which are encoded within an intron of the DLEU2
gene, are frequently deleted and/or downregulated in chronic
lymphocytic leukemia.75 Notably, a knockout of DLEU2 or of
the miR-15a/16-1-bearing intron in mice confirmed that loss
of miR-15a/16-1 causes chronic lymphocytic leukemia.76
The expression of miR-15a and miR-16-1 is induced by p53
via transcriptional33 and post-transcriptional mechanisms.28
Several studies implicated the downregulation or loss
of miR-15a and miR-16-1 expression in GI cancers. For
example, the expression of miR-16-1 was significantly
lower in primary CRC when compared to the corresponding
normal colonic mucosa.77 Moreover, decreased miR-16-1
expression was associated with lymph node metastasis and
recurrence of colorectal tumors.77 Furthermore, ectopic
expression of miR-15a and miR-16-1 inhibited the prolif-
eration of pancreatic and colorectal cancer cells78,79 and led
to a significant inhibition of subcutaneous growth of CRC
cell lines in immune-compromised mice.80 Interestingly,
hepatitis B virus X protein, which is involved in the initia-
tion and progression of HCC downregulates miR-15a/16
expression, suggesting that reintroduction of these miRNAs
may be an effective treatment of hepatitis-B-virus-related
chronic liver diseases.81 MiR-15a and miR-16-1 act tumor
suppressive, at least in part, by promoting apoptosis and
cell cycle inhibition via targeting the anti-apoptotic pro-
tein Bcl282 and cell cycle regulators, including CDK6 and
cyclin D1, respectively.83,84 Recently, we demonstrated that
miR- 15a/16-1 also inhibit EMT, invasion, and metastasis
of CRC cells by directly targeting the EMT-TF AP4.85
Interestingly, AP4 itself is a repressor of the DLEU2 gene.
We showed that miR-15a/16-1 and the EMT-inducing factor
AP486 form a double-negative feedback loop that stabilizes
low expression of miR-15a/16-1 and elevated expression of
AP4 in invasive CRC cells and tumors, thereby ultimately
promoting CRC metastasis (Figure 3C).85
miR-145
p53 controls the expression of miR-145 by two mecha-
nisms: first, p53 directly induces the transcription of
the miR-145 gene,35 and second, p53 enhances miR-145
maturation via modulation of Drosha-mediated miRNA
processing.28,87 In line with a regulation by p53, expres-
sion of miR-145 is significantly lower in various tumors
that harbor p53 mutations, including esophageal, gastric,
pancreatic, colorectal, and bladder cancers.88–92 Accord-
ingly, ectopic miR-145 suppresses migration, invasion,
and metastasis of gastric and colorectal cancer cells.89,93
Moreover, therapeutic polyethylenimine-mediated rein-
troduction of miR-145 reduces proliferation and increases
apoptosis of CRC cells in xenograft mouse models.94 The
tumor suppressing properties of miR-145 can be partially
attributed to the repression of MYC, which represents a
direct target of miR-145.35 Similar to miR-34, miR-200, and
miR-15a/16-1, miR-145 has also been shown to represent a
mediator of p53-induced MET, the reversion of EMT (Fig-
ure 3C).95 Another important oncogenic target of miR-145
is KRAS.96 Interestingly, activated KRAS also represses
miR-145 via RREB1, thereby forming a feed-forward
loop that potentiates RAS signaling. Accordingly, loss
of miR-145 is frequently observed in KRAS mutant pan-
creatic cancers, and restoration of these miRNAs inhibits
tumorigenesis.96 Xu et al showed that miR-145 negatively
regulates the pluripotency factors OCT4, SOX2, and KLF4,
and thereby represses self-renewal and induces differentia-
tion of human embryonic stem cells.97 Moreover, the same
group reported that the miR-145 promoter is bound and
repressed by OCT4, thereby forming a negative feedback
loop.97 Loss of p53 leads to increased generation of induced
pluripotent stem cells and expansion of cancer stem cells.98
This effect might at least in part be due to the lack of p53-
induced miR-145 expression and consequent upregulation
of OCT4. Finally, like miR-34a targets MDM4, miR-145
directly targets and represses the p53 inhibitor MDM2.99
The result is another positive feed-forward loop that leads
to stabilization of p53 and elevated expression of p53-
induced miRNAs (Figure 3A).
The miR-192/miR-194/
miR-215 family
MiR-192, miR-194, and miR-215 are encoded by two clusters
located at two different sites: The miR-194-1/miR-215 cluster

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on chromosome 1 (1q41) and the miR-192/miR-194-2 clus-
ter on chromosome 11 (11q13.1). Both clusters are directly
induced by p53.34,100 Interestingly, miR-194-1 and miR-194-2
have the same mature sequence, although they are derived
from two different precursors on two chromosomal locations.
MiR-192 and miR-215 have the same seed sequence, whereas
the seed sequence of miR-194 differs. All three miRNAs dis-
play decreased expression in colorectal tumors.34 Furthermore,
low expression of miR-194 and miR-215 significantly corre-
lates with a high probability of relapse and shorter survival in
colorectal patients.101 MiR-192, miR-194, and miR-215 regu-
late cell cycle progression and proliferation via the repression
of functionally important targets, such as CDC7, MAD2L1,
and CUL5.102 Moreover, miR-192 suppresses liver metasta-
sis of CRC cells by targeting BCL2, ZEB2, and VEGF-A,103
while miR-194 inhibits EMT in endometrial cells by targeting
BMI-1.104 Importantly, similar to other p53-induced miRNAs,
miR-192, miR-194, and miR-215 also directly target MDM2
and therefore interfere with the autoregulatory MDM2/p53
loop (Figure 3A).100
The miR-200 family
The two genes that give rise to the miR-200c/141 and the
200a/200b/429 miRNAs represent direct p53 target genes.32
The members of the miR-200 family are tumor suppress-
ing miRNAs and several studies showed that they play a
crucial role in regulating the balance between EMT and
MET by forming a double-negative feedback loop with
their targets, the EMT-inducers ZEB1 and ZEB2 (Figure
3C).52,105 Moreover, miR-200c also suppresses stemness
by targeting the stem cell factors KLF4, SOX2, and the
polycomb repressor BMI-1.106,107 Several studies reported
that elevated levels of cell-free, circulating miR-200c and
miR-200a in the blood of colorectal, gastric, and esophageal
cancer patients are associated with increased tumor stage,
presence of metastases, and poor survival.108–112 At first
sight, this data seems contradictory, since functional studies
showed that miR-200s repress EMT, invasion, and metas-
tasis. Yet, recent studies showed that during the formation
of metastases, cancer cells undergo MET and re-express
EMT-suppressing genes and miRNAs.113 Therefore, elevated
levels of EMT-suppressing circulating miRNAs, such as
miR-200c, might originate from metastases and indicate
metastatic dissemination.
miR-107
The miRNA miR-107 is encoded by an intron of the p53-
induced pantothenate kinase 1 (PANK1) gene.36,114 Several
studies showed that ectopic expression of miR-107 enhances
EMT, migration, and promotes metastatic dissemina-
tion, whereas the loss of miR-107 represses migration
and metastasis of colorectal, breast, and gastric cancer
cells.115–118 In line with these observations, expression of
miR-107 is higher in gastric tumors compared with adjacent
normal tissue.119 Moreover, high expression of miR-107
correlates with lymph node and distant metastasis as well
as poor survival of colorectal, breast, and gastric cancer
patients.115–120 The pro-metastatic properties of miR-107
are mediated by repression of its targets, the metastasis
suppressors DAPK and KLF4.117 Furthermore, Martello
et al showed that miR-107 targets and represses DICER1,
a key component of the miRNA processing machinery,
thereby attenuating global miRNA production.115 Therefore,
elevated levels of miR-107 in tumors may contribute to the
global reduction of miRNA abundance that was observed
in various cancer types.121 In addition to regulation of
mRNA targets, miR-107 can also directly interact with and
negatively regulate the let-7 miRNA.116 Accordingly, miR-
107 increased the tumorigenic and metastatic potential of
human breast cancer cell lines in xenograft mouse models
via inhibition of let-7 and upregulation of let-7 targets.116
However, others have shown that miR-107 also has tumor
suppressing functions by inhibiting cell proliferation and
migration of breast cancer, gastric cancer, and glioma
cells.120,122,123 These tumor suppressing effects could be par-
tially attributed to the miR-107-mediated repression of the
response to hypoxia and angiogenesis via targeting of HIF
1β, resulting in a decreased supply of oxygen and nutrients
and subsequent inhibition of tumor growth.114 The decrease
in functional HIF1α–HIF1β dimers after p53-mediated acti-
vation of miR-107 may suppress glycolysis under hypoxic
conditions. These results indicate that p53-deficient tumors
may be resistant to hypoxia not only because of decreased
apoptosis and senescence, but also because of increased
HIF1 signalling due to the decrease in miR-107 which
results in metabolic and angiogenic adaptation. Altogether,
the majority of the current data suggests that miR-107 is
an oncogenic miRNA that promotes EMT, migration, and
metastasis. However, these observations are at first sight not
compatible with the induction of miR-107 by p53, which
would be expected to mediate tumor suppressive functions.
A possible explanation may be that p53 induces miR-107
and thereby downregulates DICER1 to limit the production
of p53-induced miRNAs, which would otherwise lead to
an unrestrained induction of p53 because of the positive
feedback loops these often form with p53.

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The p53/microRNA axis in GI cancer
p53-repressed miRNAs
p53 also directly represses certain miRNAs, including
miR-224,124 miR-502,125 and the miR-17-92 cluster.126
However, this type of regulation seems to occur less fre-
quently than the induction of tumor suppressive miRNAs
by p53. As expected, miRNAs repressed by p53 mostly
have oncogenic functions. The miR-17-92 primary
transcript encodes the miRNAs miR-17, miR-18a, miR-
19a, miR-20a, miR-19b-1, and miR-92a-1. The miR-17-92
clusters undergo genomic amplification and display elevated
expression in various cancer entities, including colon can-
cer.127 The miRNAs of the miR-17-92 family promote cell
proliferation, increase angiogenesis, promote cell survival,
and exhibit strong protumorigenic activities in multiple
mouse tumor models.128 Yan et al showed that miR-17-92
is repressed upon hypoxia via direct interaction of p53 with
the miR-17-92 promoter.126 Due to the strong cell survival
promoting properties of miR-17-92 family members, it is
likely that the repression of miR-17-92 expression by p53
plays a role in p53-induced apoptosis.
Regulation of p53 by miRNAs
p53 not only regulates the expression and processing of
miRNAs, but is also under the control of certain miRNAs.
Several miRNAs repress the translation of TP53 mRNA
by directly binding to its 3′-UTR (Tables 1 and 3). Since
these miRNAs diminish the tumor suppressive activity
of p53, they often represent oncomirs. Accordingly, they
often exhibit elevated expression in tumors. Similar to the
p53-regulated miRNAs the expression of p53-regulating
miRNAs is frequently altered in GI tumors (Tables 1 and 3).
The first miRNA that was characterized as a direct suppres-
sor of p53 was miR-125b. Le et al. Showed that miR-125b
is a negative regulator of p53 expression and p53-induced
apoptosis during development and stress response.129
Furthermore, it has been shown that miR-125 targets several
Table 3 Compilation of miRNAs that directly target p53 and their alterations in GI cancers
miRNA Validated by Clinical and pathological associations in GI cancers
miR-25 Luc reporter (mut), qPCR, WB134 CRC: upregulated in tumors; Upregulation associated with invasion, metastasis, poor OS146
EC: upregulated in tumors and serum;233 Upregulation associated with pN and tumor stage137,145
GC: upregulated in serum234 and tumors;235 Upregulation associated with tumor progression236,237
miR-30d Luc reporter (mut), qPCR, WB134 CRC, PaC: gene amplication148
HCC: upregulated in tumors; Upregulation associated with metastasis238
miR-33 Luc reporter (mut), WB135 NA
miR-98 Luc reporter (mut), WB143 EC: downregulated in tumors; Downregulation associated with tumor stage and pN239
miR-125a Luc reporter (mut), WB142 EC: downregulation associated with tumor progression240
GC: downregulation associated with invasion, metastasis, poor OS240–242
HCC: downregulated in tumors; Downregulation associated with tumor stage and metastasis243,244
miR-125b Luc reporter (mut), WB129 CRC: upregulation associated with tumor size, invasion, poor OS241
EC: downregulation associated with tumor progression240
GC: upregulation associated with tumor progression;236 Downregulation associated with tumor
progression240
HCC: upregulated in serum;131 Downregulated in tumors244,245
PaC: upregulated in tumors246
miR-150 Luc reporter (mut), WB138 CRC: downregulated in tumors; Downregulation associated with poor OS247
EC: downregulated in tumors; Downregulation associated with invasion, metastasis, and poor OS248
GC: upregulated in tumors249
PaC: downregulated in tumors250
miR-214 Luc reporter (mut), WB141 CRC: upregulation associated with poor OS236
EC: upregulated in tumors;251 Downregulated in tumors239
GC: upregulated in tumors; Upregulation associated with poor OS252
HCC: downregulated in tumors; Downregulation associated with poor RFS and OS253–255
PaC: upregulated in tumors78
miR-375 Luc reporter (mut), WB139 EC: downregulated in tumors and serum; Downregulation associated with poor OS145
PaC: downregulated in tumors236
miR-380 Luc reporter, WB136 NA
miR-504 Luc reporter (mut), WB133 NA
miR-1285 Luc reporter (mut), qPCR, WB140 NA
Abbreviations: CRC, colorectal cancer; EC, esophageal cancer; GC, gastric cancer; GI, gastrointestinal; HCC, hepatocellular cancer; Luc reporter, Luciferase reporter
assay with p53 3′-UTR; miRNA, microRNA; mut, mutation in the miRNA seed sequence; NA, not applicable or not analyzed; OS, overall survival; PaC, pancreatic cancer;
pN, nodal status; qPCR, quantitative real-time polymerase chain reaction; RFS, relapse free survival; WB, Western blot.

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Rokavec et al
additional components of the p53 network, which include
both regulators of apoptosis like Bak1, Igfbp3, Itch, Puma,
Prkra, Tp53inp1, and Zac1, and components of the cell
cycle machinery such as cyclin C, Cdc25c, Cdkn2c, Edn1,
Ppp1ca, and Sel1l.130 The authors proposed that by regulat-
ing proliferative and apoptotic genes, miR-125b buffers
and fine-tunes the activity of the p53 network in order to
control the balance between proliferation and apoptosis.
Recently, it was shown that the levels of miR-125b are sig-
nificantly higher in the serum of patients with hepatitis-B-
virus-positive HCC and therefore circulating miR-125b may
represent a potential non-invasive marker for HCC.131 More-
over, elevated expression of miR-125 was also associated
with increased tumor size, enhanced invasion, and poor prog-
nosis in CRC patients.132 Another miRNA that negatively
regulates p53 expression via two seed-matching sequences
in the human TP53 3′-UTR is miR-504.133 Accordingly, ecto-
pic expression of miR-504 reduced p53 protein levels and
impaired p53 functions, especially p53-mediated apoptosis
and G1-arrest in response to stress. Furthermore, ectopic
expression of miR-504 promoted tumorigenicity of colon
cancer cells in mice.133 Additionally, miR-25, miR-30d,
miR-33, miR-98, miR-150, miR-214, miR-375, miR-380,
and miR-1285 also downregulate p53 protein levels through
seed-matching sequences in the 3′-UTR of TP53.134–144
Accordingly, ectopic expression of these miRNAs suppresses
p53 expression and induces phenotypes that are consistent
with a decrease in p53 function, such as reduced apoptosis
and senescence, and increased invasion and stem cell self-
renewal.134–137 miR-25 levels were increased in esophageal
tumors and serum of esophageal cancer patients displayed
elevated levels of circulating miR-25.145 Moreover, expres-
sion of miR-25 was significantly higher in colorectal tumors
and elevated levels of miR-25 were associated with increased
tumor invasion, lymph node metastasis, distant metastasis,
TNM (tumor, node, metastasis status based classification)
stage, and poor survival of CRC patients.146 MiR-30d is
an important regulator of autophagy,147 and interestingly,
amplification of the MIR30D gene was found in ∼30% of
1,283 analyzed solid tumors, including bladder, colorectal,
and pancreatic cancer.148
In addition to the direct repression of p53 by miRNAs,
several miRNAs also regulate the expression of p53
indirectly. As described above, the expression of the p53
inhibitors MDM2 and MDM4 is directly repressed by sev-
eral p53-induced miRNAs: MDM2 is a target of miR-145,
miR-192/194/215, miR-605, and miR-29b, whereas MDM4
is targeted by the miR-34 family members (Figure 3A).
Therefore, p53-mediated induction of these miRNAs results
in a positive feedback and enhanced p53 activation. In addi-
tion, miRNAs of the miR-29 family target the expression of
other negative regulators of p53, such as Cdc42, PPM1D,
and the regulatory subunit of phosphatidylinositol-3 kinase
(PI3K), p85α, and thereby indirectly enhance the levels and
activity of p53.149,150 In addition, miR-29 is also directly
induced by p53,149 thereby forming a positive feedback
loop that is activated during aging and DNA damage,
and reinforces p53 effector functions, such as apoptosis
and senescence. The members of the miR-29 family are
aberrantly expressed in various tumors, including gastric
cancer and HCC.151–153 Moreover, low expression of miR-29
in HCC was associated with decreased survival.154 Fur-
thermore, miR-122, which is expressed exclusively in the
liver, is frequently downregulated in liver cancer.155 It was
shown that miR-122 stabilizes and therefore increases p53
protein levels and activity via downregulation of its target
cyclin G1.156 Repression of cyclin G1 results in decreased
recruitment of the PP2A phosphatase to the p53-inhibitor
MDM2. The resulting decrease in MDM2 activity leads to
activation of p53.157 Interestingly, Cyclin G1 is also directly
induced by p53 and therefore forms a negative feedback
loop with p53.158 However, therapeutic treatment with
miR-122 mimtics might abrogate this loop by downregula-
tion of cyclin G1. Indeed, it has been shown that ectopic
miR-122 expression increases the sensitivity of HCC cell
lines to the chemotherapeutic agent doxorubicin, which is
known to induce p53.156 However, it should be noted that
miR-122 increases chemosensitivity also in the absence of
wild-type p53 and therefore seems to have p53-independent
functions.
Conclusion and outlook
Although numerous links between p53 and miRNAs have
been identified, we have only begun to understand the
complex interplay between p53 and miRNAs in tumor
suppression. Therefore, additional efforts are necessary to
uncover more details of the p53/miRNA network. Since p53
has many functions in tumor suppression, future research
should focus on identifying which miRNA is responsible
for mediating specific p53 functions. It would also be of
interest to investigate whether the complete spectrum of
tumor suppressing functions of p53, which is frequently
lost in tumors, can be restored by the introduction of spe-
cific combinations of p53-induced miRNAs. So far, the
majority of studies have rather focused on the identifica-
tion and characterization of single p53-regulated miRNAs.

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The p53/microRNA axis in GI cancer
A feasible strategy for a comprehensive, genome-wide
identification of p53-regulated miRNAs and their target
genes has been recently described by us.159 This strategy
employs a combination of various unbiased genome-wide
next generation sequencing screens to simultaneously
identify and characterize p53-regulated miRNAs and their
targets. By now, knockout mouse models of single p53-
induced miRNAs have not fully recapitulated the cancerous
phenotype of p53 knockout mice, which is characterized
by the early onset of lymphomas.160 Therefore, it would
be interesting to generate genetically modified mice
that simultaneously lack multiple p53-related miRNAs
to investigate whether loss of certain combinations of
miRNAs fully or at least partially mimics the phenotype
of p53-knockout mice. Complementarily, p53 knockout
mice could be treated with a cocktail of p53-induced
miRNAs to investigate whether certain combinations of
miRNAs can suppress the tumor promoting effects of p53
loss. In light of the central role of p53-regulated miRNAs
or p53-regulating miRNAs for tumor suppression, the
introduction of these miRNAs or of miRNA antagonists
into tumor cells represents an exciting possibility for novel
cancer-therapeutic approaches. Such therapies could also
be performed in combination with standard anticancer
therapies as has been already shown for miR-34a, which
sensitized gastric cancer cells to the chemotherapeutic
drugs docetaxel, gemcitabine, cisplatin, and doxorubicin.63
A major obstacle for such approaches is the currently low
efficiency of miRNA delivery into tumor cells. Therefore,
further research is needed to develop more efficient strate-
gies for in vivo miRNA delivery. Promisingly, improved
delivery using novel nanoparticles was recently employed
to show that a combination of miR-34a mimics and siRNAs
directed at mutant oncogenes is more effective than either
RNA alone in a pre-clinical mouse model of lung cancer.161
Since p53-regulated miRNAs are often inactivated by CpG
methylation in tumors, establishment of routine protocols
for detection of methylation of selected promoters of
miRNA-encoding genes in body fluids may represent an
important aspect of future GI cancer diagnostics.
Disclosure
The authors report no conflicts of interest in this work.
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