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Cell Cycle Regulation of Stem Cells by MicroRNAs

Michelle M. J. Mens, Mohsen Ghanbari

Stem Cell Reviews and Reports · 2018 · Review

doi:10.1007/s12015-018-9808-y

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 apoptosis 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.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Stem Cells and Cell Cycle Regulation

Stem cells are characterized by their unlimited ability to self-renew and capability to differentiate into multiple cell lineages. In this end, stem cells undergo an asymmetric cell division during which only one of the two daughter cells differentiates. This is a complex mechanism in which different transcription factors, epigenetic modifications and hormones are involved. There are two broad types of stem cells including embryonic stem cells (ESCs), which are solely present at the earliest stages of development, and somatic (or adult) stem cells, which appear during fetal development and remain throughout life. ESCs are pluripotent and therefore have the capacity to differentiate into all the possible cell types of the three germ layers. Somatic stem cells, however, are multipotent and can only differentiate into cell types of the specific tissue or organ from which they originate. It is also suggested that a certain type of stem-like cells is responsible for the initiation of cancer, so-called cancer stem cells (CSCs). It is thought that CSCs arise from either differentiated cancer cells or somatic stem cells.

In eukaryotes, the cell division cycle includes four discrete phases: Gap 1 (G1), Synthesis (S), Gap 2 (G2) and Mitosis (M). During the G1 phase, which is known as the first interphase, the cell synthesizes proteins that are needed for DNA replication and continuous growth. DNA replication takes place during the S phase and is followed by the G2 phase, which is known as the second interphase, where the DNA integrity is checked. At this point, the cell is growing and preparing for cell division. During the M phase, the cell divides into two daughter 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 G0 phase. The quiescent state is important for cellular homeostasis, meaning that it has the ability to either stop proliferating or to re-enter the cell cycle and self-renew when needed.

The duration of the cell cycle and the transition from one phase to the next is highly variable between different cell types. While the cell cycle duration in murine somatic cells is relatively long (> 16 h), the duration in murine ESCs (mESCs) is much faster (8–10 h). A reduced G1 phase and prolonged S phase in ESCs are the causes that make this difference. In addition, human ESCs (hESCs) spend only 3 h in the G1 phase, compared to human somatic cells that spend 10 h in this phase. The difference in cell cycle duration between ESCs and somatic stem cells is remarkable, an explanation could be that somatic stem cells are predominantly in a quiescent state compared to the fast dividing ESCs. Previous studies have indicated that the G1 phase is the most variable phase and that its duration contributes to cell fate determination.

When a cell enters the G1 phase, a protein called cyclin D increases in response to mitogenic stimuli. Cyclin D proteins bind to enzymes called CDK4/6 and together they form heterodimers. These complexes subsequently phosphorylate proteins of the retinoblastoma (RB) family. The E2F family is a group of genes encoding for transcription factors E2F-1, E2F-2 and E2F-3, which are downstream targets of the RB family. The central member of the RB family, the RB tumor suppressor protein (pRb), is a negative regulator of the E2F genes. When pRb is hypophosphorylated, it inactivates E2F transcription factors, which results in the inhibition of transition from G1 to S phase. Hyperphosphorylation of pRb leads to dissociation of E2F from the E2F/pRb complex and contributes to the G1/S transition. Recent findings show the importance of the E2F/pRb activity in relation to ESCs self-renewal and differentiation.

Cyclin dependent kinase proteins (CDK) tightly regulate the progression of the cell cycle. A CDK binds to its regulatory cyclin protein partner to control the different cell cycle phases. Progression through S phase is regulated by the cyclin E-CDK2 complex, while the G2/M transition is under control of cyclin B-CDK1 complex. Cyclin dependent kinase inhibitor (CDKI) proteins including p21/Cip1, p27/Kip1 and p57/Kip2, block the activity of cyclin E-CDK2 and cyclin A-CDK1. Furthermore, proteins of the INK4 family, including p16/INK4A, p15/INK4B, p18/INK4C and p19/INK4D inhibit the cyclin D-CDK4/6 activity. These mechanisms can lead to cell cycle arrest and are of major importance to regulate tissue homeostasis and prevent tumorigenesis. The p53-p21 signaling pathway is also involved in the transition of G1 to S phase and G2 to M phase. It is well established that loss of p53 is the main reason for genomic instability as the p53-null cells have disrupted the G1/S checkpoint. In addition, the expression levels of p53 and p21 in ESCs are important for the maintenance of pluripotency.

Biogenesis of MicroRNAs

Epigenetic features, such as the activity of microRNAs (miRNAs), modulate the expression of cell cycle-associated genes. MiRNAs are a conserved class of endogenously expressed small non-coding RNAs (spanning 20–24 nucleotides), that have been widely implicated in fine-tuning various biological processes. Since the discovery of the first miRNA in 1993, the knowledge on miRNAs has been rapidly increased. MiRNAs are ubiquitously expressed in plants, animals and viruses, indicating the evolutionary importance of these small molecules. According to the miRBase database (v.21), 1881 miRNAs have been identified with confidence in human. These miRNAs are suggested to regulate the expression of more than 60% of all protein-coding genes. Previous research has investigated the functional role of miRNAs in diverse mechanisms including cell proliferation, apoptosis, and differentiation. Additionally, alteration in the expression of miRNAs contribute to human diseases such as cancer and cardiovascular disease.

MiRNA maturation is a complex biological process that is subjected to tight molecular regulation. In the nucleus, miRNAs are initially transcribed as 800-3000nt long primary transcripts (pri-miRNA). These pri-miRNAs are subsequently cleaved by Drosha, RNaseII, endonuclease III, and Pasha/DGCR8 proteins to generate ~ 70nt hairpin precursor miRNAs (pre-miRNAs). Following this initial process, pre-miRNAs are transported to the cytoplasm by Exportin 5. Subsequently, the hairpin precursor is cleaved in a ~ 22nt double-stranded miRNA by the ribonuclease III enzyme called Dicer together with TRBP/ PACT proteins. The guide strand (5′ end) then associates with members of the Argonaute family and is been incorporated into the RNA-induced silencing complex (RISC). The miR-RISC complex facilitates base-pairing interaction between miRNA and the 3′ untranslated region (3′UTR) of target mRNA. The core of a mature miRNA, called the ‘seed’ region, includes nucleotides 2–7/8 from the 5′ end of the miRNA and plays a critical role in target recognition and interaction. Binding of the miRNA seed region to its complementary site in the target mRNA leads to translational repression or degradation of the target transcript.

The first studies investigating miRNA function in cell cycle regulation were published two decades ago, where two independent studies revealed that miRNAs lin-4 and let-7 induce cell cycle arrest in the nematode, C. elegans. Since then, several studies have demonstrated the importance of miRNAs in cell cycle regulation in different cell types including stem cells. The role of miRNAs in stem cell proliferation was initially observed in knockout mice lacking Dicer and Dgcr8, which are key components of the miRNA biogenesis. Dicer knockout mice were embryonic lethal and ESCs from Dicer-deficient mice exhibited defects in cell cycle progression. Similarly, ESCs derived from Dgcr8-deficient mice exhibited delay in the cell cycle progression due to downregulation of genes involved in regulation of self-renewal. These initial studies indicated that miRNAs are crucial for cell cycle regulation of stem cells. Then, other studies demonstrated that miRNAs are involved in the cell cycle progression of stem cells by direct or indirect targeting of different cell cycle-associated genes (e.g. Cyclins, CDKs and CDKIs). Understanding the tightly regulated networks of cell cycle in which miRNAs are interacting, will enhance our knowledge in the development of both healthy and disease states of the human body. In the following, we will discuss the recent advances on the functions of miRNAs in cell cycle regulation of stem cells. In addition, a promising therapeutic potential of miRNAs in controlling somatic and cancer stem cells self-renewal and proliferation will be discussed.

Embryonic Stem Cells (ESCs)

The duration of the cell cycle is variable between different types of stem cells. ESCs have a shorter cell cycle compared to somatic stem cells, which is due to a significantly abbreviated G1 phase and a prolonged S phase. Previous studies have explored the phosphorylation status of pRb as a regulator for the length of G1 phase. Since mESCs lack cyclin D-CDK4 as well as cyclin E-CDK2, pRb will not be phosphorylated and thereby not stimulating the cyclin E-CDK2 activity. Therefore, the time spent in G1 phase compared to S phase may be a key feature of the pluripotency fate. Moreover, DNA damage response pathways, which are activated in the G1 phase, are reduced or absent in both hESCs and mESCs. Several negative regulators of cell cycle progression, including p53, p16/INK4A, p19/ARF and p21/Cip1, are expressed at low levels in ESCs, while DNA repair and replication regulators are expressed at high levels.

Previous studies have shown the distinct expression pattern of miRNAs in ESCs. These studies demonstrate that ESCs express a set of miRNAs, of which a few are abundantly expressed at 60,000 or more copies per cell. The most abundantly expressed miRNAs in ESCs are miR-290-295, miR-302, miR-17-92, miR-106b-25 and miR-106a-363 clusters, which provide approximately 70% of the total miRNA molecules in ESCs. These miRNAs are expressed in homologous clusters, so-called polycistronic loci, which contribute to the same cis-regulatory elements. The miR-290-295 cluster and miR-302 share a highly conserved seed-sequence ‘AAGUGCU’, while miR-17-92, miR-106b-25 and miR-106a-363 clusters share the seed-sequence ‘AAAGUGC’. These miRNAs are called the regulators of the embryonic stem cell cycle (ESCC), because of the ability in rescuing cell cycle progression in Dgcr8 knockout ESCs. A schematic overview of the functionality of ESCC miRNAs is illustrated in Fig. 1. In general, ESCC miRNAs facilitate the G1/S transition mainly through suppressing the expression of RB proteins. In addition, these miRNAs have been demonstrated to directly regulate the expression of p21/Cip1 and cyclin E-CDK2 regulatory molecules in mESCs, including RB, RBL1, RBL2, and LATS2.

The miR-290 cluster, consisting of miR-291a-3p, miR-291b-3p, miR-294, and miR-295, is upregulated in undifferentiated ESCs, but is rapidly downregulated during differentiation. It has been shown that members of this miRNA cluster promote the G1/S transition. Cells can relatively quick enter the S phase, because members of the miR-290-295 cluster directly target cyclin D-CDK4/6 and indirectly downregulate the cyclin E-CDK2 complex (Fig. 1). MiR-290-295 downregulates diverse inhibitors of the cell cycle, including RB, RBL1, RBL2, p21 and LATS2,which change the distribution of ESC in each cell cycle phase. Furthermore, the miR-290-295 cluster enhances the somatic reprogramming by increasing the expression of pluripotent transcription factors OCT4, SOX2, KLF4, LIN28, MYC and NANOG. Also, miR-290-295 is shown to be directly involved to suppress apoptosis by targeting Caspase 2. This leads to a reduced percentage of ESCs in G1 phase and an increased fraction of cells in S or G2/M phases. Due to the enhanced proliferation, the metabolism of ESCs rather rely on glycolysis than aerobic respiration. This metabolism is similar to the Warburg effect that is known in cancer cells. Therefore, glycolysis-associated genes, such as MYC, LIN28 and HIF1, have been promoted by the miR-290-295 cluster. Moreover, members of this miRNA cluster could affect epigenetic pathways including DNA methylation, histone acetylation and activation of Polycomb proteins, which inactivates genes involved in differentiation.

The miR-17-92 cluster consists of miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a. This miRNA cluster is crucial in early mammalian development by supporting cellular reprogramming and tumorigenesis. In particular, miR-17-92 is a regulator of the MYC oncogene. MYC inhibits the expression of chromatin regulatory genes including SIN3B, HBP1, and BTG1, via miR-17-92. Through epigenetic mechanisms including reduced recruitment of histone deacetylase (HADC) via HBP1, miR-17-92 controls the chromatin stage of cell cycle related genes (Fig. 1). MYC through miR-17-92, contributes to the euchromatin formation of specific gene expression involved in DNA replication and repair mechanisms that goes along with a shift in the percentage of cells in a proliferating state. Likewise, miR-106b, which shares a high sequence homology with miR-17 and miR-20a, is shown to promote G1/S transition by directly targeting p21, which results in a higher portion of cells in S phase compared to G1 phase.

The miR-302-367 cluster, consisting of miR-302a, b, c, d, and miR-367, has also been shown to play a crucial role in the proliferation of ESCs. Members of the miR-302-367 cluster are highly expressed in early stages of embryonic development. This miRNA cluster targets genes that are involved in epigenetic mechanisms. For example, the miRNA cluster downregulates lysine demethylases and CpG binding proteins MECP1-p66 and MECP2. This facilitates the transcription of pluripotent genes and thereby contributes to the sustenance of pluripotency in mammalian ESCs. Furthermore, it has been demonstrated that the promoter of miR-302-367 is activated when bound by OCT4, SOX2, which are core transcription factors directly involved in the maintenance of ESCs. It has been also shown that this cluster promotes pluripotency in ESCs by targeting the SMAD signaling pathway and the PI3K/PKB signaling molecules. MiR-302 inhibits the expression of transforming growth factor beta-receptor 2 (TGFBR2) and RAS homolog gene family member C (RHOC), which leads to a reduction of epithelial-mesenchymal transition. In addition, the miR-302 cluster has suggested to negatively regulates p21 and LATS2 activity in both hESCs and mESCs. These molecular mechanisms enlighten the important role of the miR-302-367 cluster with respect to pluripotency and cell cycle modulations.

Another well-known miRNA family involved in the regulation of cell cycle progression is the let-7 family, which consist of let-7a-1, a-2, a-3, b, c, d, e, f-1, f-2, g, i and miR-98. Members of this miRNA family affect the G1/S transition of ESCs differently than the above-described ESCC miRNAs. While most of the ESCC miRNAs are related to promote self-renewal, the let-7 miRNAs suppress self-renewal. The mechanism underlying this antagonistic effect remains unclear. However, it has been suggested that the ESCC miRNAs positively regulate the expression of LIN28, which through a negative feedback loop suppress the let-7 maturation.

Two other miRNAs known to affect the regulation of ESCs are miR-195 and miR-372a. Both miRNAs are highly enriched in hESCs compared to differentiated cells and their function also relies on maintaining the proliferative capacity of hESCs. For example, ectopic expression of miR-195 results in reduced expression of the G2/M cell cycle checkpoint kinase WEE1 and an enhancement of BrdU incorporation. Ectopic expression of miR-372 has also shown to reduce the p21 expression levels in Dicer-knockdown hESCs.

Human ESCs have the therapeutic potential to treat a myriad of disorders by cell replacement. In theory, ESCs could be used in regenerative medicine, drugs discovery and disease modeling. However, the usage of ESCs as clinical 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 miRNAs may contribute to expansion of stem cells for regenerative medicine purposes.

Somatic Stem Cells

An extensive body of research has revealed the role of miRNAs in the cell cycle regulation of somatic stem cells. In particular, studies with tissue specific Dicer-knockout or Dgcr8-deficient mice have demonstrated that miRNAs are essential regulators of proliferation, survival and differentiation in somatic stem cells. In the following paragraphs, the role of miRNAs in the cell cycle regulation of hematopoietic and mesenchymal stem cells will be discussed. The associations of miRNAs with other somatic stem cells are summarized in Table 1.

Hematopoietic stem cell (HSC) development has been characterized by several mechanisms that lead to generating multiple cell lineages. Adult HSCs are predominantly quiescent (in the G0 phase) compared to fetal HSCs. Well established is the self-renewal function of the LIN28 gene, which is highly expressed in fetal HSCs compared to adult HSCs (Fig. 2b). This is a form-feedback loop which includes the downregulation of let-7 through LIN28, and subsequently downregulation of HMGA2. Given that HMGA2 enhances the self-renewal capacity, the LIN28-HMGA2 pathway is crucial in stem cell development. Most of the previous research has focused on determining the expression of miRNAs in hematopoietic stem and progenitor cells during lineage differentiation. Several studies have also reported differential miRNA expressions between HSCs, hematopoietic progenitor cells and both myeloid and lymphoid linages (e.g. T cell, B cell, Granulocyte, Monocyte, Erythrocyte), demonstrating that miRNAs are involved in the differentiation of specific hematopoietic lineages. Although the conventional model suggests that hematopoietic lineages are derived from a common HSC, more recent research revealed that a rather large number of progenitor cells are the main drivers behind steady-state hematopoiesis and clonal diversity. In this regards, short-term HSCs could support the heterogeneous range of progeny. Taken the functional role of miRNAs into consideration, both progenitor cells and diverse miRNAs may be equally important for clonal expansion and hematopoiesis.

For example, miRNAs are differentially expressed between long term hematopoietic stem cells (LT-HSCs) and short term HSCs, which are defined by a combination of cell surface markers such as c-Kit+/Sca-1+/Lin− (KSL). Based on the expression levels of cell surface markers including CD34, Flk-2, CD150, CD48, CD224, c-Kit, Sca-1, and Lin, the heterogeneous population of HSCs differ in proliferation and differentiation capacity. The transition of HSCs into progenitor cells is related with a switch from quiescent into rapid proliferating cells, and subsequently an alteration in expression of surface makers (Fig. 2c). Therefore, the expression of cell cycle related miRNAs in exclusively progenitor cells is likely to be involved in the alteration of cell cycle duration. One of the enhanced expressed miRNAs in LT-HSCs is the miR-125 cluster (miR-125a, miR-125b1, miR-125b2). The expression of miR-125 has been shown to be associated with self-renewal and expansion of the stem cell population in vivo. Furthermore, miR-29a has been revealed to regulate the G1/S transition in hematopoietic progenitor stem cells. MiR-29a promotes the self-renewal capacity by targeting a subset of genes that are involved in cell cycle progression, including CDC42EP2 and HBP1. Recently, Lechman et al. demonstrated that miR-126 can control the cell cycle progression by targeting the PI3K/AKT/MTOR pathway. They showed that overexpression of miR-126 results in an increased percentage of quiescent cells, whereas a knockdown of miR-126 lead to enhanced proliferation and differentiation of HSCs.

Additionally, previous studies have suggested miR-125 and miR-126 as potential target treatment for acute myeloid leukemia (AML). An indication for the potential therapeutic function is based on the alternated expression of these miRNAs between CD34+ CD38− HSC and CD34+ CD38− leukemic stem cells. A reduction of miR-126 stimulates the PI3K/AKT/MTOR pathway in HSCs and will result in an increased number of HSCs, while this effect decreases the self-renewal capacity in CD34+ CD38− leukemic stem cells. Although this miRNA-based treatment holds promising capacity to in vivo experiments, issues with respect to toxicity and delivery need to be solved before application in AML patients.

Mesenchymal stem cells (MSCs) are multipotent cells that originate from bone marrow stroma, but are present in various tissues such as adipose tissue, bone, skeletal muscle, cartilage and tendon. Evidence suggests that miRNAs are closely involved in the regulation of MSC differentiation into specific cell lineages. The role of miRNAs in proliferation and cell cycle regulation of human MSCs has been investigated through Drosha and Dicer knockdown studies. These studies have shown a significant increase in the number of cells in G1 phase and a reduced proliferation rate of MSCs. In the same study, Drosha knockdown in MSCs resulted in a decrease of pRb and an increase in p16 and p15 levels. Other studies have been implicated miR-16 and miR-143 in the regulation of MSC proliferation and differentiation. In this regard, miR-16 has been shown to inhibit MSC proliferation and induce cell cycle arrest by targeting cyclin E. Likewise, miR-143 targets ERK5 (member of MAPK family), which itself decreases the expression of cyclin D and CDK6. This reduces cell entry into S phase, suggesting miR-143 to be a negative regulator of the cell cycle progression. Moreover, a number of miRNAs have determined to control the differentiation into specific linages, such as osteoblasts. For example, Peng et al. demonstrated that miRNAs promote the osteogenic differentiation of MSCs via BMP, WNT/β-catenin and NOTCH signaling pathways. Among them, miR-27 promotes differentiation by targeting APC, which modulates the G2/M transition. On the other hand, miR-27 expression is shown to be downregulated upon adipocyte differentiation. Several cell cycle associated genes, including ERK1/2, ERK5, TGF-β1 and KLF5 are related to adipocyte differentiation, which is explained by miRNA regulation. Notably, miR-143, miR-448 and miR-375 have been reported as negative regulators and miR-21 as positive regulator of adipocyte differentiation.

Cancer Stem Cells (CSCs)

Altered expression and molecular abnormalities of the cell-cycle-regulatory proteins, such as pRB, p53, CDKs, CDKIs and cyclins, play a central role in cancer initiation and progression. Notably, it has been suggested that a class of cancer cells with characteristics of stem cells, so-called cancer stem cells (CSCs), are responsible for tumor initiation, invasion, metastasis and chemoresistance. As discussed previously in this review, miRNAs have the ability to suppress apoptosis and promote proliferation by interplaying with the cell cycle components. Therefore, miRNAs and CSCs share common properties with respect to tumorigenesis. The transcriptional levels of several miRNAs have shown to vary between normal stem cells and CSCs. Furthermore, associations between either cell cycle components including cyclins and transcription factors or miRNA expression and specific CSC markers have been investigated. Hence, miRNAs as regulators of CSCs have gain attention in recent years in multiple fields of research. The associations between miRNAs expression and various cancers are summarized in Table 2. In the following paragraph, some of the main CSC-related miRNAs will be discussed.

The miR-17-92 cluster affects the cell cycle by targeting E2F-1 and cyclin D as well as it cooperates with the oncogene MYC to prevent apoptosis in CSCs. Li et al. investigated the miR-17-92 target genes involved in the MYC suppression. They demonstrated that the functionalities of the miR-17-92 target genes rely on multiple DNA replication, cell cycle regulation, chromosome organization, RNA transcription or protein metabolism. Similarly, this miRNA cluster is shown to coordinate the timing of cell cycle progression by modulating expression of BMI1, PTEN, RBL2 and p21.

Other important regulators of CSCs are the members of the let-7 family. Evidence suggests that let-7 is among the most important miRNAs involved in tumor progression and chemoresistance. The expression of the let-7 family is reduced in various types of tumor cells, including breast, head and neck squamous (HNSCC), lung, pancreatic, neuroblastoma cells, among others. Accordingly, decreased expression of let-7 has resulted in overexpression of oncogenes MYC, RAS, HMGA2 and BLIMP1. Furthermore, members of the let-7 family have been recognized as negative regulators of PTEN that inactivate the PI3K/AKT/MTOR pathway. The let-7 family has also shown to be involved in suppressing the epithelial-to-mesenchymal transition (EMT), which is related to metastasis and chemoresistance and therefore a characteristic of CSCs. Multiple genes involved in cell cycle progression are suggested to be targets for the let-7 family. The latter include cyclin D, cyclin A, CDK1, CDK2, CDK4, CDK6, CDK8 and CDC25A. Also, it has been shown that the RNA binding protein LIN28 inhibits let-7 by stimulating cellular proliferation via cyclin D, CDK2 and CDC25A and thereby contribute to the maintenance of stemness characteristics of CSCs. LIN28 has been recognized as an oncogene, as it promotes tumor progression by repressing let-7. Previous studies based on let-7 expression and tumor progression display that ectopic expression of let-7 was sufficient enough to inhibit proliferation and clonal expansion in vitro and tumor recurrence in prostate cancer cells in vivo.

The next miRNA family, consisting of miR-34a, b, and c, is well-studied regarding to cell cycle progression and its expression is downregulated in several types of cancer cells including lung adenocarcinomas, colon cancer and liver cancer (HCC). MiR-34a induces both G1/S cell cycle arrest and cell senescence. Reduced expression of miR-34 has been associated with enhanced levels of BCL2 and NOTCH, which are target genes for tumor suppressor gene p53. Similarity, miR-34 promotes apoptosis via Caspase 3, and therefore increases sensitivity for anti-cancer treatment. By regulating CDK6, cyclin D1 and E2F, miR-34 negatively affects cell cycle progression in colon cancer cells. In addition, miR-34 represses pluripotency genes inclusive of NANOG, SOX2 and MYC. Thus, overexpression of this miRNA family may cause an accumulated percentage of cells in the G0/G1 phase and significantly reduces the population of cells in the S phase.

MiR-31 has also shown to be inversely correlated with metastasis, since its high expression in liver cancer is linked with a poor prognosis in patients. Kim et al. showed that ectopic expression of miR-31 evokes an overexpression of CDK2 and HDAC2. They demonstrated that through abnormal expression of HDAC2, negative cell cycle regulators p16/INK4A, p19/INK4D and p21/Cip1 are induced.

Furthermore, an oncogenic role has been reported for the miR-15a/16 family in chronic lymphocytic leukemia (CLL), pituitary adenomas, and gastric cancer. On the other hand, this miRNA family is shown to act as a tumor suppressor in a subset of B cell lymphoma, where deletion of this miRNA family in a subset of B cell lymphomas resulted in chronic lymphocytic leukemia in mice. In fact, miR-15a and miR-16 display an anti-proliferative potential in this type of cancer stem cell by silencing BCL2 and activating the intrinsic apoptosis pathway. In addition, some studies revealed the miR-15a/16 family as regulator of various cyclins, including cyclins D1 and D2 and cyclin E1, and pRb.

An additional miRNA that has been suggested as an oncomiR, through targeting multiple signaling pathways, is miR-21. Upregulation of miR-21 has an oncogenic potential in a wide range of tumors including lung, breast, pancreatic, brain and colon cancers, through downregulation of p21 and tumor suppressor genes PTEN and PDCD4. MiR-26a is also suggested as a negative regulator of cancer cell proliferation by targeting cyclins D2 and E2, and CDK6. It has been established that overexpression of miR-26a results in cell cycle arrest in human liver cancer cells in vitro.

Concluding Remarks and Future Prospects

A growing body of evidence has addressed the potential role of miRNAs in cell cycle regulation of stem cells. In light of recent discoveries about the role miRNAs in self-renewal, proliferation and differentiation, it is crucial to unravel the complex mechanisms and molecular interactions within this field of research. In this review, we outlined the most established miRNAs involved in the cell cycle progression of stem cells. We highlighted several clusters and single miRNAs that may control self-renewal and maintenance of the pluripotency status in ESCs. These include but are not limited to ESCC miRNAs (miR-290-295, miR-302, miR-17-92, miR-106b-25 and miR-106a-363), which are functionally upregulated to suppress negative regulators and to enhance pluripotent transcription factors such as NANOG and MYC in an epigenetic manner.

Furthermore, specific profiles of miRNA expression in distinct somatic stem cell lineages are linked with developmental control by keeping several multipotent stem cells (e.g. HSCs) in a quiescent state. Previous research based on Dicer-knockout and Dgcr8-deficient mice have elucidated that miRNAs are expressed temporally and spatially among somatic stem cells and precursor cells. It is crucial for somatic stem cells like HSCs to keep a balance between quiescent state and proliferating state. To accomplish that, a complex network of miRNAs exists that inhibit positive cell cycle regulators such as cyclins, as well as miRNAs modulating anti-apoptotic properties. Complex interactions between miRNAs, transcription factors and cell cycle-mediated components may control the gene expression upon differentiation of multipotent stem cells into progenitor cells and mature cells.

It is clear that abnormalities in the cell cycle are related to tumorigenesis and previous studies have highlighted the significant importance of miRNAs in the regulation of CSCs. Since CSC features are linked to metastasis, invasion and therapeutic resistance, it is of main clinical relevance to unravel the interactive properties between CSC-related miRNAs and cell cycle components. From the data available so far it appears that there is a great overlapping role between ESCC miRNAs that are expressed in both ESCs and CSCs. However, a subset of miRNAs is characterized as tumor suppressor genes as they are expressed regarding anti-proliferating features by targeting oncogenic pathways including MYC. Those miRNAs, including let-7, miR-34, miR-31 and miR-17-92 family, are of major interest since they are associated with a good prognosis in cancer patients. Future research should focus on targeting the CSC-related miRNAs involved in oncogenic pathways since they will provide a more effective approach to exterminate CSCs. Subsequently, a miRNA based method for cancer treatment is highly target driven as it interferes with specific abnormalities in the cell cycle within the tumor microenvironment.

Collectively, this review marks several noteworthy insights into the cell cycle regulation of stem cells by miRNAs. Understanding the tightly regulated molecular networks in which miRNAs are interacting, will greatly enhance our knowledge in the development of both healthy and disease states of the human body.

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  14. 14.

    Fabbro M, et al. BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage. The Journal of Biological Chemistry. 2004;279(30):31251-31258.

    Not in our library10.1074/jbc.m405372200

  15. 15.

    Hyun SY, Jang YJ. p53 activates G(1) checkpoint following DNA damage by doxorubicin during transient mitotic arrest. Oncotarget. 2015;6(7):4804-4815.

    Not in our library10.18632/oncotarget.3103

  16. 16.

    Lanni JS, Jacks T. Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Molecular and Cellular Biology. 1998;18(2):1055-1064.

    Not in our library10.1128/mcb.18.2.1055

  17. 17.

    Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression. Nature Reviews Cancer. 2014;14(5):359-370.

    Not in our library10.1038/nrc3711

  18. 18.
    p53 Regulates Cell Cycle and MicroRNAs to Promote Differentiation of Human Embryonic Stem Cells · 2012
    No notice
  19. 19.

    Bueno MJ, Malumbres M. MicroRNAs and the cell cycle. Biochimica et Biophysica Acta. 2011;1812(5):592-601.

    Not in our library10.1016/j.bbadis.2011.02.002

  20. 20.

    Wang Y, Blelloch R. Cell cycle regulation by MicroRNAs in embryonic stem cells. Cancer Research. 2009;69(10):4093-4096.

    Not in our library10.1158/0008-5472.can-09-0309

  21. 21.

    Wang Y, Blelloch R. Cell cycle regulation by microRNAs in stem cells. Results and Problems in Cell Differentiation. 2011;53:459-472.

    Not in our library10.1007/978-3-642-19065-0_19

  22. 22.

    Yu Z, et al. miRNAs regulate stem cell self-renewal and differentiation. Frontiers in Genetics. 2012;3:191.

    Not in our library10.3389/fgene.2012.00191

  23. 23.

    Braun CJ, et al. p53-Responsive micrornas 192 and 215 are capable of inducing cell cycle arrest. Cancer Research. 2008;68(24):10094-10104.

    Not in our library10.1158/0008-5472.can-08-1569

  24. 24.

    Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843-854.

    Not in our library10.1016/0092-8674(93)90529-y

  25. 25.
    miRBase: annotating high confidence microRNAs using deep sequencing data · 2013
    No notice
  26. 26.

    Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nature Reviews Cancer. 2006;6(4):259-269.

    Not in our library10.1038/nrc1840

  27. 27.

    van Rooij E, Olson EN. MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nature Reviews Drug Discovery. 2012;11(11):860-872.

    Not in our library10.1038/nrd3864

  28. 28.

    Ghanbari M, et al. A genetic variant in the seed region of miR-4513 shows pleiotropic effects on lipid and glucose homeostasis, blood pressure, and coronary artery disease. Human Mutation. 2014;35(12):1524-1531.

    Not in our library10.1002/humu.22706

  29. 29.

    van Rooij E, et al. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(48):18255-18260.

    Not in our library10.1073/pnas.0608791103

  30. 30.

    Goren Y, et al. Serum levels of microRNAs in patients with heart failure. European Journal of Heart Failure. 2012;14(2):147-154.

    Not in our library10.1093/eurjhf/hfr155

  31. 31.

    Karolina DS, et al. Circulating miRNA profiles in patients with metabolic syndrome. The Journal of Clinical Endocrinology and Metabolism. 2012;97(12):E2271-6.

    Not in our library10.1210/jc.2012-1996

  32. 32.

    Ghanbari M, et al. Genetic variations in microRNA-binding sites affect microRNA-mediated regulation of several genes associated with cardio-metabolic phenotypes. Circulation Cardiovascular Genetics. 2015;8(3):473-486.

    Not in our library10.1161/circgenetics.114.000968

  33. 33.

    Malumbres M. miRNAs and cancer: an epigenetics view. Molecular Aspects of Medicine. 2013;34(4):863-874.

    Not in our library10.1016/j.mam.2012.06.005

  34. 34.

    Reinhart BJ, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000;403(6772):901-906.

    Not in our library10.1038/35002607

  35. 35.

    Shim J, Nam JW. The expression and functional roles of microRNAs in stem cell differentiation. BMB Reports. 2016;49(1):3-10.

    Not in our library10.5483/bmbrep.2016.49.1.217

  36. 36.

    Huang XA, Lin H. The miRNA regulation of stem cells. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 2012;1(1):83-95.

    Not in our library10.1002/wdev.5

  37. 37.

    Wang Y, et al. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nature Genetics. 2007;39(3):380-385.

    Not in our library10.1038/ng1969

  38. 38.

    Bernstein E, et al. Dicer is essential for mouse development. Nature Genetics. 2003;35(3):215-217.

    Not in our library10.1038/ng1253

  39. 39.

    Dalton S. Exposing hidden dimensions of embryonic stem cell cycle control. Cell Stem Cell. 2009;4(1):9-10.

    Not in our library10.1016/j.stem.2008.12.003

  40. 40.

    Stein GS, et al. An architectural perspective of cell-cycle control at the G1/S phase cell-cycle transition. Journal of Cellular Physiology. 2006;209(3):706-710.

    Not in our library10.1002/jcp.20843

  41. 41.

    Sengupta S, et al. MicroRNA 92b controls the G1/S checkpoint gene p57 in human embryonic stem cells. Stem Cells. 2009;27(7):1524-1528.

    Not in our library10.1002/stem.84

  42. 42.

    Kareta MS, et al. Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis. Cell Stem Cell. 2015;16(1):39-50.

    Not in our library10.1016/j.stem.2014.10.019

  43. 43.

    Becker KA, et al. Self-renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase. Journal of Cellular Physiology. 2006;209(3):883-893.

    Not in our library10.1002/jcp.20776

  44. 44.

    Hao J, Duan FF, Wang Y. MicroRNAs and RNA binding protein regulators of microRNAs in the control of pluripotency and reprogramming. Current Opinion in Genetics & Development. 2017;46:95-103.

    Not in our library10.1016/j.gde.2017.07.001

  45. 45.

    Li N, et al. microRNAs: important regulators of stem cells. Stem Cell Research & Therapy. 2017;8(1):110.

    Not in our library10.1186/s13287-017-0551-0

  46. 46.

    Lichner Z, et al. The miR-290-295 cluster promotes pluripotency maintenance by regulating cell cycle phase distribution in mouse embryonic stem cells. Differentiation. 2011;81(1):11-24.

    Not in our library10.1016/j.diff.2010.08.002

  47. 47.

    Yuan, K., et al. (2017). The miR-290-295 cluster as multi-faceted players in mouse embryonic stem cells. Cell & Bioscience, 7(38).

    Not in our library10.1186/s13578-017-0166-2

  48. 48.

    Wang Y, et al. Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nature Genetics. 2008;40(12):1478-1483.

    Not in our library10.1038/ng.250

  49. 49.

    Calabrese JM, et al. RNA sequence analysis defines Dicer’s role in mouse embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(46):18097-18102.

    Not in our library10.1073/pnas.0709193104

  50. 50.

    Houbaviy HB, Murray MF, Sharp PA. Embryonic stem cell-specific microRNAs. Developmental Cell. 2003;5(2):351-358.

    Not in our library10.1016/s1534-5807(03)00227-2

  51. 51.

    Li Y, et al. MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state. Cancer Cell. 2014;26(2):262-272.

    Not in our library10.1016/j.ccr.2014.06.014

  52. 52.

    Melton C, Judson RL, Blelloch R. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature. 2010;463(7281):621-626.

    Not in our library10.1038/nature08725

  53. 53.

    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663-676.

    Not in our library10.1016/j.cell.2006.07.024

  54. 54.

    Zheng GX, et al. A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells. PLoS Genet. 2011;7(5):e1002054.

    Not in our library10.1371/journal.pgen.1002054

  55. 55.

    Kanellopoulou C, et al. Reprogramming of polycomb-mediated gene silencing in embryonic stem cells by the miR-290 family and the methyltransferase Ash1l. Stem Cell Reports. 2015;5(6):971-978.

    Not in our library10.1016/j.stemcr.2015.10.001

  56. 56.

    Richly H, Aloia L, Di Croce L. Roles of the Polycomb group proteins in stem cells and cancer. Cell Death & Disease. 2011;2:e204.

    Not in our library10.1038/cddis.2011.84

  57. 57.

    Aguda BD, et al. MicroRNA regulation of a cancer network: consequences of the feedback loops involving miR-17-92, E2F, and Myc. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(50):19678-19683.

    Not in our library10.1073/pnas.0811166106

  58. 58.

    Ivanovska I, et al. MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. Molecular and Cellular Biology. 2008;28(7):2167-2174.

    Not in our library10.1128/mcb.01977-07

  59. 59.

    Kuo CH, et al. A novel role of miR-302/367 in reprogramming. Biochemical and Biophysical Research Communications. 2012;417(1):11-16.

    Not in our library10.1016/j.bbrc.2011.11.058

  60. 60.

    Card DA, et al. Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells. Molecular and Cellular Biology. 2008;28(20):6426-6438.

    Not in our library10.1128/mcb.00359-08

  61. 61.

    Anokye-Danso F, et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell. 2011;8(4):376-388.

    Not in our library10.1016/j.stem.2011.03.001

  62. 62.

    Lipchina I, Studer L, Betel D. The expanding role of miR-302-367 in pluripotency and reprogramming. Cell Cycle. 2012;11(8):1517-1523.

    Not in our library10.4161/cc.19846

  63. 63.

    Dolezalova D, et al. MicroRNAs regulate p21(Waf1/Cip1) protein expression and the DNA damage response in human embryonic stem cells. Stem Cells. 2012;30(7):1362-1372.

    Not in our library10.1002/stem.1108

  64. 64.

    Liang Y, et al. Mechanism of folate deficiency-induced apoptosis in mouse embryonic stem cells: Cell cycle arrest/apoptosis in G1/G0 mediated by microRNA-302a and tumor suppressor gene Lats2. The International Journal of Biochemistry & Cell Biology. 2012;44(11):1750-1760.

    Not in our library10.1016/j.biocel.2012.07.014

  65. 65.

    Fu, Y., et al. (2017). Characterization and expression of lin-28a involved in lin28/let-7signal pathway during early development of P. olivaceus. Fish Physiol Biochem.

    Not in our library10.1007/s10695-017-0445-1

  66. 66.

    Rybak A, et al. A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Nature Cell Biology. 2008;10(8):987-993.

    Not in our library10.1038/ncb1759

  67. 67.

    Qi J, et al. microRNAs regulate human embryonic stem cell division. Cell Cycle. 2009;8(22):3729-3741.

    Not in our library10.4161/cc.8.22.10033

  68. 68.

    Bhattacharya A, et al. Regulation of cell cycle checkpoint kinase WEE1 by miR-195 in malignant melanoma. Oncogene. 2013;32(26):3175-3183.

    Not in our library10.1038/onc.2012.324

  69. 69.

    Shenoy A, Blelloch RH. Regulation of microRNA function in somatic stem cell proliferation and differentiation. Nature Reviews Molecular Cell Biology. 2014;15(9):565-576.

    Not in our library10.1038/nrm3854

  70. 70.

    Arnold CP, et al. MicroRNA programs in normal and aberrant stem and progenitor cells. Genome Research. 2011;21(5):798-810.

    Not in our library10.1101/gr.111385.110

  71. 71.

    Andersson T, et al. Reversible block of mouse neural stem cell differentiation in the absence of dicer and microRNAs. PLoS One. 2010;5(10):e13453.

    Not in our library10.1371/journal.pone.0013453

  72. 72.

    Wang D, et al. MicroRNA-205 controls neonatal expansion of skin stem cells by modulating the PI(3)K pathway. Nature Cell Biology. 2013;15(10):1153-1163.

    Not in our library10.1038/ncb2827

  73. 73.

    Jackson SJ, et al. Rapid and widespread suppression of self-renewal by microRNA-203 during epidermal differentiation. Development. 2013;140(9):1882-1891.

    Not in our library10.1242/dev.089649

  74. 74.

    Antonini D, et al. Transcriptional repression of miR-34 family contributes to p63-mediated cell cycle progression in epidermal cells. The Journal of Investigative Dermatology. 2010;130(5):1249-1257.

    Not in our library10.1038/jid.2009.438

  75. 75.

    Nagosa S, et al. microRNA-184 induces a commitment switch to epidermal differentiation. Stem Cell Reports. 2017;9(6):1991-2004.

    Not in our library10.1016/j.stemcr.2017.10.030

  76. 76.

    Ahmed MI, et al. MicroRNA-214 controls skin and hair follicle development by modulating the activity of the Wnt pathway. The Journal of Cell Biology. 2014;207(4):549-567.

    Not in our library10.1083/jcb.201404001

  77. 77.

    Zhao C, et al. A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nature Structural and Molecular Biology. 2009;16(4):365-371.

    Not in our library10.1038/nsmb.1576

  78. 78.

    Sun G, et al. miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nature Communications. 2011;2:529.

    Not in our library10.1038/ncomms1532

  79. 79.

    Liu C, et al. Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell. 2010;6(5):433-444.

    Not in our library10.1016/j.stem.2010.02.017

  80. 80.

    Liu C, et al. An epigenetic feedback regulatory loop involving microRNA-195 and MBD1 governs neural stem cell differentiation. PLoS One. 2013;8(1):e51436.

    Not in our library10.1371/journal.pone.0051436

  81. 81.

    Cheng LC, et al. miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nature Neuroscience. 2009;12(4):399-408.

    Not in our library10.1038/nn.2294

  82. 82.

    Makeyev EV, et al. The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Molecular Cell. 2007;27(3):435-448.

    Not in our library10.1016/j.molcel.2007.07.015

  83. 83.

    Visvanathan J, et al. The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes and Development. 2007;21(7):744-749.

    Not in our library10.1101/gad.1519107

  84. 84.

    Liu Z, et al. Elevated p53 activities restrict differentiation potential of microRNA-deficient pluripotent stem cells. Stem Cell Reports. 2017;9(5):1604-1617.

    Not in our library10.1016/j.stemcr.2017.10.006

  85. 85.
    miR-148b Regulates Proliferation and Differentiation of Neural Stem Cells via Wnt/β-Catenin Signaling in Rat Ischemic Stroke Model · 2017
    Not checked
  86. 86.

    Wang J, et al. MicroRNA1385p regulates neural stem cell proliferation and differentiation in vitro by targeting TRIP6 expression. Molecular Medicine Reports. 2017;16(5):7261-7266.

    Not in our library10.3892/mmr.2017.7504

  87. 87.

    Crist CG, et al. Muscle stem cell behavior is modified by microRNA-27 regulation of Pax3 expression. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(32):13383-13387.

    Not in our library10.1073/pnas.0900210106

  88. 88.

    Sarkar S, Dey BK, Dutta A. MiR-322/424 and –503 are induced during muscle differentiation and promote cell cycle quiescence and differentiation by down-regulation of Cdc25A. Molecular Biology of the Cell. 2010;21(13):2138-2149.

    Not in our library10.1091/mbc.e10-01-0062

  89. 89.

    Chen JF, et al. microRNA-1 and microRNA-206 regulate skeletal muscle satellite cell proliferation and differentiation by repressing Pax7. The Journal of Cell Biology. 2010;190(5):867-879.

    Not in our library10.1083/jcb.200911036

  90. 90.

    Dai Y, et al. The role of microRNA-1 and microRNA-206 in the proliferation and differentiation of bovine skeletal muscle satellite cells. In Vitro Cellular and Developmental Biology - Animal. 2016;52(1):27-34.

    Not in our library10.1007/s11626-015-9953-4

  91. 91.

    Han X, et al. Malat1 regulates serum response factor through miR-133 as a competing endogenous RNA in myogenesis. FASEB Journal. 2015;29(7):3054-3064.

    Not in our library10.1096/fj.14-259952

  92. 92.

    Liu B, et al. miR-221 modulates skeletal muscle satellite cells proliferation and differentiation. In Vitro Cellular and Developmental Biology – Animal. 2017;54(2):147-155.

    Not in our library10.1007/s11626-017-0210-x

  93. 93.

    Zhang WR, et al. miR-143 regulates proliferation and differentiation of bovine skeletal muscle satellite cells by targeting IGFBP5. In Vitro Cellular and Developmental Biology - Animal. 2017;53(3):265-271.

    Not in our library10.1007/s11626-016-0109-y

  94. 94.

    Dey BK, Gagan J, Dutta A. miR-206 and –486 induce myoblast differentiation by downregulating Pax7. Molecular and Cellular Biology. 2011;31(1):203-214.

    Not in our library10.1128/mcb.01009-10

  95. 95.

    Mehta A, Baltimore D. MicroRNAs as regulatory elements in immune system logic. Nature Reviews Immunology. 2016;16(5):279-294.

    Not in our library10.1038/nri.2016.40

  96. 96.

    Copley MR, et al. The Lin28b-let-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells. Nature Cell Biology. 2013;15(8):916-925.

    Not in our library10.1038/ncb2783

  97. 97.

    Zhou Y, et al. Lin28b promotes fetal B lymphopoiesis through the transcription factor Arid3a. The Journal of Experimental Medicine. 2015;212(4):569-580.

    Not in our library10.1084/jem.20141510

  98. 98.

    Bissels U, Bosio A, Wagner W. MicroRNAs are shaping the hematopoietic landscape. Haematologica. 2012;97(2):160-167.

    Not in our library10.3324/haematol.2011.051730

  99. 99.
    MicroRNA profiling of the murine hematopoietic system · 2005
    No notice
  100. 100.

    Chen CZ, Lodish HF. MicroRNAs as regulators of mammalian hematopoiesis. Seminars in Immunology. 2005;17(2):155-165.

    Not in our library10.1016/j.smim.2005.01.001

  101. 101.

    Gangaraju VK, Lin H. MicroRNAs: key regulators of stem cells. Nature Reviews Molecular Cell Biology. 2009;10(2):116-125.

    Not in our library10.1038/nrm2621

  102. 102.

    Sun J, et al. Clonal dynamics of native haematopoiesis. Nature. 2014;514(7522):322-327.

    Not in our library10.1038/nature13824

  103. 103.

    Liu L, et al. Homing and long-term engraftment of long- and short-term renewal hematopoietic stem cells. PLoS One. 2012;7(2):e31300.

    Not in our library10.1371/journal.pone.0031300

  104. 104.

    Crisan M, Dzierzak E. The many faces of hematopoietic stem cell heterogeneity. Development. 2016;143(24):4571-4581.

    Not in our library10.1242/dev.114231

  105. 105.

    Wojtowicz EE, et al. Ectopic miR-125a expression induces long-term repopulating stem cell capacity in mouse and human hematopoietic progenitors. Cell Stem Cell. 2016;19(3):383-396.

    Not in our library10.1016/j.stem.2016.06.008

  106. 106.

    Guo S, et al. MicroRNA miR-125a controls hematopoietic stem cell number. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(32):14229-14234.

    Not in our library10.1073/pnas.0913574107

  107. 107.

    Ooi AG, et al. MicroRNA-125b expands hematopoietic stem cells and enriches for the lymphoid-balanced and lymphoid-biased subsets. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(50):21505-21510.

    Not in our library10.1073/pnas.1016218107

  108. 108.

    Han YC, et al. microRNA-29a induces aberrant self-renewal capacity in hematopoietic progenitors, biased myeloid development, and acute myeloid leukemia. The Journal of Experimental Medicine. 2010;207(3):475-489.

    Not in our library10.1084/jem.20090831

  109. 109.

    Lechman ER, et al. miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells. Cancer Cell. 2016;29(4):602-606.

    Not in our library10.1016/j.ccell.2016.03.015

  110. 110.

    Lechman ER, et al. Attenuation of miR-126 activity expands HSC in vivo without exhaustion. Cell Stem Cell. 2012;11(6):799-811.

    Not in our library10.1016/j.stem.2012.09.001

  111. 111.

    de Leeuw DC, et al. Attenuation of microRNA-126 expression that drives CD34 + 38- stem/progenitor cells in acute myeloid leukemia leads to tumor eradication. Cancer Research. 2014;74(7):2094-2105.

    Not in our library10.1158/0008-5472.can-13-1733

  112. 112.

    Martianez Canales, T., et al. (2017). Specific depletion of leukemic stem cells: can microRNAs make the difference? Cancers (Basel),. 9(7).

    Not in our library10.3390/cancers9070074

  113. 113.

    Testa U, Pelosi E. MicroRNAs expressed in hematopoietic stem/progenitor cells are deregulated in acute myeloid leukemias. Leukemia & Lymphoma. 2015;56(5):1466-1474.

    Not in our library10.3109/10428194.2014.955019

  114. 114.

    Krampera M, et al. Mesenchymal stem cells: from biology to clinical use. Blood Transfusion. 2007;5(3):120-129.

    Not in our library10.2450/2007.0029-07

  115. 115.

    Guo L, Zhao RC, Wu Y. The role of microRNAs in self-renewal and differentiation of mesenchymal stem cells. Experimental Hematology. 2011;39(6):608-616.

    Not in our library10.1016/j.exphem.2011.01.011

  116. 116.

    Li JP, et al. MiR-214 inhibits human mesenchymal stem cells differentiating into osteoblasts through targeting beta-catenin. European Review for Medical and Pharmacological Sciences. 2017;21(21):4777-4783.

    Not in our library

  117. 117.

    Hodges, W. M., et al. (2017). Function of microRNAs in the osteogenic differentiation and therapeutic application of adipose-derived stem cells (ASCs). International Journal of Molecular Sciences, 18(12).

    Not in our library10.3390/ijms18122597

  118. 118.

    Oskowitz AZ, et al. Drosha regulates hMSCs cell cycle progression through a miRNA independent mechanism. The International Journal of Biochemistry & Cell Biology. 2011;43(11):1563-1572.

    Not in our library10.1016/j.biocel.2011.07.005

  119. 119.

    Wang Y, et al. miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia. FEBS Journal. 2012;279(24):4510-4524.

    Not in our library10.1111/febs.12037

  120. 120.

    Lai VK, et al. MicroRNA-143 is a critical regulator of cell cycle activity in stem cells with co-overexpression of Akt and angiopoietin-1 via transcriptional regulation of Erk5/cyclin D1 signaling. Cell Cycle. 2012;11(4):767-777.

    Not in our library10.4161/cc.11.4.19211

  121. 121.

    He B, et al. Upregulated microRNA-143 inhibits cell proliferation in human nasopharyngeal carcinoma. Oncology Letters. 2016;12(6):5023-5028.

    Not in our library10.3892/ol.2016.5363

  122. 122.

    Peng S, et al. MicroRNAs regulate signaling pathways in osteogenic differentiation of mesenchymal stem cells (Review). Molecular Medicine Reports. 2016;14(1):623-629.

    Not in our library10.3892/mmr.2016.5335

  123. 123.

    Park MG, et al. MicroRNA-27 promotes the differentiation of odontoblastic cell by targeting APC and activating Wnt/beta-catenin signaling. Gene. 2014;538(2):266-272.

    Not in our library10.1016/j.gene.2014.01.045

  124. 124.

    You L, et al. MiR-27a is essential for the shift from osteogenic differentiation to adipogenic differentiation of mesenchymal stem cells in postmenopausal osteoporosis. Cellular Physiology and Biochemistry. 2016;39(1):253-265.

    Not in our library10.1159/000445621

  125. 125.

    Zhu Y, et al. miR-27 inhibits adipocyte differentiation via suppressing CREB expression. Acta Biochim Biophys Sin (Shanghai). 2014;46(7):590-596.

    Not in our library10.1093/abbs/gmu036

  126. 126.

    Hamam D, et al. microRNAs as regulators of adipogenic differentiation of mesenchymal stem cells. Stem Cells Dev. 2015;24(4):417-425.

    Not in our library10.1089/scd.2014.0331

  127. 127.

    Bendris N, Lemmers B, Blanchard JM. Cell cycle, cytoskeleton dynamics and beyond: the many functions of cyclins and CDK inhibitors. Cell Cycle. 2015;14(12):1786-1798.

    Not in our library10.1080/15384101.2014.998085

  128. 128.

    Manning AL, Dyson NJ. RB: mitotic implications of a tumour suppressor. Nature Reviews Cancer. 2012;12(3):220-226.

    Not in our library10.1038/nrc3216

  129. 129.

    Thangavel C, et al. RB loss promotes prostate cancer metastasis. Cancer Research. 2017;77(4):982-995.

    Not in our library10.1158/0008-5472.can-16-1589

  130. 130.

    Bai X, et al. MicroRNA-142-5p induces cancer stem cell-like properties of cutaneous squamous cell carcinoma via inhibiting PTEN. Journal of Cellular Biochemistry. 2017;119(2):2179-2188.

    Not in our library10.1002/jcb.26379

  131. 131.

    Bao B, et al. Targeting CSC-related miRNAs for cancer therapy by natural agents. Current Drug Targets. 2012;13(14):1858-1868.

    Not in our library10.2174/138945012804545515

  132. 132.

    Lavon I, et al. Gliomas display a microRNA expression profile reminiscent of neural precursor cells. Neuro-Oncology. 2010;12(5):422-433.

    Not in our library10.1093/neuonc/nop061

  133. 133.

    Vira D, et al. Cancer stem cells, microRNAs, and therapeutic strategies including natural products. Cancer Metastasis Reviews. 2012;31(3–4):733-751.

    Not in our library10.1007/s10555-012-9382-8

  134. 134.

    Xia W, et al. Smad inhibitor induces CSC differentiation for effective chemosensitization in cyclin D1- and TGF-beta/Smad-regulated liver cancer stem cell-like cells. Oncotarget. 2017;8(24):38811-38824.

    Not in our library10.18632/oncotarget.16402

  135. 135.

    Garg M. Emerging role of microRNAs in cancer stem cells: Implications in cancer therapy. World Journal of Stem Cells. 2015;7(8):1078-1089.

    Not in our library10.4252/wjsc.v7.i8.1078

  136. 136.

    Xu, Y. F., Hannafon, B. N., & Ding, W. Q. (2017). microRNA regulation of human pancreatic cancer stem cells. Stem Cell Investigation, 4(5).

    Not in our library10.21037/sci.2017.01.01

  137. 137.
    H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance · 2017
    Corrected
  138. 138.

    Liu X, et al. The regulation and function of miR-21-FOXO3a-miR-34b/c signaling in breast cancer. International Journal of Molecular Sciences. 2015;16(2):3148-3162.

    Not in our library10.3390/ijms16023148

  139. 139.

    Li B, et al. miR-221/222 promote cancer stem-like cell properties and tumor growth of breast cancer via targeting PTEN and sustained Akt/NF-kappaB/COX-2 activation. Chemico-Biological Interactions. 2017;277:33-42.

    Not in our library10.1016/j.cbi.2017.08.014

  140. 140.
    MicroRNA93 Regulates Proliferation and Differentiation of Normal and Malignant Breast Stem Cells · 2012
    No notice
  141. 141.

    Engkvist ME, et al. Analysis of the miR-34 family functions in breast cancer reveals annotation error of miR-34b. Science Reporter. 2017;7(1):9655.

    Not in our library10.1038/s41598-017-10189-1

  142. 142.

    Patel N, et al. miR-15a/miR-16 down-regulates BMI1, impacting Ub-H2A mediated DNA repair and breast cancer cell sensitivity to doxorubicin. Science Reporter. 2017;7(1):4263.

    Not in our library10.1038/s41598-017-02800-2

  143. 143.

    Janaki Ramaiah M, et al. Epigenetic regulation of miR-200 as the potential strategy for the therapy against triple-negative breast cancer. Gene. 2017;641:248-258.

    Not in our library10.1016/j.gene.2017.10.018

  144. 144.

    Zhan MN, et al. MicroRNA-494 inhibits breast cancer progression by directly targeting PAK1. Cell Death & Disease. 2017;8(1):e2529.

    Not in our library10.1038/cddis.2016.440

  145. 145.

    Xiao Z, et al. A small-molecule modulator of the tumor-suppressor miR34a inhibits the growth of hepatocellular carcinoma. Cancer Research. 2014;74(21):6236-6247.

    Not in our library10.1158/0008-5472.can-14-0855

  146. 146.

    Li M, et al. miR-365 induces hepatocellular carcinoma cell apoptosis through targeting Bcl-2. Experimental and Therapeutic Medicine. 2017;13(5):2279-2285.

    Not in our library10.3892/etm.2017.4244

  147. 147.

    Kim HS, et al. MicroRNA-31 functions as a tumor suppressor by regulating cell cycle and epithelial-mesenchymal transition regulatory proteins in liver cancer. Oncotarget. 2015;6(10):8089-8102.

    Not in our library10.18632/oncotarget.3512

  148. 148.

    Ma, D. N., et al. (2016). MicroRNA-26a suppresses epithelial-mesenchymal transition in human hepatocellular carcinoma by repressing enhancer of zeste homolog 2. Journal of Hematology & Oncology, 9(1).

    Not in our library10.1186/s13045-015-0229-y

  149. 149.

    Sun W, et al. MicroRNA-150 suppresses cell proliferation and metastasis in hepatocellular carcinoma by inhibiting the GAB1-ERK axis. Oncotarget. 2016;7(10):11595-11608.

    Not in our library10.18632/oncotarget.7292

  150. 150.

    Yu CC, et al. MicroRNA let-7a represses chemoresistance and tumourigenicity in head and neck cancer via stem-like properties ablation. Oral Oncol. 2011;47(3):202-210.

    Not in our library10.1016/j.oraloncology.2010.12.001

  151. 151.

    Wang Y, et al. Lin28B facilitates the progression and metastasis of pancreatic ductal adenocarcinoma. Oncotarget. 2017;8(36):60414-60428.

    Not in our library10.18632/oncotarget.19578

  152. 152.

    Wang P, et al. The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL. Molecular Oncology. 2013;7(3):334-345.

    Not in our library10.1016/j.molonc.2012.10.011

  153. 153.

    Karamitopoulou E, et al. MicroRNA dysregulation in the tumor microenvironment influences the phenotype of pancreatic cancer. Modern Pathology. 2017;30(8):1116-1125.

    Not in our library10.1038/modpathol.2017.35

  154. 154.

    Cioffi M, et al. The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells. Gut. 2015;64(12):1936-1948.

    Not in our library10.1136/gutjnl-2014-308470

  155. 155.

    Kang M, et al. Concurrent treatment with simvastatin and NF-kappaB inhibitor in human castration-resistant prostate cancer cells exerts synergistic anti-cancer effects via control of the NF-kappaB/LIN28/let-7 miRNA signaling pathway. PLoS One. 2017;12(9):e0184644.

    Not in our library10.1371/journal.pone.0184644

  156. 156.

    Nabavi N, et al. miR-100-5p inhibition induces apoptosis in dormant prostate cancer cells and prevents the emergence of castration-resistant prostate cancer. Science Reporter. 2017;7(1):4079.

    Not in our library10.1038/s41598-017-03731-8

  157. 157.

    Liu C, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nature Medicine. 2011;17(2):211-215.

    Not in our library10.1038/nm.2284

  158. 158.

    Galardi S, et al. miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. The Journal of Biological Chemistry. 2007;282(32):23716-23724.

    Not in our library10.1074/jbc.m701805200

  159. 159.

    Silber J, et al. Expression of miR-124 inhibits growth of medulloblastoma cells. Neuro-Oncology. 2013;15(1):83-90.

    Not in our library10.1093/neuonc/nos281

  160. 160.

    Tamim S, et al. Genomic analyses reveal broad impact of miR-137 on genes associated with malignant transformation and neuronal differentiation in glioblastoma cells. PLoS One. 2014;9(1):e85591.

    Not in our library10.1371/journal.pone.0085591

  161. 161.

    Nie X, Lin Y, Yang X, Guo L, Que S, Li X, Ge J, Wang G, Xiong W, Guo P, Qiu Y. IDH1R132H decreases the proliferation of U87 glioma cells through upregulation of microRNA-128a. Molecular Medicine Reports. 2015;12(5):6695-6701.

    Not in our library10.3892/mmr.2015.4241

  162. 162.

    Geng J, et al. Methylation mediated silencing of miR-23b expression and its role in glioma stem cells. Neuroscience Letters. 2012;528(2):185-189.

    Not in our library10.1016/j.neulet.2012.08.055

  163. 163.

    Shi L, et al. Functional differences of miR-125b on the invasion of primary glioblastoma CD133-negative cells and CD133-positive cells. Neuromolecular Medicine. 2012;14(4):303-316.

    Not in our library10.1007/s12017-012-8188-8

  164. 164.

    Rupaimoole R, Slack FJ. A role for miR-34 in colon cancer stem cell homeostasis. Stem Cell Investigation. 2016;3:42.

    Not in our library10.21037/sci.2016.08.04

  165. 165.

    Ye Y, et al. microRNA-605 promotes cell proliferation, migration and invasion in non-small cell lung cancer by directly targeting LATS2. Experimental and Therapeutic Medicine. 2017;14(1):867-873.

    Not in our library10.3892/etm.2017.4538

  166. 166.

    Yang G, et al. MicroRNA let-7: regulation, single nucleotide polymorphism, and therapy in lung cancer. Journal of Cancer Research and Therapeutics. 2015;11(Suppl 1):C1-6.

    Not in our library10.4103/0973-1482.163830

  167. 167.

    Okada N, et al. A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression. Genes & Development. 2014;28(5):438-450.

    Not in our library10.1101/gad.233585.113

  168. 168.

    Bandi N, et al. miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer. Cancer Research. 2009;69(13):5553-5559.

    Not in our library10.1158/0008-5472.can-08-4277

  169. 169.

    O’Donnell KA, et al. c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005;435(7043):839-843.

    Not in our library10.1038/nature03677

  170. 170.

    Sylvestre Y, et al. An E2F/miR-20a autoregulatory feedback loop. The Journal of Biological Chemistry. 2007;282(4):2135-2143.

    Not in our library10.1074/jbc.m608939200

  171. 171.

    Pickering MT, Stadler BM, Kowalik TF. miR-17 and miR-20a temper an E2F1-induced G1 checkpoint to regulate cell cycle progression. Oncogene. 2009;28(1):140-145.

    Not in our library10.1038/onc.2008.372

  172. 172.

    Yu Z, et al. A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation. The Journal of Cell Biology. 2008;182(3):509-517.

    Not in our library10.1083/jcb.200801079

  173. 173.

    Babashah S, Soleimani M. The oncogenic and tumour suppressive roles of microRNAs in cancer and apoptosis. European Journal of Cancer. 2011;47(8):1127-1137.

    Not in our library10.1016/j.ejca.2011.02.008

  174. 174.

    Mu P, et al. Genetic dissection of the miR-17 ~ 92 cluster of microRNAs in Myc-induced B-cell lymphomas. Genes & Development. 2009;23(24):2806-2811.

    Not in our library10.1101/gad.1872909

  175. 175.

    Olive V, Jiang I, He L. mir-17-92, a cluster of miRNAs in the midst of the cancer network. Int J Biochem Cell Biol. 2010;42(8):1348-1354.

    Not in our library10.1016/j.biocel.2010.03.004

  176. 176.

    Wong P, et al. The miR-17-92 microRNA polycistron regulates MLL leukemia stem cell potential by modulating p21 expression. Cancer Research. 2010;70(9):3833-3842.

    Not in our library10.1158/0008-5472.can-09-3268

  177. 177.
    The LIN28/let-7 Pathway in Cancer · 2017
    No notice
  178. 178.

    Jakymiw A, et al. Overexpression of dicer as a result of reduced let-7 microRNA levels contributes to increased cell proliferation of oral cancer cells. Genes, Chromosomes & Cancer. 2010;49(6):549-559.

    Not in our library10.1002/gcc.20765

  179. 179.

    Li XX, et al. Reduced expression levels of let-7c in human breast cancer patients. Oncology Letters. 2015;9(3):1207-1212.

    Not in our library10.3892/ol.2015.2877

  180. 180.

    Bueno MJ, et al. Combinatorial effects of microRNAs to suppress the Myc oncogenic pathway. Blood. 2011;117(23):6255-6266.

    Not in our library10.1182/blood-2010-10-315432

  181. 181.

    Lewis BP, et al. Prediction of mammalian microRNA targets. Cell. 2003;115(7):787-798.

    Not in our library10.1016/s0092-8674(03)01018-3

  182. 182.

    Bommer GT, et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Current Biology. 2007;17(15):1298-1307.

    Not in our library10.1016/j.cub.2007.06.068

  183. 183.

    He L, et al. A microRNA component of the p53 tumour suppressor network. Nature. 2007;447(7148):1130-1134.

    Not in our library10.1038/nature05939

  184. 184.

    Tazawa H, et al. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(39):15472-15477.

    Not in our library10.1073/pnas.0707351104

  185. 185.

    Sun F, et al. Downregulation of CCND1 and CDK6 by miR-34a induces cell cycle arrest. FEBS Letters. 2008;582(10):1564-1568.

    Not in our library10.1016/j.febslet.2008.03.057

  186. 186.

    Calin GA, et al. MiR-15a and miR-16-1 cluster functions in human leukemia. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(13):5166-5171.

    Not in our library10.1073/pnas.0800121105

  187. 187.

    Bottoni A, et al. miR-15a and miR-16-1 down-regulation in pituitary adenomas. Journal of Cellular Physiology. 2005;204(1):280-285.

    Not in our library10.1002/jcp.20282

  188. 188.

    Klein U, et al. The DLEU2/miR-15a/16 – 1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell. 2010;17(1):28-40.

    Not in our library10.1016/j.ccr.2009.11.019

  189. 189.

    Calin GA, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(24):15524-15529.

    Not in our library10.1073/pnas.242606799

  190. 190.

    Cimmino A, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(39):13944-13949.

    Not in our library10.1073/pnas.0506654102

  191. 191.

    Linsley PS, et al. Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Molecular and Cellular Biology. 2007;27(6):2240-2252.

    Not in our library10.1128/mcb.02005-06

  192. 192.

    Asangani IA, et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27(15):2128-2136.

    Not in our library10.1038/sj.onc.1210856

  193. 193.

    Frankel LB, et al. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. The Journal of Biological Chemistry. 2008;283(2):1026-1033.

    Not in our library10.1074/jbc.m707224200

  194. 194.

    Meng F, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133(2):647-658.

    Not in our library10.1053/j.gastro.2007.05.022

  195. 195.

    Chen L, et al. Tumor-specific expression of microRNA-26a suppresses human hepatocellular carcinoma growth via cyclin-dependent and -independent pathways. Molecular Therapy. 2011;19(8):1521-1528.

    Not in our library10.1038/mt.2011.64

  196. 196.

    Zhu Y, et al. MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein. Nucleic Acids Research. 2012;40(10):4615-4625.

    Not in our library10.1093/nar/gkr1278

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