The miR-290-295 cluster as multi-faceted players in mouse embryonic stem cells
© The Author(s) 2017
Received: 12 June 2017
Accepted: 1 August 2017
Published: 7 August 2017
Increasing evidence indicates that embryonic stem cell specific microRNAs (miRNAs) play an essential role in the early development of embryo. Among them, the miR-290-295 cluster is the most highly expressed in the mouse embryonic stem cells and involved in various biological processes. In this paper, we reviewed the research progress of the function of the miR-290-295 cluster in embryonic stem cells. The miR-290-295 cluster is involved in regulating embryonic stem cell pluripotency maintenance, self-renewal, and reprogramming somatic cells to an embryonic stem cell-like state. Moreover, the miR-290-295 cluster has a latent pro-survival function in embryonic stem cells and involved in tumourigenesis and senescence with a great significance. Elucidating the interaction between the miR-290-295 cluster and other modes of gene regulation will provide us new ideas on the biology of pluripotent stem cells. In the near future, the broad prospects of the miRNA cluster will be shown in the stem cell field, such as altering cell identities with high efficiency through the transient introduction of tissue-specific miRNA cluster.
microRNAs (miRNAs) are about 22 nucleotide (nt) endogenously non-coding RNAs that negatively regulate the expression of various target genes at the post-transcriptional level. Currently, in the human genome, it is reported that there are ~1500 miRNAs and each miRNA potentially modulates hundreds of target genes [1, 2]. miRNAs play important roles in various signaling pathway regulation, such as metabolism, proliferation, apoptosis, differentiation and the development of tumor.
Gene clusters are generally composed of more than two related genes which are closely located on a chromosome, and they usually share sequence similarity . Increasing evidence suggests that clustered miRNA genes are generally located in a polycistron [4, 5], and co-expressed with neighboring miRNAs . From the consistent expression of most miRNA clusters, it is speculated that homologous miRNA clusters may share common cis-regulatory elements, resulting in a cooperative effect for those clusters. On the other hand, for the inconsistent expression of some miRNA clusters, perhaps have different transcriptional or maturation processes. Due to functional limitations, most miRNAs are highly conserved among species. Yu et al.  found that partial duplications from an ancestral gene often resulted in the formation of the miRNA clusters. In addition, tandem and segmental duplications were critical for the evolution of miRNA clusters. Compared with single miRNA in regulating a complex cell signaling network, the clustered miRNAs seemed more efficient and complicated.
In 1981, Evans et al.  isolated mouse embryonic stem cells (mESCs) for the first time, and in 1998, Thomson et al.  established human ESC cell line. Since then, the research field of the stem cells has developed rapidly. With the further study in the regulation mechanism of ESCs, Shinya Yamanaka  successfully got the induced pluripotent stem cells (iPSCs) by introducing transcription factors Oct4, Sox2, Klf4 and c-Myc into mouse fibroblasts in 2006. Meanwhile, it has been proposed that ESCs originate from the inner cell mass of mammalian blastocysts, and hold the promise of medical applications, such as tissue engineering and stem cell therapy, which becomes a hot spot in the field of stem cell research in recent years due to their ability to self-renew and differentiate into all kinds of cell types.
There are ESC-specific miRNA clusters in human and mouse, such as miR-302 and miR-371-373 clusters in human embryonic stem cells (hESCs), miR-302 and miR-290-295 clusters in mESCs. In fact, the miR-290-295 cluster is homolog of human miR-371-373, furthermore, the miR-302 and miR-290-295 clusters share the same seed sequence, as a result, they tend to have similar function in mESCs. But miR-290-295 cluster is highly expressed in mESCs compare to the miR-302 cluster. Dgcr8 is essential for the biogenesis of miRNAs, so knocking out of Dgcr8 results in the loss of all canonical miRNAs. It has been reported that the introduction of the miR-290-295 cluster members into the Dgcr8 −/− ESCs induces a highly transcriptionally homogenous population as well as wild-type ESCs [11, 12]. Furthermore, animals mostly die as embryo or infertile of female survivors when the miR-290-295 cluster is deleted [13–15], which shows the powerful features of the cluster. Therefore, it has become the focus of research. In recent years, it has been revealed that the miR-290-295 cluster plays an important role in the regulation of mESC pluripotent regulatory networks, differentiation, anti-apoptosis, as well as in the process of tumorigenesis and senescence in mouse embryonic fibroblasts. Therefore, intense research of miR-290-295 cluster will not only contribute to understanding the regulatory mechanisms in the early development of mESCs, but also help to explore the mechanisms of iPSCs and tumor regulation, so as to promote its application in the medical field.
The structure of the miR-290-295 cluster
The miR-290-295 cluster as a part of the pluripotency regulation network
ESC and iPSC self-renewals need to eliminate differentiation signal and obtain the pluripotency signal, in addition, the differentiation process trigger the closure of pluripotency procedure and the induction of lineage specification. Previously, the opinion is that regulating the pluripotent regulatory network is solely in a protein-centric approach, in recent years, however, the roles of miRNAs, especially the miR-290-295 cluster, attract more and more attention. Therefore, it will provide new insights for further study of miRNAs in the establishment and the maintenance of pluripotent regulation mechanisms of stem cells.
The miR-290-295 cluster promotes the process of MET
The miR-290-295 cluster affects the cell cycle phase distribution of ESCs
The miR-290-295 cluster regulates the expression of core transcription factors
The miR-290-295 cluster establishes and maintains pluripotency of stem cells by enhancing the expression of core transcription factors. The Oct4, Sox2, Klf4/Lin28, and c-Myc/Nanog are the core transcription factors of somatic cells reprogrammed into iPSCs. Lin28 was upregulated by transfection of miR-294 into Dicer-deficient cells, but the molecular mechanism is unknown . Judson et al.  showed the high inductive efficiency production of iPSCs with introduction of miR-290-295 cluster, and c-Myc was substituted for miR-294 successfully in somatic cell reprogramming. Thus, miR-294 is a downstream gene of c-Myc, and that miR-294 and c-Myc have some common downstream regulatory genes according to the prediction of GeneGo software, which can explain the ability of miR-294 to induce the pluripotent stem cells. The Wnt signaling pathway has been shown to be essential for maintaining pluripotency of stem cells [45, 46]. Dkk-1 has multiple roles in the cells, and the most prominent role is considered as an inhibitor of the Wnt signaling pathway . Zovoilis et al. demonstrated that the Dkk-1 was a direct target of miR-294 and miR-295, and the other members of the miR-290-295 cluster controlled Wnt or Dkk-1 activation indirectly . It is also confirmed that the overexpression of the miR-290-295 cluster increased c-Myc levels, which is a downstream target of the Wnt signaling pathway, while its inhibition had an opposite effect . So the miR-290-295 cluster upregulates the expression of c-Myc, but the exact molecular mechanism needs to be further explored. In addition, the miR-290-295 cluster promotes the re-activation of endogenous pluripotency factor Oct3/4 by repressing NR2F2 which is a transcriptional repressor of Oct3/4 . The miR-290-295 cluster also upregulates other pluripotency factors, such as N-myc, Sal4 (Fig. 2), but the specific molecular mechanism is still unclear [25, 43].
The miR-290-295 cluster regulates the metabolism of stem cells
The miR-290-295 cluster involves in epigenetic modifications mediated by PcG proteins
The miR-290-295 cluster also ensures the differentiation potential of pluripotent stem cells
Intriguingly, it is known that the miR-290-295/302 clusters have also been shown to promote pluripotency in different circumstances, but how the same miRNAs possess two opposite functions remains unresolved. It is possible that the context-dependent function of the clusters in different developmental stages determines the outcome of the activity of some signaling pathways.
The miR-290-295 cluster has the potential to promote survival of mESCs
Recent studies have shown that the miR-290-295 cluster plays an important role in cell apoptosis. Zheng et al.  found that the miR-290-295 cluster protected mESC cells from apoptosis during exposure to genotoxic stress through gain and loss of function studies. Further study demonstrated that the miR-290-295 cluster targeted Caspase 2 and Ei24 resulting in preventing from apoptosis of mESC gene toxicity stress through inhibiting their expression. It is the first time to link the miR-290-295 cluster with apoptosis. Ei24 promotes cell death by binding to Bcl2 , while Caspase 2 is an important regulatory gene in apoptosis. Subsequently, Guo et al. showed that miR-290-295/miR-302 clusters downregulated apoptosis-promoting factors Bhlhe40, Casp8, Ikbkg, Perp, on the other hand, they also upregulated the apoptosis-inhibiting factor Aven under the condition of let-7c-induced apoptosis . In addition, Caspase 2 and Ei24 act as tumor suppressor genes, and their loss may contribute to tumor metastasis. For example, knockout of Ei24 in mouse fibroblasts or human breast cancer cell line, results in increasing resistance to etoposide induced apoptosis . Therefore, the miR-290-295 cluster was presumed to be tumorigenic. Moreover, the miR-371-373 cluster, that is the homologue of the human miR-290-295 cluster, has been found to be highly expressed in various tumors [77–79] and to promote malignant transformation [80, 81]. Therefore, it is reasonable to speculate that this cluster has a dual role, on the one hand, it helps to protect against harmful physiological stress during development in normal cells; on the other hand, it makes cancer cells to resist the genetic toxicity of chemotherapeutic drugs.
The miR-290-295 cluster plays a role in tumourigenesis and senescence
Except for a critical role in maintaining pluripotency of stem cells, the activation of Wnt signaling pathway also occurs in various of human cancers [90, 91]. It is reported that miR-372 and miR-373 activate Wnt signaling by targeting Dkk-1, which promotes the invasive activity of tumor cells . However, in hESCs, it is not reported yet whether miR-371-373 cluster maintains the pluripotency of stem cells through the activation of the Wnt signaling pathway or not. miR-373 has also been reported to promote tumor invasion and metastasis by suppression of CD44 . Moreover, miR-373 drives the EMT and metastasis via the miR-373-TXNIP-HIF1α-TWIST signaling axis in breast cancer , but in ESCs, the miR-371-373 cluster might also maintain pluripotency by promoting MET.
KY and W-BA contributed equally to this work and wrote the manuscript. L-YW gave some helps for this work. XT and J-FW revised and approved the article prior to its being submitted for publication. All authors read and approved the final manuscript.
The authors thank Shan-Bing Yin for English language editing. We are thankful for the financial support of the National Natural Science Foundation of China (Grant Number: 81670555). We are also thankful for John Wiley & Sons, Inc. and Yang Cao, et al. about permission us to use Fig. 4 in this review.
The authors declare that they have no competing interests.
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- Saito Y, et al. Role of CTCF in the regulation of microRNA expression. Front Genet. 2012;3:186.PubMedPubMed CentralGoogle Scholar
- Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhang Y, et al. Diversity and evolution of MicroRNA gene clusters. Sci China C Life Sci. 2009;52:261–6.View ArticlePubMedGoogle Scholar
- Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.View ArticlePubMedGoogle Scholar
- Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–5.View ArticlePubMedGoogle Scholar
- Baskerville S, et al. Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA. 2005;11:241–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Yu J, et al. Human microRNA clusters: genomic organization and expression profile in leukemia cell lines. Biochem Biophys Res Commun. 2006;349:59–68.View ArticlePubMedGoogle Scholar
- Evans MJ, et al. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154–6.View ArticlePubMedGoogle Scholar
- Thomson JA, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–7.View ArticlePubMedGoogle Scholar
- Takahashi K, et al. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.View ArticlePubMedGoogle Scholar
- Gambardella G, et al. The impact of microRNAs on transcriptional heterogeneity and gene co-expression across single embryonic stem cells. Nat Commun. 2017;8:14126.View ArticlePubMedPubMed CentralGoogle Scholar
- Kumar RM, et al. Deconstructing transcriptional heterogeneity in pluripotent stem cells. Nature. 2014;516:56–61.View ArticlePubMedPubMed CentralGoogle Scholar
- Houbaviy HB, et al. Embryonic stem cell-specific MicroRNAs. Dev Cell. 2003;5:351–8.View ArticlePubMedGoogle Scholar
- Ambros V, et al. The regulation of genes and genomes by small RNAs. Development. 2007;134:1635–41.View ArticlePubMedGoogle Scholar
- Medeiros LA, et al. Mir-290-295 deficiency in mice results in partially penetrant embryonic lethality and germ cell defects. Proc Natl Acad Sci USA. 2011;108:14163–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Marson A, et al. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell. 2008;134:521–33.View ArticlePubMedPubMed CentralGoogle Scholar
- Berezikov E. Evolution of microRNA diversity and regulation in animals. Nat Rev Genet. 2011;12:846–60.View ArticlePubMedGoogle Scholar
- Griffiths-Jones S. The microRNA registry. Nucleic Acids Res. 2004;32(Database issue):D109–11.View ArticlePubMedPubMed CentralGoogle Scholar
- Lau NC, et al. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science. 2001;294:858–62.View ArticlePubMedGoogle Scholar
- Wu S, et al. Evolution of the miR-290-295/miR-371-373 cluster family seed repertoire. PLoS ONE. 2014;9:e108519.View ArticlePubMedPubMed CentralGoogle Scholar
- 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;81:11–24.View ArticlePubMedGoogle Scholar
- Landgraf P, et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell. 2007;129:1401–14.View ArticlePubMedPubMed CentralGoogle Scholar
- Tata PR, et al. Identification of a novel epigenetic regulatory region within the pluripotency associated microRNA cluster, EEmiRC. Nucleic Acids Res. 2011;39:3574–81.View ArticlePubMedPubMed CentralGoogle Scholar
- Gingold JA, et al. A genome-wide RNAi screen identifies opposing functions of Snai1 and Snai2 on the Nanog dependency in reprogramming. Mol Cell. 2014;56:140–52.View ArticlePubMedPubMed CentralGoogle Scholar
- Li MA, et al. microRNAs as novel regulators of stem cell pluripotency and somatic cell reprogramming. BioEssays. 2012;34:670–80.View ArticlePubMedPubMed CentralGoogle Scholar
- Li R, et al. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell. 2010;7:51–63.View ArticlePubMedGoogle Scholar
- Subramanyam D, et al. Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nat Biotechnol. 2011;29:443–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Li Z, et al. Small RNA-mediated regulation of iPS cell generation. EMBO J. 2011;30:823–34.View ArticlePubMedPubMed CentralGoogle Scholar
- Luningschror P, et al. miR-290 cluster modulates pluripotency by repressing canonical NF-kappaB signaling. Stem Cells. 2012;30:655–64.View ArticlePubMedGoogle Scholar
- Guo WT, et al. Suppression of epithelial-mesenchymal transition and apoptotic pathways by miR-294/302 family synergistically blocks let-7-induced silencing of self-renewal in embryonic stem cells. Cell Death Differ. 2015;22:1158–69.View ArticlePubMedGoogle Scholar
- Liao B, et al. MicroRNA cluster 302-367 enhances somatic cell reprogramming by accelerating a mesenchymal-to-epithelial transition. J Biol Chem. 2011;286:17359–64.View ArticlePubMedPubMed CentralGoogle Scholar
- Miyoshi N, et al. Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell. 2011;8:633–8.View ArticlePubMedGoogle Scholar
- Berthet C, et al. Cell-specific responses to loss of cyclin-dependent kinases. Oncogene. 2007;26:4469–77.View ArticlePubMedGoogle Scholar
- Lee MH, et al. Regulators of G1 cyclin-dependent kinases and cancers. Cancer Metastasis Rev. 2003;22:435–49.View ArticlePubMedGoogle Scholar
- Burdon T, et al. Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol. 2002;12:432–8.View ArticlePubMedGoogle Scholar
- Gong Z, et al. miR-290 contributes to the low abundance of cyclin D1 protein in mouse embryonic stem cells. Acta Biochim Biophys Sin (Shanghai). 2017;49:635–42.View ArticleGoogle Scholar
- Dalton S. Exposing hidden dimensions of embryonic stem cell cycle control. Cell Stem Cell. 2009;4:9–10.View ArticlePubMedPubMed CentralGoogle Scholar
- Wang Y, et al. Embryonic stem cell–specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nat Genet. 2008;40:1478–83.View ArticlePubMedPubMed CentralGoogle Scholar
- Kim VN. Cell cycle micromanagement in embryonic stem cells. Nat Genet. 2008;40:1391–2.View ArticlePubMedGoogle Scholar
- Qi J, et al. microRNAs regulate human embryonic stem cell division. Cell Cycle. 2009;8:3729–41.View ArticlePubMedPubMed CentralGoogle Scholar
- Wang Y, et al. miR-294/miR-302 promotes proliferation, suppresses G1-S restriction point, and inhibits ESC differentiation through separable mechanisms. Cell Rep. 2013;4:99–109.View ArticlePubMedPubMed CentralGoogle Scholar
- Gonzales KA, et al. Deterministic restriction on pluripotent state dissolution by cell-cycle pathways. Cell. 2015;162:564–79.View ArticlePubMedGoogle Scholar
- Hanina SA, et al. Genome-wide identification of targets and function of individual MicroRNAs in mouse embryonic stem cells. PLoS Genet. 2010;6:e1001163.View ArticlePubMedPubMed CentralGoogle Scholar
- Judson RL, et al. Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat Biotechnol. 2009;27:459–61.View ArticlePubMedPubMed CentralGoogle Scholar
- Nusse R, et al. Wnt signaling and stem cell control. Cold Spring Harb Symp Quant Biol. 2008;73:59–66.View ArticlePubMedGoogle Scholar
- Sato N, et al. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med. 2004;10:55–63.View ArticlePubMedGoogle Scholar
- Niehrs C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene. 2006;25:7469–81.View ArticlePubMedGoogle Scholar
- Zovoilis A, et al. Members of the miR-290 cluster modulate in vitro differentiation of mouse embryonic stem cells. Differentiation. 2009;78:69–78.View ArticlePubMedGoogle Scholar
- Rosa A, et al. A regulatory circuitry comprised of miR-302 and the transcription factors OCT4 and NR2F2 regulates human embryonic stem cell differentiation. EMBO J. 2011;30:237–48.View ArticlePubMedGoogle Scholar
- Varum S, et al. Energy metabolism in human pluripotent stem cells and their differentiated counterparts. PLoS ONE. 2011;6:e20914.View ArticlePubMedPubMed CentralGoogle Scholar
- Kondoh H, et al. A high glycolytic flux supports the proliferative potential of murine embryonic stem cells. Antioxid Redox Signal. 2007;9:293–9.View ArticlePubMedGoogle Scholar
- Vander HM, et al. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.View ArticleGoogle Scholar
- Zhu S, et al. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell. 2010;7:651–5.View ArticlePubMedGoogle Scholar
- Panopoulos AD, et al. The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming. Cell Res. 2012;22:168–77.View ArticlePubMedGoogle Scholar
- Zhang J, et al. Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal. Cell Stem Cell. 2012;11:589–95.View ArticlePubMedPubMed CentralGoogle Scholar
- Hanna J, et al. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature. 2009;462:595–601.View ArticlePubMedPubMed CentralGoogle Scholar
- Prigione A, et al. HIF1alpha modulates cell fate reprogramming through early glycolytic shift and upregulation of PDK1-3 and PKM2. Stem Cells. 2014;32:364–76.View ArticlePubMedGoogle Scholar
- Cao Y, et al. miR-290/371-Mbd2-Myc circuit regulates glycolytic metabolism to promote pluripotency. EMBO J. 2015;34:609–23.View ArticlePubMedPubMed CentralGoogle Scholar
- Pietersen AM, et al. Stem cell regulation by polycomb repressors: postponing commitment. Curr Opin Cell Biol. 2008;20:201–7.View ArticlePubMedGoogle Scholar
- Voigt P, et al. A double take on bivalent promoters. Genes Dev. 2013;27:1318–38.View ArticlePubMedPubMed CentralGoogle Scholar
- Bernstein BE, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125:315–26.View ArticlePubMedGoogle Scholar
- Boyer LA, et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature. 2006;441:349–53.View ArticlePubMedGoogle Scholar
- Onder TT, et al. Chromatin-modifying enzymes as modulators of reprogramming. Nature. 2012;483:598–602.View ArticlePubMedPubMed CentralGoogle Scholar
- Miyazaki H, et al. Ash1l methylates Lys36 of histone H3 independently of transcriptional elongation to counteract polycomb silencing. PLoS Genet. 2013;9:e1003897.View ArticlePubMedPubMed CentralGoogle Scholar
- 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 Rep. 2015;5:971–8.View ArticleGoogle Scholar
- Graham B, et al. MicroRNAs of the miR-290-295 family maintain bivalency in mouse embryonic stem cells. Stem Cell Rep. 2016;6:635–42.View ArticleGoogle Scholar
- Jaenisch R, et al. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl):245–54.View ArticlePubMedGoogle Scholar
- Melcer S, et al. Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation. Nat Commun. 2012;3:910.View ArticlePubMedPubMed CentralGoogle Scholar
- Fouse SD, et al. Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell. 2008;2:160–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Tan MH, et al. An Oct4-Sall4-Nanog network controls developmental progression in the pre-implantation mouse embryo. Mol Syst Biol. 2013;9:632.View ArticlePubMedPubMed CentralGoogle Scholar
- Sinkkonen L, et al. MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nat Struct Mol Biol. 2008;15:259–67.View ArticlePubMedGoogle Scholar
- Benetti R, et al. A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nat Struct Mol Biol. 2008;15:268–79.View ArticlePubMedPubMed CentralGoogle Scholar
- Gu KL, et al. Pluripotency-associated miR-290/302 family of microRNAs promote the dismantling of naive pluripotency. Cell Res. 2016;26:350–66.View ArticlePubMedPubMed CentralGoogle Scholar
- Zheng GX, et al. A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells. PLoS Genet. 2011;7:e1002054.View ArticlePubMedPubMed CentralGoogle Scholar
- Gu Z, et al. ei24, a p53 response gene involved in growth suppression and apoptosis. Mol Cell Biol. 2000;20:233–41.View ArticlePubMedPubMed CentralGoogle Scholar
- Mork CN, et al. Loss of putative tumor suppressor EI24/PIG8 confers resistance to etoposide. FEBS Lett. 2007;581:5440–4.View ArticlePubMedPubMed CentralGoogle Scholar
- Rippe V, et al. The two stem cell microRNA gene clusters C19MC and miR-371-3 are activated by specific chromosomal rearrangements in a subgroup of thyroid adenomas. PLoS ONE. 2010;5:e9485.View ArticlePubMedPubMed CentralGoogle Scholar
- Lee KH, et al. MicroRNA-373 (miR-373) post-transcriptionally regulates large tumor suppressor, homolog 2 (LATS2) and stimulates proliferation in human esophageal cancer. Exp Cell Res. 2009;315:2529–38.View ArticlePubMedGoogle Scholar
- Palmer RD, et al. Malignant germ cell tumors display common microRNA profiles resulting in global changes in expression of messenger RNA targets. Cancer Res. 2010;70:2911–23.View ArticlePubMedPubMed CentralGoogle Scholar
- Voorhoeve PM, et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Adv Exp Med Biol. 2007;604:17–46.View ArticlePubMedGoogle Scholar
- Voorhoeve PM, et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell. 2006;124:1169–81.View ArticlePubMedGoogle Scholar
- D’Adda DFF, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426:194–8.View ArticleGoogle Scholar
- Parrinello S, et al. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol. 2003;5:741–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol. 2001;11:S27–31.View ArticlePubMedGoogle Scholar
- Rizzo M, et al. miR-20a and miR-290, multi-faceted players with a role in tumourigenesis and senescence. J Cell Mol Med. 2010;14:2633–40.View ArticlePubMedPubMed CentralGoogle Scholar
- Pitto L, et al. miR-290 acts as a physiological effector of senescence in mouse embryo fibroblasts. Physiol Genom. 2009;39:210–8.View ArticleGoogle Scholar
- Bracken AP, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007;21:525–30.View ArticlePubMedPubMed CentralGoogle Scholar
- Lewis BP, et al. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.View ArticlePubMedGoogle Scholar
- Li Y, et al. MicroRNA-294 promotes cellular proliferation and motility through the PI3K/AKT and JAK/STAT pathways by upregulation of NRAS in bladder cancer. Biochemistry (Mosc). 2017;82:474–82.View ArticlePubMedGoogle Scholar
- Dravid G, et al. Defining the role of Wnt/beta-catenin signaling in the survival, proliferation, and self-renewal of human embryonic stem cells. Stem Cells. 2005;23:1489–501.View ArticlePubMedGoogle Scholar
- Reya T, et al. Wnt signalling in stem cells and cancer. Nature. 2005;434:843–50.View ArticlePubMedGoogle Scholar
- Zhou AD, et al. beta-Catenin/LEF1 transactivates the microRNA-371-373 cluster that modulates the Wnt/beta-catenin-signaling pathway. Oncogene. 2012;31:2968–78.View ArticlePubMedGoogle Scholar
- Huang Q, et al. The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol. 2008;10:202–10.View ArticlePubMedGoogle Scholar
- Chen D, et al. MiR-373 drives the epithelial-to-mesenchymal transition and metastasis via the miR-373-TXNIP-HIF1α-TWIST signaling axis in breast cancer. Oncotarget. 2015;6:32701–12.View ArticlePubMedPubMed CentralGoogle Scholar