Stem Cell Reviews and Reports (2018) 14:309 –322

https://doi.org/10.1007/s12015-018-9808-y

Cell Cycle Regulation of Stem Cells by MicroRNAs

Michelle M. J. Mens1 · Mohsen Ghanbari1,2

Published Online: 14 March 2018

© The Author(s) 2018

Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNA molecules involved in the regulation of gene expression. They
are involved in the fine-tuning of fundamental biological processes such as proliferation, differentiation, survival and apop-
tosis in many cell types. Emerging evidence suggests that miRNAs regulate critical pathways involved in stem cell function.
Several miRNAs have been suggested to target transcripts that directly or indirectly coordinate the cell cycle progression of
stem cells. Moreover, previous studies have shown that altered expression levels of miRNAs can contribute to pathological
conditions, such as cancer, due to the loss of cell cycle regulation. However, the precise mechanism underlying miRNA-
mediated regulation of cell cycle in stem cells is still incompletely understood. In this review, we discuss current knowledge
of miRNAs regulatory role in cell cycle progression of stem cells. We describe how specific miRNAs may control cell cycle
associated molecules and checkpoints in embryonic, somatic and cancer stem cells. We further outline how these miRNAs
could be regulated to influence cell cycle progression in stem cells as a potential clinical application.

Keywords  MicroRNA · Cell cycle · Stem cells · ESC · Somatic stem cell · Cancer stem cell

Introduction are multipotent and can only differentiate into cell types of
the specific tissue or organ from which they originate. It
Stem Cells and Cell Cycle Regulation is also suggested that a certain type of stem-like cells is
responsible for the initiation of cancer, so-called cancer stem
Stem cells are characterized by their unlimited ability to cells (CSCs). It is thought that CSCs arise from either dif-
self-renew and capability to differentiate into multiple cell ferentiated cancer cells or somatic stem cells [2].
lineages [1]. In this end, stem cells undergo an asymmetric In eukaryotes, the cell division cycle includes four
cell division during which only one of the two daughter cells discrete phases: Gap 1 (G1), Synthesis (S), Gap 2 (G2)
differentiates. This is a complex mechanism in which differ- and Mitosis (M). During the G1 phase, which is known
ent transcription factors, epigenetic modifications and hor- as the first interphase, the cell synthesizes proteins that
mones are involved. There are two broad types of stem cells are needed for DNA replication and continuous growth.
including embryonic stem cells (ESCs), which are solely DNA replication takes place during the S phase and is
present at the earliest stages of development, and somatic (or followed by the G2 phase, which is known as the second
adult) stem cells, which appear during fetal development and interphase, where the DNA integrity is checked. At this
remain throughout life. ESCs are pluripotent and therefore point, the cell is growing and preparing for cell division.
have the capacity to differentiate into all the possible cell During the M phase, the cell divides into two daughter
types of the three germ layers. Somatic stem cells, however, cells. After the mitotic phase, the daughter cells re-enter
the G1 phase or go into the quiescent state. This is defined
as a state of reversible cell cycle arrest and is known as the
* Mohsen Ghanbari
[email protected] G0 phase [3]. The quiescent state is important for cellular
homeostasis, meaning that it has the ability to either stop
1
Department of Epidemiology, Erasmus University proliferating or to re-enter the cell cycle and self-renew
Medical Center, P.O. Box 2040, 3000 CA Rotterdam, when needed [4, 5].
The Netherlands
The duration of the cell cycle and the transition from
2
Department of Genetics, School of Medicine, Mashhad one phase to the next is highly variable between different
University of Medical Sciences, Mashhad, Iran

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310 Stem Cell Reviews and Reports (2018) 14:309 –322

cell types. While the cell cycle duration in murine somatic Biogenesis of MicroRNAs
cells is relatively long (> 16 h), the duration in murine ESCs
(mESCs) is much faster (8–10 h). A reduced G1 phase and Epigenetic features, such as the activity of microRNAs
prolonged S phase in ESCs are the causes that make this (miRNAs), modulate the expression of cell cycle-asso-
difference. In addition, human ESCs (hESCs) spend only ciated genes [19–23]. MiRNAs are a conserved class of
3 h in the G1 phase, compared to human somatic cells that endogenously expressed small non-coding RNAs (span-
spend 10 h in this phase [6]. The difference in cell cycle ning 20–24 nucleotides), that have been widely implicated
duration between ESCs and somatic stem cells is remark- in fine-tuning various biological processes. Since the dis-
able, an explanation could be that somatic stem cells are pre- covery of the first miRNA in 1993 [24], the knowledge on
dominantly in a quiescent state compared to the fast dividing miRNAs has been rapidly increased. MiRNAs are ubiqui-
ESCs. Previous studies have indicated that the G1 phase is tously expressed in plants, animals and viruses, indicat-
the most variable phase and that its duration contributes to ing the evolutionary importance of these small molecules.
cell fate determination [7–9]. According to the miRBase database (v.21), 1881 miRNAs
When a cell enters the G1 phase, a protein called cyclin have been identified with confidence in human [25]. These
D increases in response to mitogenic stimuli. Cyclin D pro- miRNAs are suggested to regulate the expression of more
teins bind to enzymes called CDK4/6 and together they form than 60% of all protein-coding genes. Previous research
heterodimers. These complexes subsequently phosphorylate has investigated the functional role of miRNAs in diverse
proteins of the retinoblastoma (RB) family. The E2F family mechanisms including cell proliferation, apoptosis, and
is a group of genes encoding for transcription factors E2F-1, differentiation. Additionally, alteration in the expression
E2F-2 and E2F-3, which are downstream targets of the RB of miRNAs contribute to human diseases such as cancer
family. The central member of the RB family, the RB tumor and cardiovascular disease [26–33].
suppressor protein (pRb), is a negative regulator of the E2F MiRNA maturation is a complex biological process that
genes. When pRb is hypophosphorylated, it inactivates E2F is subjected to tight molecular regulation. In the nucleus,
transcription factors, which results in the inhibition of tran- miRNAs are initially transcribed as 800-3000nt long pri-
sition from G1 to S phase. Hyperphosphorylation of pRb mary transcripts (pri-miRNA). These pri-miRNAs are
leads to dissociation of E2F from the E2F/pRb complex and subsequently cleaved by Drosha, RNaseII, endonuclease
contributes to the G1/S transition. Recent findings show the III, and Pasha/DGCR8 proteins to generate ~ 70nt hairpin
importance of the E2F/pRb activity in relation to ESCs self- precursor miRNAs (pre-miRNAs). Following this initial
renewal and differentiation [10–12]. process, pre-miRNAs are transported to the cytoplasm by
Cyclin dependent kinase proteins (CDK) tightly regu- Exportin 5. Subsequently, the hairpin precursor is cleaved
late the progression of the cell cycle. A CDK binds to in a ~ 22nt double-stranded miRNA by the ribonuclease III
its regulatory cyclin protein partner to control the dif- enzyme called Dicer together with TRBP/ PACT proteins.
ferent cell cycle phases. Progression through S phase The guide strand (5′ end) then associates with members
is regulated by the cyclin E-CDK2 complex, while the of the Argonaute family and is been incorporated into
G2/M transition is under control of cyclin B-CDK1 com- the RNA-induced silencing complex (RISC). The miR-
plex. Cyclin dependent kinase inhibitor (CDKI) proteins RISC complex facilitates base-pairing interaction between
including p21/Cip1, p27/Kip1 and p57/Kip2, block the miRNA and the 3′ untranslated region (3′UTR) of target
activity of cyclin E-CDK2 and cyclin A-CDK1 [13]. mRNA. The core of a mature miRNA, called the ‘seed’
Furthermore, proteins of the INK4 family, including region, includes nucleotides 2–7/8 from the 5′ end of the
p16/INK4A, p15/INK4B, p18/INK4C and p19/INK4D miRNA and plays a critical role in target recognition and
inhibit the cyclin D-CDK4/6 activity. These mechanisms interaction. Binding of the miRNA seed region to its com-
can lead to cell cycle arrest and are of major importance plementary site in the target mRNA leads to translational
to regulate tissue homeostasis and prevent tumorigen- repression or degradation of the target transcript.
esis. The p53-p21 signaling pathway is also involved in The first studies investigating miRNA function in cell
the transition of G1 to S phase and G2 to M phase. It is cycle regulation were published two decades ago, where
well established that loss of p53 is the main reason for two independent studies revealed that miRNAs lin-4 and
genomic instability as the p53-null cells have disrupted let-7 induce cell cycle arrest in the nematode, C. elegans
the G1/S checkpoint [14–17]. In addition, the expression [24, 34]. Since then, several studies have demonstrated the
levels of p53 and p21 in ESCs are important for the main- importance of miRNAs in cell cycle regulation in different
tenance of pluripotency [18]. cell types including stem cells [21, 35, 36]. The role of
miRNAs in stem cell proliferation was initially observed
in knockout mice lacking Dicer and Dgcr8, which are key

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components of the miRNA biogenesis [37]. Dicer knock- loci, which contribute to the same cis-regulatory elements
out mice were embryonic lethal and ESCs from Dicer- [47]. The miR-290-295 cluster and miR-302 share a highly
deficient mice exhibited defects in cell cycle progression conserved seed-sequence ‘AAG​UGC​U’, while miR-17-92,
[38]. Similarly, ESCs derived from Dgcr8-deficient mice miR-106b-25 and miR-106a-363 clusters share the seed-
exhibited delay in the cell cycle progression due to down- sequence ‘AAA​GUG​C’ [20]. These miRNAs are called the
regulation of genes involved in regulation of self-renewal regulators of the embryonic stem cell cycle (ESCC), because
[37]. These initial studies indicated that miRNAs are cru- of the ability in rescuing cell cycle progression in Dgcr8
cial for cell cycle regulation of stem cells. Then, other knockout ESCs [20, 44, 48–50]. A schematic overview of
studies demonstrated that miRNAs are involved in the cell the functionality of ESCC miRNAs is illustrated in Fig. 1. In
cycle progression of stem cells by direct or indirect target- general, ESCC miRNAs facilitate the G1/S transition mainly
ing of different cell cycle-associated genes (e.g. Cyclins, through suppressing the expression of RB proteins [44]. In
CDKs and CDKIs). Understanding the tightly regulated addition, these miRNAs have been demonstrated to directly
networks of cell cycle in which miRNAs are interacting, regulate the expression of p21/Cip1 and cyclin E-CDK2
will enhance our knowledge in the development of both regulatory molecules in mESCs, including RB, RBL1, RBL2,
healthy and disease states of the human body. In the fol- and LATS2 [21, 48–50].
lowing, we will discuss the recent advances on the func- The miR-290 cluster, consisting of miR-291a-3p, miR-
tions of miRNAs in cell cycle regulation of stem cells. In 291b-3p, miR-294, and miR-295, is upregulated in undiffer-
addition, a promising therapeutic potential of miRNAs in entiated ESCs, but is rapidly downregulated during differen-
controlling somatic and cancer stem cells self-renewal and tiation [21, 50, 52]. It has been shown that members of this
proliferation will be discussed. miRNA cluster promote the G1/S transition. Cells can rela-
tively quick enter the S phase, because members of the miR-
290-295 cluster directly target cyclin D-CDK4/6 and indi-
MiRNAs and Cell Cycle Regulation of Stem rectly downregulate the cyclin E-CDK2 complex (Fig. 1).
Cells MiR-290-295 downregulates diverse inhibitors of the cell
cycle, including RB, RBL1, RBL2, p21 and LATS2,which
Embryonic Stem Cells (ESCs) change the distribution of ESC in each cell cycle phase [47].
Furthermore, the miR-290-295 cluster enhances the somatic
The duration of the cell cycle is variable between different reprogramming by increasing the expression of pluripotent
types of stem cells. ESCs have a shorter cell cycle compared transcription factors OCT4, SOX2, KLF4, LIN28, MYC and
to somatic stem cells, which is due to a significantly abbrevi- NANOG [47, 53]. Also, miR-290-295 is shown to be directly
ated G1 phase and a prolonged S phase [39–41]. Previous involved to suppress apoptosis by targeting Caspase 2 [54].
studies have explored the phosphorylation status of pRb as This leads to a reduced percentage of ESCs in G1 phase and
a regulator for the length of G1 phase. Since mESCs lack an increased fraction of cells in S or G2/M phases. Due to
cyclin D-CDK4 as well as cyclin E-CDK2, pRb will not the enhanced proliferation, the metabolism of ESCs rather
be phosphorylated and thereby not stimulating the cyclin rely on glycolysis than aerobic respiration. This metabo-
E-CDK2 activity [42]. Therefore, the time spent in G1 phase lism is similar to the Warburg effect that is known in cancer
compared to S phase may be a key feature of the pluripo- cells [44, 47, 48]. Therefore, glycolysis-associated genes,
tency fate [12]. Moreover, DNA damage response pathways, such as MYC, LIN28 and HIF1, have been promoted by the
which are activated in the G1 phase, are reduced or absent miR-290-295 cluster [44, 47]. Moreover, members of this
in both hESCs and mESCs [43]. Several negative regulators miRNA cluster could affect epigenetic pathways includ-
of cell cycle progression, including p53, p16/INK4A, p19/ ing DNA methylation, histone acetylation and activation of
ARF and p21/Cip1, are expressed at low levels in ESCs, Polycomb proteins, which inactivates genes involved in dif-
while DNA repair and replication regulators are expressed ferentiation [55, 56].
at high levels [6, 43]. The miR-17-92 cluster consists of miR-17, miR-18a,
Previous studies have shown the distinct expression pat- miR-19a, miR-19b, miR-20a and miR-92a. This miRNA
tern of miRNAs in ESCs. These studies demonstrate that cluster is crucial in early mammalian development by sup-
ESCs express a set of miRNAs, of which a few are abun- porting cellular reprogramming and tumorigenesis [44]. In
dantly expressed at 60,000 or more copies per cell. The most particular, miR-17-92 is a regulator of the MYC oncogene
abundantly expressed miRNAs in ESCs are miR-290-295, [51, 57]. MYC inhibits the expression of chromatin regula-
miR-302, miR-17-92, miR-106b-25 and miR-106a-363 tory genes including SIN3B, HBP1, and BTG1, via miR-
clusters, which provide approximately 70% of the total 17-92. Through epigenetic mechanisms including reduced
miRNA molecules in ESCs [20, 44–46]. These miRNAs are recruitment of histone deacetylase (HADC) via HBP1, miR-
expressed in homologous clusters, so-called polycistronic 17-92 controls the chromatin stage of cell cycle related genes

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Fig. 1  An overview of cell cycle regulation in ESCs by miRNAs. multiple transcription factors and proteins (e.g. E2F-1, E2F-2, E2F-
The figure illustrates the cell cycle progression in embryonic stem 3, CDK2, CDC25A), resulting in a reduction of G1 phase duration.
cells (ESCs). As shown, multiple key regulatory elements includ- Furthermore, the expression of main G1/S and G2/M checkpoint
ing cyclins, CDKs and CDK inhibitors are forming a network that regulator p53 is decreased via indirect targeting by miR-290-295
progress cells through the four different phases of cell cycle. Sev- and miR-302 in ESCs. This facilitates the G1/S transition. Moreover,
eral miRNA clusters and single miRNAs are involved in the regula- p21 expression is reduced via miR-290-295, miR-372a, miR-302 and
tion of cell cycle in ESCs by directly or indirectly targeting the cell miR-106b-25 in a direct manner. This inhibits cyclin E-CDK2 activ-
cycle-associated components (e.g. RB, p53, p21, LATS2, PTEN, cyc- ity, and therefore facilitates the G1/S transition. Additionally, miR-
lin D, cyclin E). Among them, miR-17-92, miR-290-295, miR-302, 106b-25 and miR-17-92 can target pro-apoptotic gene BIM, resulting
miR-106b-25 and miR-106a-363 are abundantly expressed in ESCs. in a reduction of cells entering apoptosis [51]
Inhibition of E2F by miR-92 and miR-195 decreases transcription of

(Fig. 1) [51]. MYC through miR-17-92, contributes to the contributes to the sustenance of pluripotency in mammalian
euchromatin formation of specific gene expression involved ESCs [59]. Furthermore, it has been demonstrated that the
in DNA replication and repair mechanisms that goes along promoter of miR-302-367 is activated when bound by OCT4,
with a shift in the percentage of cells in a proliferating state SOX2, which are core transcription factors directly involved
[51]. Likewise, miR-106b, which shares a high sequence in the maintenance of ESCs [59, 60]. It has been also shown
homology with miR-17 and miR-20a, is shown to promote that this cluster promotes pluripotency in ESCs by targeting
G1/S transition by directly targeting p21, which results in the SMAD signaling pathway and the PI3K/PKB signaling
a higher portion of cells in S phase compared to G1 phase molecules. MiR-302 inhibits the expression of transforming
[58]. growth factor beta-receptor 2 (TGFBR2) and RAS homolog
The miR-302-367 cluster, consisting of miR-302a, b, c, gene family member C (RHOC), which leads to a reduction
d, and miR-367, has also been shown to play a crucial role of epithelial-mesenchymal transition [59, 61, 62]. In addi-
in the proliferation of ESCs. Members of the miR-302-367 tion, the miR-302 cluster has suggested to negatively regu-
cluster are highly expressed in early stages of embryonic lates p21 and LATS2 activity in both hESCs and mESCs [63,
development [59]. This miRNA cluster targets genes that 64]. These molecular mechanisms enlighten the important
are involved in epigenetic mechanisms. For example, the role of the miR-302-367 cluster with respect to pluripotency
miRNA cluster downregulates lysine demethylases and and cell cycle modulations.
CpG binding proteins MECP1-p66 and MECP2 [59]. This Another well-known miRNA family involved in the regu-
facilitates the transcription of pluripotent genes and thereby lation of cell cycle progression is the let-7 family, which

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consist of let-7a-1, a-2, a-3, b, c, d, e, f-1, f-2, g, i and miR- Table 1  miRNAs associated with cell cycle regulation in somatic
98. Members of this miRNA family affect the G1/S tran- stem cells
sition of ESCs differently than the above-described ESCC Stem cell miRNA ID Potential target gene(s) Reference
miRNAs. While most of the ESCC miRNAs are related
Epidermal miR-205 PI3K-AKT [72]
to promote self-renewal, the let-7 miRNAs suppress self-
miR-203 SNAI2, p63, SNAP2 [73]
renewal [35, 52]. The mechanism underlying this antagonis-
miR-34 p63 [74]
tic effect remains unclear. However, it has been suggested
miR-184 NOTCH, p63, FIH1 [75]
that the ESCC miRNAs positively regulate the expression
miR-214 WNT/β-catenin [76]
of LIN28, which through a negative feedback loop suppress
Neural miR-9 TLX, BAF53A [77]
the let-7 maturation [65, 66].
miR-137 TLX [78]
Two other miRNAs known to affect the regulation of
miR-184 MBD1 [79]
ESCs are miR-195 and miR-372a. Both miRNAs are highly
miR-195 MBD1 [80]
enriched in hESCs compared to differentiated cells and
miR-124 SOX-2, PTBP1, SCP1 [81–83]
their function also relies on maintaining the proliferative
miR-302 p53, OCT4, SOX2, NANOG [84]
capacity of hESCs [67]. For example, ectopic expression
miR-148b WNT/β-catenin [85]
of miR-195 results in reduced expression of the G2/M cell
miR-138 TRIP6 [86]
cycle checkpoint kinase WEE1 and an enhancement of BrdU
Muscle miR-27 PAX3 [87]
incorporation [67, 68]. Ectopic expression of miR-372 has
miR-322 CDC25A [88]
also shown to reduce the p21 expression levels in Dicer-
miR-206 HDAC4, PAX7 [89, 90]
knockdown hESCs [67].
miR-1 HDAC4, PAX7 [90]
Human ESCs have the therapeutic potential to treat a
miR-133 SRF, MALAT1 [91]
myriad of disorders by cell replacement. In theory, ESCs
miR-221 PI3K-AKT [92]
could be used in regenerative medicine, drugs discovery
miR-143 IGFBP5, ERK1/2 [93]
and disease modeling. However, the usage of ESCs as clini-
miR-486 PAX7 [94]
cal application is limited because of high tumorigenicity
and ethical restrictions. A miRNA-based therapy that use
induced pluripotent stem cells (iPSC) might overcome these
limitations. In this regard, ectopic expression of ESCC miR- LIN28-HMGA2 pathway is crucial in stem cell development
NAs may contribute to expansion of stem cells for regenera- [97]. Most of the previous research has focused on determin-
tive medicine purposes [12, 20, 44]. ing the expression of miRNAs in hematopoietic stem and
progenitor cells during lineage differentiation [98]. Several
Somatic Stem Cells studies have also reported differential miRNA expressions
between HSCs, hematopoietic progenitor cells and both
An extensive body of research has revealed the role of miR- myeloid and lymphoid linages (e.g. T cell, B cell, Granulo-
NAs in the cell cycle regulation of somatic stem cells [45, cyte, Monocyte, Erythrocyte), demonstrating that miRNAs
69, 70]. In particular, studies with tissue specific Dicer- are involved in the differentiation of specific hematopoietic
knockout or Dgcr8-deficient mice have demonstrated that lineages [95, 99–101]. Although the conventional model
miRNAs are essential regulators of proliferation, survival suggests that hematopoietic lineages are derived from a
and differentiation in somatic stem cells [71]. In the follow- common HSC, more recent research revealed that a rather
ing paragraphs, the role of miRNAs in the cell cycle regula- large number of progenitor cells are the main drivers behind
tion of hematopoietic and mesenchymal stem cells will be steady-state hematopoiesis and clonal diversity [102]. In this
discussed. The associations of miRNAs with other somatic regards, short-term HSCs could support the heterogeneous
stem cells are summarized in Table 1. range of progeny [102]. Taken the functional role of miR-
Hematopoietic stem cell (HSC) development has been NAs into consideration, both progenitor cells and diverse
characterized by several mechanisms that lead to generat- miRNAs may be equally important for clonal expansion and
ing multiple cell lineages. Adult HSCs are predominantly hematopoiesis.
quiescent (in the G0 phase) compared to fetal HSCs [4]. For example, miRNAs are differentially expressed
Well established is the self-renewal function of the LIN28 between long term hematopoietic stem cells (LT-HSCs) and
gene, which is highly expressed in fetal HSCs compared short term HSCs, which are defined by a combination of cell
to adult HSCs (Fig. 2b) [95, 96]. This is a form-feedback surface markers such as c-Kit+/Sca-1+/Lin− (KSL). Based
loop which includes the downregulation of let-7 through on the expression levels of cell surface markers including
LIN28, and subsequently downregulation of HMGA2. CD34, Flk-2, CD150, CD48, CD224, c-Kit, Sca-1, and Lin,
Given that HMGA2 enhances the self-renewal capacity, the the heterogeneous population of HSCs differ in proliferation

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Fig. 2  miRNA-mediated regulation of cell cycle in HSCs. (a) The ily and contributes to self-renewal [95, 96]. (c) Adult HSCs are a het-
schematic describes miRNAs (e.g. miR-125, miR-126, miR-33, miR- erogeneous population that differ in self-renewal and differentiation
146 and let-7) with critical roles in the cell cycle regulation in adult capacity based on their surface markers. Long-term HSCs (LT-HSCs)
HSCs by directly targeting cell cycle components. Furthermore, miR- are predominantly quiescent (c-kit+ Sca-1+ ­Lin− Flk-2− ­CD34−)
29 and miR-124, which target components involved in DNA meth- [103]. However, a large fraction of short term-HSCs (c-kit+ Sca-1+
ylation, indirectly influence the expression of cell cycle-associated ­Lin− Flk-2− ­CD34+) gives rise to the differentiated progeny, and also
genes. (b) The LIN28-HMGA2 feed-forward loop is among the most shows greater cell proliferation capacity than LT-HSCs [102, 103].
important mechanisms that drive fetal HSC self-renewal. LIN28 is Progenitor cells are associated with proliferation and differentiation
highly expressed in fetal HSCs compared to adult HSCs. As LIN28 into hematopoietic lineages. KSL (c-kit+ Sca-1+ ­Lin−) with high
directly inhibits let-7 expression, this indicates the important role of ­CD150+ expression may give predominant rise to myeloid linages,
miRNA let-7 upon stem cell differentiation. Decreased level of let-7 whereas KSL-CD150− are more likely to a lymphoid outcome [104].
has resulted in higher expression of HMGA2, which induces self- Several studies also  demonstrate that specific miRNAs are differen-
renewal. Additionally, LIN28 can acts independently of the let-7 fam- tially expressed among HSCs and progenitor cells

and differentiation capacity [104]. The transition of HSCs are involved in cell cycle progression, including CDC42EP2
into progenitor cells is related with a switch from quiescent and HBP1 [108]. Recently, Lechman et al. demonstrated that
into rapid proliferating cells, and subsequently an alteration miR-126 can control the cell cycle progression by targeting
in expression of surface makers (Fig. 2c). Therefore, the the PI3K/AKT/MTOR pathway [109]. They showed that
expression of cell cycle related miRNAs in exclusively pro- overexpression of miR-126 results in an increased percent-
genitor cells is likely to be involved in the alteration of cell age of quiescent cells, whereas a knockdown of miR-126
cycle duration [70]. One of the enhanced expressed miR- lead to enhanced proliferation and differentiation of HSCs
NAs in LT-HSCs is the miR-125 cluster (miR-125a, miR- [109–111].
125b1, miR-125b2). The expression of miR-125 has been Additionally, previous studies have suggested miR-125
shown to be associated with self-renewal and expansion of and miR-126 as potential target treatment for acute myeloid
the stem cell population in vivo [105–107]. Furthermore, leukemia (AML) [112, 113]. An indication for the poten-
miR-29a has been revealed to regulate the G1/S transition tial therapeutic function is based on the alternated expres-
in hematopoietic progenitor stem cells. MiR-29a promotes sion of these miRNAs between ­CD34+ ­CD38− HSC and
the self-renewal capacity by targeting a subset of genes that ­CD34+ ­CD38− leukemic stem cells. A reduction of miR-126

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stimulates the PI3K/AKT/MTOR pathway in HSCs and will 131]. As discussed previously in this review, miRNAs have
result in an increased number of HSCs, while this effect the ability to suppress apoptosis and promote proliferation
decreases the self-renewal capacity in ­CD34+ ­CD38− leuke- by interplaying with the cell cycle components. Therefore,
mic stem cells [112]. Although this miRNA-based treatment miRNAs and CSCs share common properties with respect
holds promising capacity to in vivo experiments, issues with to tumorigenesis. The transcriptional levels of several miR-
respect to toxicity and delivery need to be solved before NAs have shown to vary between normal stem cells and
application in AML patients [112]. CSCs [132]. Furthermore, associations between either cell
Mesenchymal stem cells (MSCs) are multipotent cells cycle components including cyclins and transcription factors
that originate from bone marrow stroma, but are present or miRNA expression and specific CSC markers have been
in various tissues such as adipose tissue, bone, skeletal investigated [133, 134]. Hence, miRNAs as regulators of
muscle, cartilage and tendon [114]. Evidence suggests that CSCs have gain attention in recent years in multiple fields
miRNAs are closely involved in the regulation of MSC dif- of research [131, 133, 135, 136]. The associations between
ferentiation into specific cell lineages [101, 115–117]. The miRNAs expression and various cancers are summarized in
role of miRNAs in proliferation and cell cycle regulation Table 2. In the following paragraph, some of the main CSC-
of human MSCs has been investigated through Drosha and related miRNAs will be discussed.
Dicer knockdown studies [118]. These studies have shown a The miR-17-92 cluster affects the cell cycle by target-
significant increase in the number of cells in G1 phase and a ing E2F-1 and cyclin D as well as it cooperates with the
reduced proliferation rate of MSCs [118]. In the same study, oncogene MYC to prevent apoptosis in CSCs [169–172]. Li
Drosha knockdown in MSCs resulted in a decrease of pRb et al. investigated the miR-17-92 target genes involved in
and an increase in p16 and p15 levels [118]. Other studies the MYC suppression. They demonstrated that the function-
have been implicated miR-16 and miR-143 in the regulation alities of the miR-17-92 target genes rely on multiple DNA
of MSC proliferation and differentiation. In this regard, miR- replication, cell cycle regulation, chromosome organization,
16 has been shown to inhibit MSC proliferation and induce RNA transcription or protein metabolism [51]. Similarly,
cell cycle arrest by targeting cyclin E [119]. Likewise, this miRNA cluster is shown to coordinate the timing of cell
miR-143 targets ERK5 (member of MAPK family), which cycle progression by modulating expression of BMI1, PTEN,
itself decreases the expression of cyclin D and CDK6. This RBL2 and p21 [154, 173–176].
reduces cell entry into S phase, suggesting miR-143 to be a Other important regulators of CSCs are the members
negative regulator of the cell cycle progression [120, 121]. of the let-7 family. Evidence suggests that let-7 is among
Moreover, a number of miRNAs have determined to control the most important miRNAs involved in tumor progres-
the differentiation into specific linages, such as osteoblasts sion and chemoresistance [131, 177]. The expression of
[122]. For example, Peng et al. demonstrated that miRNAs the let-7 family is reduced in various types of tumor cells,
promote the osteogenic differentiation of MSCs via BMP, including breast, head and neck squamous (HNSCC), lung,
WNT/β-catenin and NOTCH signaling pathways. Among pancreatic, neuroblastoma cells, among others [131, 133,
them, miR-27 promotes differentiation by targeting APC, 178, 179]. Accordingly, decreased expression of let-7
which modulates the G2/M transition [122, 123]. On the has resulted in overexpression of oncogenes MYC, RAS,
other hand, miR-27 expression is shown to be downregu- HMGA2 and BLIMP1 [115, 177, 180]. Furthermore, mem-
lated upon adipocyte differentiation [124, 125]. Several cell bers of the let-7 family have been recognized as negative
cycle associated genes, including ERK1/2, ERK5, TGF-β1 regulators of PTEN that inactivate the PI3K/AKT/MTOR
and KLF5 are related to adipocyte differentiation, which is pathway. The let-7 family has also shown to be involved
explained by miRNA regulation [126]. Notably, miR-143, in suppressing the epithelial-to-mesenchymal transition
miR-448 and miR-375 have been reported as negative regu- (EMT), which is related to metastasis and chemoresistance
lators and miR-21 as positive regulator of adipocyte differ- and therefore a characteristic of CSCs [131, 177]. Multi-
entiation [126]. ple genes involved in cell cycle progression are suggested
to be targets for the let-7 family. The latter include cyc-
Cancer Stem Cells (CSCs) lin D, cyclin A, CDK1, CDK2, CDK4, CDK6, CDK8 and
CDC25A [115, 177, 180]. Also, it has been shown that the
Altered expression and molecular abnormalities of the cell- RNA binding protein LIN28 inhibits let-7 by stimulating
cycle-regulatory proteins, such as pRB, p53, CDKs, CDKIs cellular proliferation via cyclin D, CDK2 and CDC25A and
and cyclins, play a central role in cancer initiation and pro- thereby contribute to the maintenance of stemness charac-
gression [17, 127–129]. Notably, it has been suggested that teristics of CSCs [46, 181]. LIN28 has been recognized as
a class of cancer cells with characteristics of stem cells, so- an oncogene, as it promotes tumor progression by repress-
called cancer stem cells (CSCs), are responsible for tumor ing let-7 [177]. Previous studies based on let-7 expression
initiation, invasion, metastasis and chemoresistance [130, and tumor progression display that ectopic expression of

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Table 2  miRNAs associated with the cell cycle progression in cancer stem cells
Cancer type miRNA ID Potential target gene(s) Exp. of miRNA Reported biological effect Reference

Breast let-7 LIN28 Downregulated Upregulation of LIN28 results in sup- [137]

porting RAS, MYC and HMGA2
miR-21 PTEN Upregulated Promote PI3K/AKT signaling activa- [138]
tion through directly inhibiting
PTEN expression
miR-221/222 PTEN Upregulated Promote AKT/NF-κβ/COX-2 pathway [139]
by targeting PTEN
miR-93 JAK1, SOX4, STAT3, AKT, EZH1, Upregulated Regulate CSC proliferation [140]
HMGA2
miR-34 CDK4, CDK6, NOTCH1 Downregulated Regulate p53 [141]
miR-16 BMI1 Upregulated Inhibit DNA repair by repressing [142]
BMI1
miR-200 ZEB1, ZEB2, WNT-signaling Downregulated Reduction of EMT [143]
miR-494-3p PAK1 Downregulated Inhibit proliferation via MAPK by [144]
targeting PAK1
Liver (HCC) miR-34 Cyclin D1, BCL2 Downregulated Regulate p53 [145]
miR-365 BCL2 Upregulated Apoptosis [146]
miR-31 HDCA2, CDK2 Downregulated Induction of p16 and p21. Repression [147]
of cyclin D, CDK4, CDK2
miR-26a EZH2 Upregulated Reduction of EMT [148]
miR-150 GAB1 Downregulated Suppress proliferation and invasion [149]
via MAPK pathway by targeting
GAB1 and ERK1/2
Head and Neck let-7 ABCB1 Downregulated Reduction of cell proliferation [150]
Pancreatic let-7 LIN28 Downregulated Inhibit EMT, induces cell cycle arrest [151]
when LIN28 is reduced
miR-21 PTEN, PDCD4 Upregulated Promote metastasis [152]
miR-203 ZEB1, ZEB2 Downregulated Reduction of EMT [153]
miR-34 BCL2, NOTCH1/2 Downregulated Regulate p53 [136]
miR-17-92 p21, p57, TBX3 Downregulated Maintain stemness characteristics in [154]
pancreatic CSC. Downregulation
of MYC
Prostate let-7 LIN28 Upregulated Upregulating cell cycle via cyclin D1 [155]
miR-100 CDK6, RB1, mTOR Downregulated Regulation of cell growth [156]
miR-34 Cyclin D1, CDK4, CDK6, c-MET, Downregulated Mediating p53. Tumor metastasis [157]
CD44
miR-221/222 p27/Kip1 Upregulated Regulate activation of cyclin E and [158]
cyclin D
Glioblastoma miR-124 CDK6 Upregulated Inhibit cell proliferation [159]
miR-137 CDK6 Upregulated Inhibit cell proliferation [160]
miR-128 BMI1 Upregulated Decreasing cell proliferation in IDH1 [161]
mutant glioma
miR-23b HMGA2 Upregulated Cell cycle arrest and proliferation [162]
inhibition
miR-125b CDK6, E2F3, CDC25A Downregulated Induce G1/S cell cycle arrest [163]
miR-34 BCL2, NOTCH1 Downregulated Targeting p53. Anti-apoptotic, [164]
increase cell proliferation
Lung miR-605 LATS2 Upregulated Promote cell proliferation, migration [165]
and invasion
let-7 KRAS, MYC, CDK6 HMGA2, Downregulated Suppression of multiple oncogenic [166]
TGFBR2 members
miR-21 MDM4 Upregulated Repress MDM4 to activate p53 [167]
miR-15a/ miR-16 RB Downregulated Cell cycle arrest [168]

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Stem Cell Reviews and Reports (2018) 14:309 –322 317

let-7 was sufficient enough to inhibit proliferation and Concluding Remarks and Future Prospects
clonal expansion in vitro and tumor recurrence in prostate
cancer cells in vivo [173]. A growing body of evidence has addressed the potential
The next miRNA family, consisting of miR-34a, b, and role of miRNAs in cell cycle regulation of stem cells.
c, is well-studied regarding to cell cycle progression and its In light of recent discoveries about the role miRNAs in
expression is downregulated in several types of cancer cells self-renewal, proliferation and differentiation, it is cru-
including lung adenocarcinomas, colon cancer and liver can- cial to unravel the complex mechanisms and molecular
cer (HCC) [141, 167, 182–185]. MiR-34a induces both G1/S interactions within this field of research. In this review,
cell cycle arrest and cell senescence [167]. Reduced expres- we outlined the most established miRNAs involved in the
sion of miR-34 has been associated with enhanced levels cell cycle progression of stem cells. We highlighted sev-
of BCL2 and NOTCH, which are target genes for tumor eral clusters and single miRNAs that may control self-
suppressor gene p53 [131, 135, 167]. Similarity, miR-34 renewal and maintenance of the pluripotency status in
promotes apoptosis via Caspase 3, and therefore increases ESCs. These include but are not limited to ESCC miR-
sensitivity for anti-cancer treatment [135]. By regulating NAs (miR-290-295, miR-302, miR-17-92, miR-106b-25
CDK6, cyclin D1 and E2F, miR-34 negatively affects cell and miR-106a-363), which are functionally upregulated
cycle progression in colon cancer cells [131, 184, 185]. In to suppress negative regulators and to enhance pluripo-
addition, miR-34 represses pluripotency genes inclusive of tent transcription factors such as NANOG and MYC in an
NANOG, SOX2 and MYC [135]. Thus, overexpression of epigenetic manner [45].
this miRNA family may cause an accumulated percentage Furthermore, specific profiles of miRNA expression in
of cells in the G0/G1 phase and significantly reduces the distinct somatic stem cell lineages are linked with devel-
population of cells in the S phase. opmental control by keeping several multipotent stem cells
MiR-31 has also shown to be inversely correlated with (e.g. HSCs) in a quiescent state. Previous research based on
metastasis, since its high expression in liver cancer is linked Dicer-knockout and Dgcr8-deficient mice have elucidated
with a poor prognosis in patients. Kim et al. showed that that miRNAs are expressed temporally and spatially among
ectopic expression of miR-31 evokes an overexpression of somatic stem cells and precursor cells [37]. It is crucial for
CDK2 and HDAC2 [147]. They demonstrated that through somatic stem cells like HSCs to keep a balance between
abnormal expression of HDAC2, negative cell cycle regu- quiescent state and proliferating state. To accomplish that,
lators p16/INK4A, p19/INK4D and p21/Cip1 are induced. a complex network of miRNAs exists that inhibit positive
Furthermore, an oncogenic role has been reported for cell cycle regulators such as cyclins, as well as miRNAs
the miR-15a/16 family in chronic lymphocytic leukemia modulating anti-apoptotic properties. Complex interactions
(CLL), pituitary adenomas, and gastric cancer [186, 187]. between miRNAs, transcription factors and cell cycle-medi-
On the other hand, this miRNA family is shown to act ated components may control the gene expression upon dif-
as a tumor suppressor in a subset of B cell lymphoma, ferentiation of multipotent stem cells into progenitor cells
where deletion of this miRNA family in a subset of B and mature cells.
cell lymphomas resulted in chronic lymphocytic leukemia It is clear that abnormalities in the cell cycle are related
in mice [188]. In fact, miR-15a and miR-16 display an to tumorigenesis and previous studies have highlighted
anti-proliferative potential in this type of cancer stem cell the significant importance of miRNAs in the regulation of
by silencing BCL2 and activating the intrinsic apoptosis CSCs [132]. Since CSC features are linked to metastasis,
pathway [189, 190]. In addition, some studies revealed invasion and therapeutic resistance, it is of main clinical
the miR-15a/16 family as regulator of various cyclins, relevance to unravel the interactive properties between
including cyclins D1 and D2 and cyclin E1, and pRb [168, CSC-related miRNAs and cell cycle components. From the
180, 191]. data available so far it appears that there is a great over-
An additional miRNA that has been suggested as an lapping role between ESCC miRNAs that are expressed
oncomiR, through targeting multiple signaling pathways, in both ESCs and CSCs. However, a subset of miRNAs
is miR-21 [33]. Upregulation of miR-21 has an oncogenic is characterized as tumor suppressor genes as they are
potential in a wide range of tumors including lung, breast, expressed regarding anti-proliferating features by target-
pancreatic, brain and colon cancers, through downregulation ing oncogenic pathways including MYC. Those miRNAs,
of p21 and tumor suppressor genes PTEN and PDCD4 [33, including let-7, miR-34, miR-31 and miR-17-92 family,
192–194]. MiR-26a is also suggested as a negative regula- are of major interest since they are associated with a good
tor of cancer cell proliferation by targeting cyclins D2 and prognosis in cancer patients. Future research should focus
E2, and CDK6. It has been established that overexpression on targeting the CSC-related miRNAs involved in onco-
of miR-26a results in cell cycle arrest in human liver cancer genic pathways since they will provide a more effective
cells in vitro [195, 196].

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318 Stem Cell Reviews and Reports (2018) 14:309 –322

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Conflict of Interest  The authors declare no potential conflicts of interest. 19. Bueno, M. J., & Malumbres, M. (2011). MicroRNAs and the cell
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Open Access  This article is distributed under the terms of the Crea- 20. Wang, Y., & Blelloch, R. (2009). Cell cycle regulation by
tive Commons Attribution 4.0 International License (http://creat​iveco​ MicroRNAs in embryonic stem cells. Cancer Research, 69(10),
mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribu- 4093–4096.
tion, and reproduction in any medium, provided you give appropriate 21. Wang, Y., & Blelloch, R. (2011). Cell cycle regulation by micro-
credit to the original author(s) and the source, provide a link to the RNAs in stem cells. Results and Problems in Cell Differentiation,
Creative Commons license, and indicate if changes were made. 53, 459–472.
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