Oncogene (2008) 27, 5959–5974
& 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00
www.nature.com/onc
REVIEW
MicroRNAs: key players in the immune system, differentiation,
tumorigenesis and cell death
R Schickel, B Boyerinas, S-M Park and ME Peter
The Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
Micro (mi)RNAs are small, highly conserved noncoding
RNAs that control gene expression post-transcriptionally
either via the degradation of target mRNAs or the
inhibition of protein translation. Each miRNA is believed
to regulate the expression of multiple mRNA targets, and
many miRNAs have been linked to the initiation and
progression of human cancer. miRNAs control various
activities of the immune system and different stages of
hematopoietic development, and their misexpression is the
cause of various blood malignancies. Certain miRNAs
have oncogenic activities, whereas others have the
potential to act as tumor suppressors. Because they
control fundamental processes such as differentiation, cell
growth and cell death, the study of the role of miRNAs in
human neoplasms holds great promise for novel forms of
therapy. Here, we summarize the role of miRNAs and
their targets in contributing to human cancers and their
function as regulators of apoptotic pathways and the
immune system.
Oncogene (2008) 27, 5959–5974; doi:10.1038/onc.2008.274
Keywords: apoptosis;
progression
miRNA;
oncomiRs;
tumor
Introduction
Micro RNAs (miRNAs) are small noncoding RNAs of
about 19–22 nucleotides (nt) that regulate protein
expression by posttranscriptional silencing. The relevance of this class of novel small RNA regulators has
only become clear over the past few years. However, it
was realized early on that miRNAs are fundamental
regulators of cellular processes that have physiological
significance, and hence deregulation of various miRNAs
is emerging as an important contributor to many human
diseases including cancer. It was long known in the
Caenorhabditis elegans community that a decrease in the
expression of the heterochronic gene lin-14 that regulates developmental timing was critical for early larval
stage transition, and that the lin-4 gene was required to
reduce lin-14 levels and allow the larval transition to
Correspondence: Professor ME Peter, The Ben May Department for
Cancer Research, University of Chicago, Chicago, IL 60637, USA.
E-mail: [email protected]
occur (Chalfie et al., 1981). The mechanism of repression
was not known until groundbreaking work by two
groups showed that repression occurred through complementary binding of the small RNA lin-4 to the
30 -UTR (untranslated region) of the lin-14 mRNA
(Lee et al., 1993; Wightman et al., 1993). Subsequent
discovery of the small non-coding RNA let-7 in
C. elegans as a critical regulator in the determination
of developmental cellular fate (Reinhart et al., 2000),
and concurrent discovery of conserved sequence and
temporal expression patterns of let-7-related genes
across multiple species (Pasquinelli et al., 2000),
suggested that these miRNAs may act as fundamental
developmental regulators. In addition, these findings
opened the floodgates of information to the understanding that miRNAs act as key participants in cellular
differentiation. Later work revealed or suggested the
role of miRNAs in neuronal patterning (Johnston and
Hobert, 2003), lineage commitment in hematopoiesis
(Chen et al., 2004), tissue homeostasis (Cui et al., 2006;
Plaisance et al., 2006; Rodriguez et al., 2007) and
apoptosis (Baehrecke, 2003; Cimmino et al., 2005).
Currently, there are 678 mature human miRNA
sequences listed in the miRNA registry (http://www.
microrna.sanger.ac.uk/sequences) with approximately
1000 predicted miRNAs, each potentially targeting
approximately 200 genes (Lewis et al., 2003). Lewis
et al. (2005) further refined the identification of miRNA
target sites and found that 5300 of 17 850 genes in their
data set contained conserved miRNA target sites.
Therefore, the possibility exists that >30% of the
human genome may be under the translational regulation of miRNAs.
The emerging role of miRNAs in such a diverse and
fundamental set of cellular mechanisms clearly suggests
that proper control of these regulatory elements is
essential for the maintenance of a non-pathologic state.
A basic understanding of cancer formation revolves
around the oncogene/tumor suppressor model of
carcinogenesis—with RAS as an example of a classic
oncogene and p53 the most common example of a
tumor suppressor that inhibits cellular proliferation and
induces apoptosis. Despite the simplicity of this model,
it provides a solid foundation for an understanding of
how two main classes of proteins function in the
development of cancer. We are now beginning to
understand miRNAs as master regulators that, in some
cases, can act as either an oncogene or a tumor
Regulation by miRNAs
R Schickel et al
5960
suppressor, whereas in other cases, they can affect both
phases of tumorigenesis. Loss of let-7, for example,
contributes to multiple facets of tumor progression by
wholesale alteration of differentiation status. As our
understanding of miRNA biology continues to increase,
we will likely need to comprehend miRNA function
more on a systems level, where linear relationships
between miRNAs and target genes are less important
than changes in the overall gene expression pattern
induced by altered miRNA levels.
miRNA biogenesis
miRNAs negatively regulate protein expression at the
point of protein translation. In the following, we will
cover the basic pathway of miRNA biogenesis and
maturation as well as the mechanism of translational
repression. These topics have been reviewed in detail
elsewhere (Bartel, 2004; Kim, 2005; Engels and
Hutvagner, 2006; Zeng, 2006). miRNA biogenesis
requires several posttranscriptional processing steps to
yield the functional mature miRNA. Primary miRNAs
(pri-miRNAs) are generally >1 kb transcriptional
products of RNA polymerase-II and contain a
50 7-methylguanosine cap and 30 poly-A tail (Cullen,
2004). Key to miRNA production is a hairpin within an
imperfectly base-paired double-stranded RNA. The
hairpin of the pri-miRNA is recognized by the nuclear
RNAse-III enzyme Drosha and its cofactor DGCR8.
The Drosha/DGCR8 complex cleaves the pri-miRNA
to an approximately 70 nt double-stranded RNA
hairpin pre-miRNA with a 2 nt 30 overhang. The 2 nt
30 overhang is recognized by exportin-5 and the
Ran-GTPase, mediating the pre-miRNA nuclear export
(Zeng and Cullen, 2006).
Once in the cytoplasm, the pre-miRNA is further
digested by Dicer, the RNAse III enzyme of the RNA
silencing pathway, yielding the B22 nt mature miRNA
that enters the RNA-induced silencing complex (RISC)
complex to mediate mRNA translational repression.
Translational repression is a consequence of the
miRNA/RISC complex binding to a target site in the
30 -UTR of the targeted mRNA that is complementary to
the 50 -miRNA seed sequence, but usually not completely
complementary along the entire miRNA/mRNA complex (Lai, 2002). Binding of the RISC/miRNA complex
to the 30 -UTR of a target mRNA results in steric
hindrance of the translational machinery and a consequent inability to translate the message. In the case of
perfect complementarity between an miRNA and its
target, the mRNA is degraded through the RNA
silencing mechanism in a process distinct from
miRNA-mediated translational repression (Engels and
Hutvagner, 2006). The location, number and proximity
of the miRNA binding sites along a target mRNA are
all relevant in the translational repression, and this
allows for prediction and ranking of putative miRNA
targets based solely on sequence information (Grimson
et al., 2007; Nielsen et al., 2007).
Oncogene
miRNAs in hematopoiesis and immune function
The study of miRNAs is now moving beyond descriptions of target analysis and toward a global understanding of how miRNAs impact entire developmental
and differentiation processes. Several groups have
targeted components within the miRNA-processing
pathway and determined the effects of general loss of
miRNA on development, differentiation, homeostasis
and tumorigenesis. Particularly, it was found that
Dicer-null mouse embryos fail to survive beyond
embryonic day 7.5 and that Dicer is required for murine
stem cell differentiation (Bernstein et al., 2003).
Furthermore, knocking down Dicer implicated miRNAs
in the maintenance of skeletal muscle development
(O’Rourke et al., 2007), transformation and tumorigenesis (Kumar et al., 2007).
Hematopoiesis represents an elegant developmental
model to observe normal changes in miRNA expression
and to test the effects of miRNA levels on differentiation and tumorigenesis. There are a number of miRNAs
that are prominently expressed in hematopoietic cells
(for example, miR-142, miR-146, miR-150, miR-155,
miR-181 and miR-223) (Chen et al., 2004; Ramkissoon
et al., 2006). Differential expression of miRNAs during
hematopoiesis is most likely involved in the regulation
of hematopoietic differentiation. One such observation
implicates miR-221 and miR-222 in maintaining
hematopoietic stem cells by preventing the formation
of early erythroblasts by directly targeting the receptor
c-kit (Felli et al., 2005). Thus, downmodulation of
these miRNAs is believed to allow the formation of
early erythroblasts. Furthermore, the introduction
of miR-221 or miR-222 also leads to an increase in cell
death at a time point consistent with that of the terminal
maturation of erythrocytes. This mechanism may be an
evolutionarily conserved response to protect cells from
temporal misregulation and de-differentiation during
erythropoiesis. Contrary to increasing cell death, miR-221
and miR-222 were shown to directly target p27Kip1 in a
prostate tumor cell line model, resulting in proliferation
and increased oncogenesis (Galardi et al., 2007; Gillies
and Lorimer, 2007; le Sage et al., 2007). Therefore, it
appears that these miRNAs, which help maintain a
normal stem cell state during erythropoiesis, act as
oncogenes when misexpressed in a prostate tumor
model, supporting the notion that miRNAs most likely
have unique temporal regulatory roles during both
differentiation and normal physiologic responses.
The descriptions of miR-181a and miR-150 clearly
support the multifunctional physiologic roles of
miRNAs. miR-181a directs hematopoietic stem cells
toward differentiation into B cells (Chen et al., 2004).
In addition, it was shown to modulate the intrinsic
sensitivity of T cells to antigen by targeting a number of
phosphatases that are known negative regulators of
T-cell responses (Li et al., 2007). Furthermore, miR-150,
found to exist at high levels in mature B and T cells but
not their progenitors (Zhou et al., 2007), is required for
mature B-cell development and the attenuation of the
humoral immune response by translational repression of
Regulation by miRNAs
R Schickel et al
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c-Myb (Xiao et al., 2007). The physiologic expression of
mir-150 has a significant impact on limiting antibody
production upon activation. Therefore, miR-181a and
miR-150 have at least dual roles in normal physiologic
processes.
Elevated c-Myc expression is common in many
cancers (Grandori et al., 2000). A hallmark of Burkitt’s
lymphoma is a chromosomal translocation juxtaposing
the c-myc and immunoglobulin genes and yielding high
c-MYC expression (Janz, 2006). Furthermore, c-Myc is
known to drive the expression of the pro-tumorigenic
miR-17-92 cluster of miRNAs (O’Donnell et al., 2005;
Dews et al., 2006), and a high level of c-Myc also leads
to a decrease of multiple miRNAs known to have
anti-tumorigenic properties (Chang et al., 2008). Chang
et al. found that a majority of the c-Myc-repressed
miRNAs provided a selective disadvantage when stably
re-expressed in Myc3 cells, a B-cell lymphoma cell line,
or in 38B9 cells, an Abl1-transformed pro-B cell line,
and analysed 3 weeks after injection in an SCID mouse
model.
The miR-17–92 cluster is a group of miRNAs
(consisting of miR-17-5p, miR-18, miR-19a, miR-20 and
miR-92) located on chromosome 13q31 that is transcribed
as a polycistronic unit. miR-17-92 members have been
described to target p21, a critical regulator of G1–S phase
checkpoint, as well as the pro-apoptotic factor BIM,
allowing cells to bypass the DNA damage checkpoint and
obtain a survival advantage. The 17–92 miRNA cluster
also targets anti-angiogenic factors Tsp1 and connective
tissue growth factor (CTGF), resulting in an increase in
angiogenesis in solid tumors. Recently, it was shown that
this cluster regulates monocyte differentiation by targeting
the transcription factor AML1 (Fontana et al., 2007),
which is required for the expression of the macrophage
colony stimulating factor (M-CSF) receptor. Taken
together, these studies suggest that elevated c-Myc levels
can contribute to multiple levels of tumorigenesis by direct
modulation of miR-17-92 levels.
miR-223 has been shown to be involved in the
differentiation of granulocytes (Fazi et al., 2005), and
the transcription of miR-223 is competitively regulated
by nuclear factor I/A (NFIA) and CCAAT/enhancer
binding protein a (CEBPA); NFIA transcriptionally
represses the expression of miR-223, whereas CEBPA
causes the upregulation of miR-223 in response to
differentiation induced by retinoic acid. Interestingly,
miR-223 specifically targets NFIA favoring its own
expression upon induced differentiation. Furthermore,
CEBPA binding to the miR-223 promoter is required for
the retinoic acid response, suggesting that miR-223 has a
significant role in induced differentiation and that NFIA
levels are critical in blocking this process.
In most cases, the functions of miRNAs were identified
by studying predicted targets, and only a few examples
exist in which a functional role was established without
knowing a putative target. An example of a miRNA that
was studied both in terms of its regulation and its targets
is miR-146a, which has an important function in the
innate immune system. miR-146a was found to be
upregulated in cells treated with lipopolysaccharide
(LPS) through the activation of toll-like receptor (TLR)
4 and concurrent activation of the nuclear factor-kB
pathway (Taganov et al., 2006). Interestingly, two of its
main predicted targets, interleukin-1 (IL-1) receptorassociated kinase 1 (IRAK1) and TRAF6, are both
signaling components of the TLRs. Both were confirmed
to be direct targets of miR-146a, placing this miRNA into
a negative feedback loop that limits inflammatory
signaling and could potentially cause chronic inflammation or become detrimental through the induction of
septic shock if it became deregulated.
Another TLR-responsive gene, miR-155, was
identified to respond to the stimulation of TLR3 on
macrophages (O’Connell et al., 2007) and immunoglobulin heavy chain enhancer (Em-miR-155 transgenic
mice were hypersensitive to LPS/D-galactosamineinduced septic shock; Tili et al., 2007). Similar to
miR-146a, evidence suggests that the putative targets of
miR-155 are components of the TLR signaling machinery. Because miR-155 is best known through its
involvement in the development of B-cell malignancies
(see below), this discovery adds to the connection
between inflammation and cancer that has recently
attracted significant attention (Karin et al., 2006). In
addition to its function in monocytes, miR-155 was
shown to have a physiological function in B and T cells
(Thai et al., 2007). miR-155-deficient mice have a defect
in the germinal center (GC) reaction and a concurrent
weak T-cell-dependent antibody response. It was suggested that this might be due to an impaired production
of tumor necrosis factor a (TNFa) by the B cells that is
required for a proper GC response. In the T-cell
compartment, these mice were skewed toward TH2
differentiation, as their T cells produced more IL-4 and
less interferon-g than T cells from control mice (Thai
et al., 2007). These data illustrate that miRNAs play
important roles in the development of various bloodderived cell types and often are part of complex
feedback regulatory networks. Interestingly, in many
reported cases, it is not the miRNA that drives
differentiation, but rather miRNAs are expressed to
prevent de-differentiation and/or maintain pools of cells
at certain stages of differentiation. Hence, their downregulation seems to assist in driving cells down certain
de-differentiation paths (Georgantas et al., 2007).
OncomiRs as tumor suppressors and oncogenes
We have just described the important role of various
miRNAs in immune function and hematopoietic fate
determination, and have suggested that the deregulation
of this control system can lead to oncogenesis and other
pathologies. Not surprisingly, multiple pieces of
evidence point at miRNAs playing a profound role in
cancer formation and progression (Table 1). Gene
expression array analyses as well as real-time PCR
analyses of cancers reveal cancer specific changes in the
expression of miRNAs, when compared with noncancerous tissues (Liu et al., 2004; Lu et al., 2005; Volinia
et al., 2006). In addition, an expression analysis of 217
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Table 1 miRNAs with relevance in cancer and cell death
Normal function
Cancer relevance
Cell death relevance
Targets
References
Let-7/miR-98
Upregulated late during Caenorhabditis
elegans development; increased expression in differentiated cells; may act
to maintain differentiated states
Downregulated in lung colon and
ovarian cancer; expression inversely
correlates to patient survival in
ovarian cancer, NSCLC and adenocarcinoma; possible growth suppressor
in colon carcinoma (let-7a-1)
Contributes to IL-6-directed survival signaling and
reduces chemotherapymediated cell death in
human malignant
cholangiocytes (let-7a)
HMGA2, RAS,
IGF2BP1, c-Myc,
NF2 and LIN28Ba
miR-1
Involved in cardiogenic and myogenic
differentiation; involved in maintaining
proper cardiac depolarization
Upregulated in primary brain tissue
upon introduction of reactive oxygen
species production
Possible inhibitor of megakaryocytic
differentiation
Pro-apoptotic effect in response to oxidative stress
HSP60, HSP70,
KCNJ2 and GJA1
Akao et al. (2006); Boyerinas et al. (2008);
Gramantieri et al. (2007); Guo et al.
(2006); Hebert et al. (2007); Iorio et al.
(2005); Johnson et al. (2005); Lee et al.
(2006a); Lee and Dutta (2007); Lu et al.
(2007a); Mayr et al. (2007); Meng et al.
(2007b); Park et al. (2007); Pasquinelli
et al. (2000); Reinhart et al. (2000);
Sampson et al. (2007); Shell et al. (2007);
Yanaihara et al. (2006)
Chen et al. (2006); Xu et al. (2007);
Yang et al. (2007)
miR-9
miR-10a
miR-10b
miR-15a
Regulation of pancreatic regeneration
miR-16
Involved in the regulation of pancreatic
regeneration; negatively regulates cell
cycle progression and cell growth
miR-21
miR-29
Suggested to participate in maintaining
proper DNA methylation
miR-34a
p53 inducible; translationally regulates
cell cycle, anti-apoptotic and check
point genes; shown to induce growth
arrest
miR-34b/c
p53 inducible; translational regulation
of proliferation and adhesion-independent growth
miR-122
Hepatocellular-specific miRNA highly
expressed in the normal liver and
involved in fatty acid and cholesterol
metabolism
Hypermethylated in breast cancer
Inversely correlates with prognosis
and initiates invasion and metastasis
in breast cancer cell lines
Frequently deleted or downregulated
in CLL patients
Frequently deleted or downregulated
in CLL patients
Granuphilin (Slp4)
Pro-apoptotic effects
mediated through targeting
BCL2
Pro-apoptotic effects
mediated through BCL2
HOXA1
Bredenkamp et al. (2007); Lehmann et al.
(2008); Lukiw and Pogue (2007); Plaisance
et al. (2006)
Garzon et al. (2006)
HOXD10
Ma et al. (2007)
BCL2 and NGN3a
Calin et al. (2005); Cimmino et al. (2005);
Joglekar et al. (2007)
BCL2 and NGN3a
Calin et al. (2005); Cimmino et al. (2005);
Joglekar et al. (2007); Linsley et al. (2007)
Asangani et al. (2008); Chan et al. (2005);
Frankel et al. (2007); Loffler et al. (2007);
Meng et al. (2007a); Roldo et al. (2006);
Si et al. (2007); Zhu et al. (2007)
Fabbri et al. (2007); Mott et al. (2007);
Pekarsky et al. (2006)
Widely overexpressed in cancer;
promotes growth; shown to induce
a metastatic phenotype
Shown to inhibit apoptosis
PTEN, TPM1
and PDCD4
Reduced levels in B-CLL and NSCLC,
enforced expression restores normal
methylation in NSCLC and reduces
tumorigenicity in vitro and in vivo
Decreased expression in lung and
colon cancer, and neuroblastomas;
shown to be highly expressed in CLL
but not in ALL; gene locus is subject
to heterozygous deletions in some
tumors
Decreased/loss of expression in p53
null tumors and described to inhibit
neoplastic growth; often deleted in
NSCLC
Increases apoptosis sensitivity to TRAIL
TCL1 and Mcl-1
Increases p53-mediated
apoptotic sensitivity
CDK4, E2F3
and BCL2a
He et al. (2007); Raver-Shapira et al.
(2007); Tazawa et al. (2007); Versteeg
et al. (1995); Welch et al. (2007);
Zanette et al. (2007)
Increases apoptotic sensitivity possibly through
translational or indirect
repression of anti-apoptotic
factors
CDK6, c-Meta
and c-Myca
Bommer et al. (2007); Corney et al. (2007);
Raver-Shapira et al. (2007)
CCNG1 and
CAT-1ba
Chang et al. (2004); Esau et al. (2006);
Gramantieri et al. (2007); Kutay et al.
(2006)
Commonly downregulated in HCC;
loss suggested to facilitate genomic
instability due to the loss of
translational repression of CCNG1,
a p53 pathway antagonist
Regulation by miRNAs
R Schickel et al
miRNA
Table 1 Continued
miRNA
Normal function
Cancer relevance
miR-126
Expressed in endothelial cells
miR-130a
Involved in megakaryocytic
differentiation; suggested to inhibit
differentiation by targeting
transcription factors that mediate
megakaryocyte differentiation
in an ERK-dependent manner
Promotes myoblast proliferation
and inhibits cardiac hypertrophy
Downregulated in metastasizing
breast cancer
Inhibits pro-angiogenic factors,
suppressing angiogenesis in
vascular endothelial cells
miR-133
Highly expressed in hematopoietic
tissues and fetal liver
miR-143
Required for adipocyte differentiation
miR-146
NF-kB inducible, attenuates the
TLR4 signaling pathway
Controls B-cell differentiation in vivo;
highly expressed in mature B and T
cells
Regulates cytokine expression,
optimizing germinal center T-cell response; JNK-induced expression during
the macrophage response and in
activated B cells; involved in
maintaining erythroblasts
B-cell linage; increases T-cell sensitivity
to antigens and exhibits increased
expression in mature T cells
miR-150
miR-155
miR-181a
miR-195
miR-196
miR-221/222
miR-223
miR-335
Stress-responsive miRNA involved in
cardiac tissue growth and hypertrophy;
mediates pancreatic postoperative
regeneration
Involved in developmental patterning
and myeloid differentiation
Maintains progenitor cells in
erythropoiesis; suggested to
promote proliferation
Regulator of myelopoiesis; suggested
involvement in chorioamniotic
membrane development
Targets
References
VCAM-1
Harris et al. (2008); Tavazoie et al. (2008)
GAX, HOXA5 and
MAFB
Chen and Gorski (2008); Garzon et al.
(2006); Sevinsky et al. (2004)
Inhibits intrinsically
SRF and caspase-9
activated apoptosis
mediated through caspase-9
Locus is a common translocation site
in aggressive B-cell leukemia generating a miR-142-myc fusion transcript,
producing high levels of pre-miR-142
Downregulated in B-cell leukemias
and colorectal neoplasia; reduced
expression led to an increase in miR-21
expression; strongly downregulated in
multiple tumor types
Upregulated in papillary thyroid
carcinoma
Overexpressed in multiple tumor
types, particularly in leukemia;
suspected oncogenic effect due to
translational repression of a
known tumor suppressor
Chen et al. (2004); Gauwerky et al. (1989)
Akao et al. (2007); Esau et al. (2004);
Lui et al. (2007); Michael et al. (2003);
Yanaihara et al. (2006)
IRAK1 and
TRAF6
c-Myb
Inhibits TP53INP1mediated apoptosis
Induces polyclonal premalignant
expansion; loss of expression noted in
transition to aggressive B-cell chronic
lymphoma
Highly expressed in CLL
AGTR1 and
TP53INP1
TCL1, HOXA11,
SHP-2, DUSP5,
DUSP6 and
PTPN-22
NGN3a
HOXB8
Inhibits cell growth in erythroleukemic
cell lines; upregulated in glioblastoma,
papillary thyroid carcinoma, prostate
and pancreatic tumors
Epigenetically silenced by AML1/
ETO, an oncogenic protein; increased
expression in bladder cancer
Downregulated in metastasizing
breast cancer; inhibits metastatic
cell invasion
Care et al. (2007); Chen et al. (2006);
Xu et al. (2007)
c-Kit and
p27(Kip1)
Pro-apoptotic factor
antagonizing miR-21
SOX4 and Tenascin
C Jagged-1a
He et al. (2005a); Taganov et al. (2006)
Xiao et al. (2007); Zhou et al. (2007)
Regulation by miRNAs
R Schickel et al
miR-142
Cell death relevance
Eis et al. (2005); Georgantas et al. (2007);
Gironella et al. (2007); Lawrie et al.
(2007); Masaki et al. (2007); Metzler et al.
(2004); O’Connell et al. (2007); Ramkissoon et al. (2006); Sethupathy et al. (2007);
Thai et al. (2007)
Chen et al. (2004); Ciafre et al. (2005);
Costinean et al. (2006); Li et al. (2007);
Marton et al. (2008); Naguibneva et al.
(2006); Pekarsky et al. (2006)
Joglekar et al. (2007); van Rooij et al.
(2006); Zanette et al. (2007)
Hornstein et al. (2005); Kawasaki
and Taira (2004); Yekta et al. (2004)
Ciafre et al. (2005); Felli et al. (2005);
Galardi et al. (2007); Gillies and Lorimer
(2007); He et al. (2005a); le Sage et al.
(2007); Lee et al. (2007)
Fukao et al. (2007); Garzon et al. (2006);
Gottardo et al. (2007); Ramkissoon et al.
(2006)
Sathyan et al. (2007); Tavazoie et al.
(2008)
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Abbreviations: ALL, acute lymphocytic leukemia; CLL, chronic lymphocytic leukemia; ERK, extracellular signal-regulated kinase; HCC, hepatocellular carcinoma; IL, interleukin; JNK, Jun
N-terminal kinase; miRNA, micro RNA; NSCLC, non-small-cell lung cancer.
a
Predicted target.
Dews et al. (2006); Hayashita et al. (2005);
He et al. (2005b); Landais et al. (2007);
Lu et al. (2007b); Matsubara et al. (2007);
O’Donnell et al. (2005); Venturini et al.
(2007); Zanette et al. (2007)
miR-17-92 cluster
17-5p
Shown to inhibit differentiation of lung
18
tissue; c-Myc inducible
19a
20a
92
AIB1, AML1, MCSFR and Rb2
Inhibition of miRNA cluster leads to an increase in
apoptosis
Limits tumor growth in breast cancer
but promotes proliferation in lung
epithelial progenitor cells; increased
expression in B-cell lymphoma and
facilitated cancer progression in a
lymphoma murine model
Fontana et al. (2007); Hossain et al.
(2006); Landais et al. (2007);
Matsubara et al. (2007); Sylvestre et al.
(2007); Volinia et al. (2006)
AML1, M-CSFR,
Rb, Mylip, Rbp1like and HIPK3a
Implicated in inducing
apoptosis
miR-372/373
miR-106-363 cluster
106a
Key regulators of monocytopoiesis;
19b-2
expression induced under c-Myc
92-2
and N-Myc regulation
20b
363
Overexpressed in B50% of T-cell
leukemias; high expression levels noted
in multiple solid tumors;
downregulated in CML; overexpression enhances blast proliferation
Voorhoeve et al. (2007)
LATS2
Inhibits p53 directed CDK signaling,
promoting tumorigenesis in testicular
germ cells
Cell death relevance
miRNA
Normal function
Cancer relevance
Table 1 Continued
Targets
References
5964
miRNAs in various human cancers clearly described the
developmental origin of tumors based on miRNA
profile, and it also identified a global downregulation
of miRNAs in tumors regardless of cell type (Lu et al.,
2005). It has also been found that the induction of
miRNAs coincides with normal cellular differentiation,
supporting the hypothesis that miRNA loss leads to a
de-differentiation process and less-differentiated tumors
(Lu et al., 2005). Interestingly, Lu et al. showed that the
expression levels of the 217 miRNAs allowed for a
better stratification of cancer material, when compared
with information obtained from a gene array analysis of
about 16 000 mRNAs. The prognostic power of these
miRNA profiles is quite striking and strongly argues
for the ultimate importance of miRNAs in developing
and maintaining cellular fates. It is then quite easy to
envisage how gain or loss of a single miRNA or a set of
miRNAs in either differentiated adult tissues or more
differentiated tumors could both induce and further
neoplastic progression.
Further support for the relevance of miRNAs in cancer
came from studies that demonstrated that half of the
known miRNAs are located in regions of chromosomal
instability associated with cancer (Calin et al., 2004), and
that a high proportion of genomic loci containing miRNA
genes shows DNA copy number alterations (Zhang et al.,
2006). As we have described above, specific roles of
miRNAs in certain cancers have been established, and
many miRNA targets are emerging that allow one to
explain or predict some of the activities of miRNAs in
cancer. Oncogenic miRNAs include miR-155, miR-17-5p
and miR-21, whereas miRNAs with tumor-suppressing
activities include miR-15a, miR-16–1 and let-7 (Table 1).
Both oncogenic-and tumor-suppressing miRNAs are
collectively called oncomiRs because of their respective
roles in cancer progression (Esquela-Kerscher and Slack,
2006). One key pathway in which various miRNAs play
the role of both tumor suppressor and oncogene is that of
apoptosis.
Apoptosis in immune system maintenance
Apoptosis is of key importance in maintaining tissue
homeostasis, developmental tissue remodeling, the
defense against microbial and viral infections and in
preventing tumor formation. Apoptosis also plays
essential roles in various processes in the immune
system, such as lymphocyte development, homeostatic
control of immune response and also in the elimination
of virally infected or tumor cells. During lymphocyte
development, autoreactive T and B lymphocytes are
eliminated by apoptosis in the primary lymphoid
organs, the thymus and bone marrow, respectively, in
a process termed negative selection. This process is
important for preventing autoimmunity.
Apoptosis induction is initiated intracellularly upon
various cellular insults mediated through the mitochondria (the intrinsic pathway) or through transmembrane
receptors (death receptors) that initiate apoptosis at the
cell surface (the extrinsic pathway). In the intrinsic
Regulation by miRNAs
R Schickel et al
5965
apoptosis pathway, sentinel proteins sense changes in
the endoplasmic reticulum (ER stress), the nucleus
(DNA damage), or directly at the mitochondria, which
are the central command center of the apoptotic process.
Key regulators of mitochondrial apoptotic activities are
members of the BCL-2 protein family. They can be
roughly divided into pro- and anti-apoptotic members
and are characterized by the presence of BCL-2
homology (BH) domains. The multidomain-containing
members that function directly on the outer mitochondrial membrane include pro-apoptotic BAX and BAK
(containing BH1-BH3) and anti-apoptotic BCL-2 and
BCL-XL (containing BH1–BH4). Upstream of these
proteins are a number of very diverse pro-apoptotic
sensor proteins containing only the BH3 domain (e.g.,
BIM, BID, BAD and NOXA). These proteins are
activated by various pro-apoptotic stimuli and all act
by either activating BAX/BAK or inhibiting BCL-2/
BCL-XL (Coultas and Strasser, 2003).
Among the BH3-only proteins, BIM, in particular,
has been well recognized to play a critical role in the
apoptosis of autoreactive T cells during negative
selection in the thymus. Bim knockout mice accumulate
three- to five-fold excess numbers of lymphoid and
myeloid cells, and activated T cells from these mice are
abnormally resistant to cytokine withdrawal-induced
apoptosis (Bouillet et al., 1999). BIM has also been
demonstrated to be essential for the deletion of
autoreactive B lymphocytes in both bone marrow and
periphery (Enders et al., 2003).
Once activated, mitochondria release factors, including cytochrome c and SMAC/Diablo, that act by
triggering the formation of the apoptosome (comprising
cytochrome c, APAF-1, the initiator caspase 9 and
dATP/ATP) and by inhibiting apoptosis inhibitors of
the IAP family (Salvesen and Duckett, 2002), respectively. Both of these events contribute to the activation
of the executioner caspases 3 and 7. In the extrinsic
apoptosis pathway, surface receptors of the death
receptor family that include TNFRI, CD95 (Fas/APO-1)
and the TNF-related apoptosis inducing ligand
(TRAIL) receptors DR4 and DR5 (Schulze-Osthoff
et al., 1998), once triggered by their cognate ligands,
recruit adaptor proteins (FADD and TRADD) to
form a high-order receptor signaling structure that is
collectively called the death-inducing signaling complex
(DISC) (Peter and Krammer, 2003). Additional components of the DISC are the initiator caspases 8 and 10,
and the caspase-8/10 regulator c-FLIP. Once activated,
caspase-8 cleaves a number of substrates including the
executioner caspase 3 and the BH3 protein BID (Barry
et al., 2000; Waterhouse et al., 2005).
The involvement of death receptors in negative
selection has not been consistent and is somewhat
controversial. TRAIL-deficient mice displayed increased
numbers of immature thymocytes and accelerated
autoimmune disease (Lamhamedi-Cherradi et al.,
2003), but no defects in lymphoid homeostasis or in
T-cell function (Sedger et al., 2002; Cretney et al., 2003).
Although negative selection is intact in CD95/CD95L
(Singer and Abbas, 1994; Adachi et al., 1996), TNFR1
(Pfeffer et al., 1993), TNFR2 (Erickson et al., 1994) or
TNFR1 and TNFR2 double-deficient mice (Page et al.,
1998), there has been evidence supporting roles of TNF
and CD95 in negative selection in some models (Castro
et al., 1996; Kishimoto et al., 1998). Death receptormediated apoptosis does not appear to play a critical
role in thymic central tolerance; however, genetic
deletion of members of the BCL-2 family, especially
BIM in mice, has shown BIM to be a critical mediator of
apoptosis for negative selection in the thymus (Bouillet
et al., 2002; Strasser et al., 2008). Recently, studies have
shown that BIM functions together with the death
receptor CD95 in the apoptotic process during T-cell
clonal contraction or peripheral deletion during acute
and chronic infection (Hughes et al., 2008; Hutcheson
et al., 2008; Weant et al., 2008).
Both intrinsic and extrinsic apoptotic pathways
converge on the level of caspase-3 activation, which
then goes on to cleave various intracellular substrates
that cause the typical changes observed in apoptotic
cells. The ability to evade the grips of the apoptotic
pathway has been described as a hallmark of cancer, and
all neoplasms contain disruptions of the apoptotic
machinery. As >30% of the human genome is now
believed to be under the control of miRNAs, and
considering the fundamental role of miRNAs in
important differentiation and homeostatic processes, it
became an intriguing possibility that a relationship
existed between miRNAs and the apoptotic machinery.
Apoptosis-regulating miRNAs (‘apoptomiRs’)
The first miRNA described as an apoptotic regulator
was the Drosophila gene bantam (Brennecke et al., 2003).
Bantam was found to directly regulate the pro-apoptotic
factor hid, suppressing the apoptotic activity and
allowing proliferation to occur. Furthermore, miR-14
was found to suppress pro-apoptotic activity of reaper
during the eye formation (Xu et al., 2003). Although
spatially and temporally regulated as observed in other
cell-fate-determining miRNAs, both bantam and miR14 are described to function as anti-apoptotic miRNAs.
In the following, we will give examples of miRNAs that
have been shown to regulate cell death in mammalian
cells.
Chromosome 13q14 is a region deleted in more than
half of B-cell chronic lymphocytic leukemia (CLL). The
identification of miR-15 and miR-16 as being the tumor
suppressors at this chromosomal location represented
the first link between miRNAs and cancer (Calin et al.,
2002). Groundbreaking studies by Cimmino et al. (2005)
looking into tumorigenic effects of the miR-15a/miR-16-1
deletion demonstrated that the expression of miR-15a
and miR-16-1 inversely correlated with BCL-2 expression in CLL cells, providing the first description of direct
miRNA mediation of apoptotic activity in human tissue.
The 30 -UTR of BCL2 contains a target site for each of
these miRNAs, and miR-15a/16-1 controls the expression of BCL-2. Post-translational regulation of BCL-2
by miR-15a and miR-16-1 opens the door to potential
Oncogene
Regulation by miRNAs
R Schickel et al
5966
therapeutic development of miRNAs in BCL-2 overexpressing tumors. Another link between miRNAs and
CLL is the finding that the TCL1 oncogene, which is
often found in aggressive CLL, is regulated by miR-29
and miR-181b (Pekarsky et al., 2006).
In contrast to miR-15/miR-16, whose expression is
often reduced in cancers, the miR-17-92 cluster is
overexpressed in many cancers including B-cell lymphoma (Ota et al., 2004; Hayashita et al., 2005; He et al.,
2005b). Recently, it was demonstrated that the inhibition of two miRNAs in this cluster, miR-17-5p and
miR-20a, sensitized lung cancer cells to apoptotic
insults (Matsubara et al., 2007), which suggests that
these miRNAs may be useful as a potential therapeutic modality. miR-20a negatively regulates E2F1
(O’Donnell et al., 2005), E2F2 and E2F3 (Sylvestre
et al., 2007), and all three E2Fs regulate the expression
of miR-17-92 through binding to its promoter, suggesting an autoregulatory feedback loop. The E2F transcriptional networks are believed to link cell cycle
progression to apoptosis, and perturbation of their
various levels can induce either proliferation or apoptosis depending on the cellular context. miR-20a
overexpression protects cancer cell lines from apoptosis,
suggesting that overexpression of the miR-17-92 cluster
promotes oncogenesis, in part, by perturbing the E2F
network in a way that induces proliferation and inhibits
apoptosis (Sylvestre et al., 2007).
Recently, the identification of MCL-1 regulation by
miR-29a,b and c expanded what is known about miRNA
regulation within the BCL-2 family (Mott et al., 2007).
MCL-1, a member of the BCL-2 family of anti-apoptotic
proteins, is upregulated in malignant cells, whereas miR29b is downregulated in cancer. The mechanism of
sensitization of cancer cells to TRAIL-induced apoptosis
differs among cell types and is regulated by multiple
downstream factors. Enforced expression of miR-29b
renders tumor cells more sensitive to the apoptosisinducing activity of TRAIL, suggesting that the miR-29b/
MCL-1 connection is functionally important and could be
exploited for cancer therapy. Recently, it was demonstrated that acquired resistance to TRAIL therapy
involves c-Myc-dependent upregulation of both MCL-1
and cIAP2 (Ricci et al., 2007), suggesting that targeting
MCL-1 using miR-29 could therefore be a viable
treatment option in this situation.
It seems clear that tight regulation of anti-apoptotic
function through miRNAs is critical in development and
other cellular processes. Interestingly, a database search
using TargetScan (http://www.targetscan.org) for
potential miRNA regulators of BCL-2 family members
found a notable lack of conserved miRNAs that could
regulate the pro-apoptotic Bcl-2 members (with the
exception of BIM), but revealed that a majority of
the anti-apoptotic BCL-2 members maintain conserved
potential miRNA-binding sites (Table 2). Pro-survival
members have on average six miRNA target sites
in their 30 -UTRs as compared with 2.2 sites found in
pro-apoptosis members. BCL-2, BCL-W and MCL-1
have multiple conserved miRNA target sites in their
30 -UTR. BCL-XL only has three such sites, and this
Oncogene
could be due to the fact that the alternative splice form
BCL-XS, which shares the same 30 -UTR with BCL-XL,
has pro-apoptotic activities. This may indicate that
evolutionary pressure favored the fine-tuning of the
anti-apoptotic process over the pro-apoptotic process as
part of the regulation of development and tissue
homeostasis. Consistent with this hypothesis is an
analysis of the 30 -UTRs of all caspases that revealed
that most caspases are not predicted miRNA targets
with the exception of caspase-3 (Table 2). It is
interesting to note that caspase-3 has been shown to
have nonapoptotic functions as well (Algeciras-Schimnich
et al., 2002), which could be regulated by miRNAs.
With the goal of identifying miRNAs that are relevant
for proliferation or cell death, Cheng et al. (2005)
individually knocked down 90 human miRNAs in HeLa
and A549 cells. MiR-21 was identified among miRNAs
that were identified as regulators of apoptosis. Subsequently, miR-21 was shown to be highly overexpressed
in breast tumors compared with normal breast tissue,
and the inhibition of miR-21 was shown to inhibit
tumor growth (Si et al., 2007). Further work identified
PTEN and tropomyosin 1 as direct targets of miR-21 in
cancer cell lines (Zhu et al., 2007; Meng et al., 2007a). In
glioblastoma, miR-21 was described as an anti-apoptotic factor (Chan et al., 2005), and a combination
treatment of anti-miR-21 and TRAIL was able to
eradicate apoptosis-resistant glioma cells in vitro and
in vivo (Corsten et al., 2007). A recent study linked
miR-21 to the pro-apoptotic tumor suppressor p53 and
identified programmed cell death 4 (PDCD4) as a direct
target (Frankel et al., 2008). The fundamental significance of miR-21 is most likely best documented by the
fact that it is the only miRNA that was consistently
upregulated in six out of six solid human cancers (breast,
colon, lung, pancreas, prostate and stomach), when
compared with matching noncancerous tissues (Volinia
et al., 2006). Hence, this single miRNA provides a
significant survival advantage to cancer cells upon its
upregulation, and this may be a fundamental mechanism
utilized by cancers to elude apoptotic cell death.
Other apoptosis regulators targeted by miRNAs
include HSP60 and HSP70 (targeted by miR-1) and
caspase-9 (targeted by miR-133), and both of these
miRNAs are predominantly expressed in cardiac and
skeletal muscles (Xu et al., 2007). miR-1 and miR-133
have opposing affects on apoptosis, with miR-1 being
pro-apoptotic and miR-133 being anti-apoptotic. Interestingly, miR-1 and miR-133 are transcribed together
from the same chromosomal locus, suggesting that their
relative levels might be regulated at a post-transcriptional level, and that it is the post-transcriptional
regulation of these miRNAs that determines the
eventual physiological outcome within cardiac and
skeletal muscle tissues.
A key regulator in the activation of the intrinsic
apoptosis pathway in response to DNA damage, cellular
stress and/or improper mitotic stimulation is p53. As
a transcriptional regulator, p53 both activates and
represses gene expression, and is the most frequently
dysregulated protein in cancer with a majority of
Regulation by miRNAs
R Schickel et al
5967
Table 2 Predicted miRNA target sites in Bcl-2 family members and caspases
Gene
Size of
30 -UTR (kb)
Pro-survival Bcl-2 genes
BCL-2
BCL-XL
BCL-W
No. of conserved
TargetScan sites
5.2
1.5
2.7
10
3
12
A1
MCL-1
0.2
2.8
0
11
BOO
0.2
0
Pro-apoptotic Bcl-2 genes
Bax/Bak-like
BAX
0.2
BOK
1.7
1.5
BCL-XS
BAK
1.3
0
0
3
3
BFK
BCL-GL
BH3-only proteins
BAD
BIK
BID
HRK
BIM
NOXA
PUMA
BMF
Caspases
CASP1
CASP2
CASP3
CASP4
CASP5
CASP6
CASP7
CASP8
CASP9
CASP10
CASP11-14
4.3
0.7
15/16/195/424/497, 21, 30-5p, 34/449, 153, 181, 204/211, 205, 217, 365
let-7/98, 133, 142-3p
10, 15/16/195/424/497 (2x), 17-5p/20/93/106/519, 24, 29, 30-3p, 103/107, 122, 133, 140,
148/152
17-5p/20/93/106/519, 25/32/92/363/367, 26, 29, 125/351, 133, 142-5p, 153, 181, 193,
19/191-3p/294/295/302/372/37
let-7/98, 133, 142-3p
miR-26, miR-29, miR-125/351
No information in TargetScan
0
0.4
0.4
1.4
0.3
4.2
0
0
0
0
19
1.5
1
3.9
1
0
4
0.1
2.6
1.6
0.1
0.1
0.7
1.4
1.1
0.6
3.9
Conserved sites for miRNA families
9, 10, 17-5p/20/93/106/519, 19, 24 (2x), 25/32/9,25/32/92/363/367, 30, 93/291-3p/294/295/
302/372/373/520, 101, 124.1, 124.2/506 (2x), 130/301, 148/152 (2x), 181, 221/222
142-3p
29, 125/351 (2x), 221/222
0
No information in TargetScan
3
let-7/98, 30-5p/138
0
0
0
1
23
0
0
0
No information in TargetScan
Analyses were performed using TargetScan 4.2 (http://www.targetscan.org).
cancers harboring functional loss of p53. Five groups
independently identified miR-34 as a target for p53
(Bommer et al., 2007; Chang et al., 2007; He et al., 2007;
Raver-Shapira et al., 2007; Tarasov et al., 2007). He
et al. (2007) described that miR-34 expression correlates
with p53 expression. Using a p53-inducible system, they
reported that the miR-34 family of miRNAs is directly
regulated by p53, and that miR-34 mediates growth
arrest in multiple cell lines via direct 30 -UTR regulation
of cell cycle regulatory factors, such as cyclin-E2
(CCNE2), cyclin-dependent kinase 4 (CDK4) and the
hepatocyte growth factor receptor (c-Met). Ectopic
expression of miR-34 also resulted in a decrease of
phospho-Rb, supporting the hypothesis that miR-34
regulates CDK4 and CCNE2. Furthermore, miR-34a
was shown to directly target E2F3. In addition, miR-34a
resulted in an increase in caspase-dependent death when
introduced into two cell lines (Welch et al., 2007) and
contributed to an increase in p53-mediated apoptosis
(Chang et al., 2007; Raver-Shapira et al., 2007). miR-34
was therefore described as a general sensitizer to
apoptosis mainly through its link to p53, although its
targets are still speculative. Interestingly, the other main
activity of p53 to induce growth arrest, and cellular
senescence also seems to involve miR-34a, as it was
recently demonstrated that HCT116 colon cancer cells
that were suppressed in their growth upon the introduction of miR-34a acquired a senescence-like phenotype
(Tazawa et al., 2007).
It remains to be determined how many of the
activities of p53 depend on regulation by miR-34a.
For instance, tumor protein p53-induced nuclear protein
(TP53INP1) is a stress-induced p53 target gene that
induces caspase-3-dependent apoptosis. TP53INP1 was
shown to be dramatically reduced in its expression in
pancreatic ductal adenocarcinoma (Gironella et al.,
2007). TP53INP1 was demonstrated to be a direct
target of miR-155, and consistently miR-155 is often
Oncogene
Regulation by miRNAs
R Schickel et al
5968
overexpressed in pancreatic cancer (Lee et al., 2007;
Szafranska et al., 2007). Other miRNAs functionally
connected to p53 are miR-372 and miR-373, which were
identified as oncogenes in testicular germ cell tumors,
and target the tumor-suppressor LATS2 and neutralize
p53-mediated CDK inhibition (Voorhoeve et al., 2006).
Taken together, this body of evidence demonstrates that
multiple miRNA families target p53, which is universally known as one of the most important tumor
suppressors with apoptosis-inducing activities. As with
the processes of differentiation and cell fate determination, it has become quite clear that miRNAs play a
fundamental role in regulating key cogs of the apoptotic
machinery.
OncomiRs not (yet) directly connected to apoptosis
Transcripts of miR-155 and its host gene BIC accumulate in B-cell malignancies. Elevated miR-155 levels are
found in diffuse large B-cell lymphoma (Eis et al., 2005),
Hodgkin’s lymphoma (Kluiver et al., 2005) and certain
Burkitt’s lymphomas (Kluiver et al., 2006), supporting
its role in B-cell development and lymphomagenesis.
Consistently, transgenic mice expressing mmu-miR-155
driven by the pre-B-cell-specific immunoglobulin transcriptional enhancer element (Em-mmu-miR-155) exhibit
preleukemic pre-B-cell proliferation that result in B-cell
malignancy (Costinean et al., 2006).
miRNAs have also been directly linked to metastasis
formation. miR-10b was one of a few miRNAs whose
expression was found to be elevated in metastatic breast
cancer (Ma et al., 2007). Exogenous miR-10b increased
both in vitro and in vivo invasion of established breast
cancer cells combined with increased proliferation,
whereas inhibition of miR-10b led to a 10-fold reduction
in invasion. The bHLH transcription factor TWIST, a
known inducer of epithelial-to-mesenchymal transition
(EMT) and driving force of breast metastases (Yang
et al., 2004), induces expression of miR-10b, and this
induction indirectly upregulates levels of the prometastatic gene RHOC because miR-10b directly targets
HOXD10 (Ma et al., 2007). These studies are important
because they were the first to establish a connection
between a particular miRNA and metastasis formation
of a human cancer. Additional miRNAs such as miR335 and miR-126 have since been identified as key
metastasis suppressors in vivo (Tavazoie et al., 2008).
Recently, the miR-200 family of miRNAs (which
includes miR-200a, b, c, miR-141 and miR-429) was
identified as both a marker for epithelial cells and a
powerful master regulator of EMT. Its activity was
found to be mainly mediated through targeting two
E-box-binding E-cadherin repressors, ZEB1 and ZEB2
(Gregory et al., 2008; Park et al., 2008). Interestingly,
ZEB1 has been shown to regulate T-cell differentiation,
to repress IL-2 production and to regulate the expression of CD4 (Yasui et al., 1998; Brabletz et al., 1999;
Postigo and Dean, 1999). It will be interesting to
determine whether miR-200 also regulates T-cell development or activation.
Oncogene
The case of let-7
Although much of the research on the role of miRNAs
in apoptosis regulation focuses on direct relationships
between a miRNA and its putative apoptosis-regulating
target and because miRNAs can regulate global
differentiation pathways, it is likely that activities
exerted by miRNAs on apoptosis pathways may often
be indirect. Cells with gains or losses of specific miRNAs
may be altered in a way that changes entire genetic
programs and results in new phenotypes that have
different apoptotic properties. In the following, we will
review such a differentiation process that is regulated by
miRNAs and affects apoptosis sensitivity of cells.
The receptor-mediated activation of apoptosis is well
defined in the TNF receptor superfamily. CD95 receptor
is the best-characterized member of the death receptors
in this superfamily, and it induces apoptosis by two
distinct mechanisms in Type I or Type II cells, the latter
discriminated by the requirement of mitochondrial
involvement. Interestingly, T-cell activation was shown
to represent another case of a conversion from Type II
to Type I (Scaffidi et al., 1999; Schmitz et al., 2003).
Upon binding of its ligand (CD95L), CD95 forms the
DISC. The characteristics of the Type I pathway are
receptor internalization followed by the formation of
large amount of DISC on endosomes and the activation
of caspase-8 that directly cleaves the executioner caspase
3 (Scaffidi et al., 1998; Barnhart et al., 2003; Lee et al.,
2006b). In contrast, the mitochondrial-dependent
Type II pathway does not involve internalization of
the receptor to the same extent, and only a small amount
of active caspase-8 is generated, which is sufficient to
cleave Bid causing it to translocate to the mitochondria
where it induces the release of mitochondrial factors that
amplify the apoptotic signal (Li et al., 1998; Luo et al.,
1998). Another difference between Type I and Type II
cells is their response to stimulation with CD95L and to
Taxanes. Type II cells were found to be much more
sensitive to apoptosis induction by soluble CD95L
and growth inhibition by Taxanes than Type I cells
(Algeciras-Schimnich et al., 2003). The difference in
CD95 apoptosis sensitivity was used to classify the
60 cell lines of the drug-screening panel at the NCI
(NCI60). Of 58 cell lines tested, 22 cell lines were found
to be sensitive to CD95-mediated apoptosis—11 of them
were classified as Type I and 11 as Type II (AlgecirasSchimnich et al., 2003). In a previous study, the NCI60
cells had been subjected to a gene chip analysis
(Ross et al., 2000), revealing that the cell lines genetically
fell into two major superclusters (SCs). SC1 cells were
found to express genes that expressed a less differentiated and stromal phenotype, when compared with SC2
cells that expressed a gene signature consistent with a
more differentiated phenotype. We recently identified
the let-7 family as being preferentially expressed in
Type II cells. Because let-7 is a marker for more
differentiated tissues, this suggests that let-7 levels
could directly affect the differentiation state of cancer
cells and hence their sensitivity to death ligands and
Taxanes.
Regulation by miRNAs
R Schickel et al
5969
Let-7 is downregulated in a number of human cancers
such as lung, colon, or ovarian cancer, and it serves as a
prognostic marker for disease outcome (Takamizawa
et al., 2004; Johnson et al., 2005; Akao et al., 2006;
Yanaihara et al., 2006; Shell et al., 2007). It was also
suggested to be a tumor suppressor for lung cancer
through targeting RAS (Johnson et al., 2005). More
recently, high-mobility group A2 (HMGA2) was identified as a major target for let-7 (Hebert et al., 2007; Lee
and Dutta, 2007; Mayr et al., 2007; Shell et al., 2007),
and indeed HMGA2, which is not expressed in most
adult tissues, is upregulated in various cancers, such as
neuroblastoma (Giannini et al., 2000), pancreatic cancer
(Abe et al., 2003), thyroid neoplasms (Chiappetta et al.,
1995), squamous carcinoma (Miyazawa et al., 2004)
and lung cancer (Sarhadi et al., 2006). Interestingly,
HMGA2 is an early embryonic gene. Consistently, let-7
is one of the main miRNAs that is upregulated late
during embryonic development (Lagos-Quintana et al.,
2001; Abbott et al., 2005; Schulman et al., 2005), and
this is conserved from C. elegans to humans (Pasquinelli
et al., 2000). The physiological targets for let-7 are
therefore most likely embryonic genes. We have recently
demonstrated that let-7 is selectively expressed by Type
II human cancer cells that are at an early stage of dedifferentiation (Shell et al., 2007), and we proposed that
let-7 controls a number of oncofetal genes to prevent the
de-differentiation process of reverse embryogenesis that
might give tumor cells properties of embryonic cells
(Park et al., 2007). Recently, a set of 12 let-7-regulated
oncofetal genes (LOGs) was identified using a genomewide bioinformatics approach (Boyerinas et al., 2008).
Overexpression of let-7 inhibits cancer growth (Takamizawa et al., 2004; Akao et al., 2006; Johnson et al.,
2007) and its inhibition promotes growth (Kumar et al.,
2007). Recently, it was shown that let-7 effectively
suppresses cancer development in a mouse model of
spontaneous lung cancer (Esquela-Kerscher et al., 2008;
Kumar et al., 2008), giving hope that it could be useful
for cancer therapy.
Another target for cancer therapy are the recently
discovered regulators of let-7 processing LIN28 and
LIN28B (which happens to be LOG3) (Newman et al.,
2008; Viswanathan et al., 2008). The stem cell factor
LIN28 (Yu et al., 2007) has been shown to selectively
block the processing of most let-7 family members at the
Drosha level and it is likely to be upregulated in many
different cancers. So far, this has been shown for
hepatocellular carcinoma in which LIN28B was found
to be upregulated in more advanced cancer (Guo et al.,
2006).
Although let-7 is downregulated in many human
tumors, it cannot be viewed as a classical tumor
suppressor gene. First, it consists of 12 individual genes
transcribed from 8 chromosomal loci (Park et al., 2007),
and although all 12 miRNAs are predicted to have a
similar set of targets, it is not clear whether all 12
miRNAs have the same function. Secondly, miRNAs
exert their function through targeting other genes, and it
is therefore conceivable that, in certain tissues under
certain conditions, let-7 could have a set of targets that
have tumor-suppressing functions, whereas in other
contexts it may not. In fact, let-7a-3 was described to be
epigenetically silenced in a human lung cancer cell line
and was suggested to have oncogenic function (Brueckner et al., 2007). In another study, it was shown that the
pro-inflammatory cytokine IL-6 can contribute to
tumor growth and drug resistance through the upregulation of let-7a (Meng et al., 2007b). Other examples of
miRNAs with no clearly defined activity with respect to
tumorigenesis are miR-21 and miR-24, which, depending on the cell type, can either promote or inhibit cell
growth (Cheng et al., 2005). As such, a miRNA can only
be considered a tumor suppressor in particular tissues
where its expression inhibits the expression of genes
considered to have oncogenic properties. It is therefore
most appropriate to refer to miRNAs that are involved
in cancer development in more general terms as
oncomiRs.
Concluding remarks
It has become quite clear that microRNAs regulate a
diverse set of cellular processes in both the immune
system and solid tissues. From proper immune function,
to hematopoietic lineage commitment, to embryonic
development, to apoptosis and cell cycle regulation,
many miRNAs act as master regulators that enforce
particular patterns of gene expression by both directly
and indirectly modulating the expression of target genes.
The field of miRNA studies is no longer in its infancy,
yet we are many years from developing a comprehensive
understanding of the subject. In many cases, there is a
direct relationship between a particular miRNA and
expression of a target gene—miR15a and BCL2.
However, what has become clear is the importance of
context when attempting to determine the functional
outcome of gain or loss of any particular miRNA. The
relationship between a miRNA and a particular target
may be more important in some situations than others—
mir-21, for instance, can play the part of both tumor
suppressor and oncogene depending on cellular context.
As the current evidence suggests that many miRNAs
play an essential role in differentiation and cell fate
determination, we will most likely find that many
miRNAs function similar to let-7, which seems to
control a program of differentiation, and whose loss
contributes to carcinogenesis by modulating both
apoptotic and cell cycle pathways.
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