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Regulation and biological roles of the multifaceted miRNA-23b (MIR23B)
Accepted Manuscript Regulation and biological roles of the multifaceted miRNA-23b (MIR23B)
Wei Wang, Yuji Wang, Weijun Liu, Andre J. van Wijnen PII: DOI: Reference:
S0378-1119(17)30931-9 doi:10.1016/j.gene.2017.10.085 GENE 42306
To appear in:
Gene
Received date: Accepted date:
29 September 2017 31 October 2017
Please cite this article as: Wei Wang, Yuji Wang, Weijun Liu, Andre J. van Wijnen , Regulation and biological roles of the multifaceted miRNA-23b (MIR23B). The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Gene(2017), doi:10.1016/j.gene.2017.10.085
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ACCEPTED MANUSCRIPT Regulation and biological roles of the multifaceted miRNA-23b (MIR23B) Wei Wang 1,2, Yuji Wang2,3, Weijun Liu1 , Andre J.van Wijnen2 * 1
Department of Orthopeadics, Pu Ai Hospital, Tongji Medical College, Huazhong University of Science and
Technology, Hubei, China. 2
Department of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905,
Department of Orthopaedics, Changzhou No. 2 People’s Hospital, Nanjing Medical University, 29 Xinglong
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USA
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Alley, Jiangsu, China.
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* Correspondence to:
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Andre J. van Wijnen, Ph.D. Department of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
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Tel: 507-293-2105 Fax: 507-284-5075 Email: [email protected]
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Running headline: Biological control by miR-23b
ACCEPTED MANUSCRIPT ABSTRACT MicroRNAs (miRNAs) are important short endogenous non-coding RNAs that have critical biological roles by acting as post-transcriptional regulators of gene expression. Chromosomal region 9q22.32 encodes the miR23b/27b/24-1 cluster and produces miR-23b, which is a pleiotropic modulator in many developmental processes and pathological conditions. Expression of miR-23b is actively suppressed and induced in response to many different stimuli. We discuss the biological functions and transcriptional regulation of this multifaceted
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miRNA in different tumor types, during development, upon viral infection, as well as in various clinical disorders,
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immune responses, as well as cardiovascular and thyroid functions. The combined body of work suggests that miR-23b expression is modulated by a diverse array of stimuli in cells from different lineages and participates
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in multiple gene regulatory feedback loops. Elevation of miR-23b levels appears to instruct cells to limit their proliferative and migratory potential, while promoting the acquisition of specialized phenotypes or protection
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from invading viruses and parasites. In contrast, loss of miR-23b can deregulate normal tissue homeostasis by removing constraints on cell cycle progression and cell motility. Collectively, the findings on miR-23b indicate that it is a very potent post-transcriptional regulator of growth and differentiation during development, multiple
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cancers and other biological processes. Understanding the regulation and activity of miR-23b has significant diagnostic value in many biological disorders and may identify cellular pathways that are amenable to
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therapeutic intervention.
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Key words: non-coding RNA, cancer, tumor, transcriptional control
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1. Introduction
MicroRNAs have emerged as a major class of gene expression modulators linked to a wide range of biological
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processes, such as cellular proliferation, differentiation and apoptosis (Miska 2005; Park and Peter 2008). Many members of this class of single-stranded short non-coding RNAs are evolutionarily conserved and endogenously generated from chromosomal loci interspersed throughout the genome. Mature miRNA forms are about 22 nucleotides in length on average. Some precursor miRNAs are either encoded in the introns of regular protein-coding host genes, while others are derived from unique long non-coding transcripts encoding one or more miRNAs (miRNA genes or clusters). As is the case for protein coding mRNAs, miRNA genes are transcribed by RNA polymerase II in the nucleus. This review focuses on miR-23b (MIR23B) which is encoded by a long non-coding RNA transcript referred to as Chromosome 9 Open Reading Frame 3 (C9orf3) in human and RIKEN cDNA 2010111I01 gene (2010111I01Rik) in mouse that also contain the miR-27b (MIR27B) and miR-24-1 (MIR24-1).
ACCEPTED MANUSCRIPT The generation of miR-26b and other miRNAs from long precursors is a multistage process that takes place first in the nucleus and then moves to the cytoplasm (Bartel 2004; Ha and Kim 2014). Long primary miRNA transcripts (pri-miRNAs) like C9ORF3 are cleaved by the RNase III enzyme Drosha into ~70 nt stem-loop precursor miRNAs (pre-miRNAs). Pre-miRNAs are exported from the nucleus into the cytoplasm via Exportin-5 and cleaved by a Dicer containing protein complex into a miRNA duplex (~19–24 nucleotides). This duplex is composed of a guide RNA sequence (e.g., miR-23b) and the passenger RNA that together facilitate a miRNAinduced silencing complex (miRISC) in which miR-23b interacts with complementary sequences in its target
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mRNAs, while the passenger strand is typically degraded. Most miRNAs have tens if not hundreds of target
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genes, and many protein-encoding genes (>60%) have one or more predicted miRNA binding sites. Therefore,
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miRNAs constitute one of the largest and most important classes of gene regulatory molecules (Ha and Kim 2014). Of these, miR-23b is a particularly potent pleiotropic modulator in different diseases and disorders. Recent advances necessitate a critical appraisal of how this multifaceted miRNA is transcriptionally controlled
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and affects both normal and disease related cellular signaling pathways and gene regulatory networks.
2.1 Regulation of cardiovascular cells by miR-23b
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2. The regulation and functional role of miR-23b in different diseases
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Expression of miR23b is highly elevated in many vascularized tissues and play critical roles in cardiovascular development, angiogenesis, cardiac ischemia and endothelial cells (ECs) homeostasis (Bang, Fiedler et al.
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2012) (Fig 1). Recent studies have shown that miR-23b enhance angiogenesis by promoting angiogenic signaling by targeting Sprouty2 and Sema6A proteins, which exert antiangiogenic activity (Zhou, Gallagher et
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al. 2011). Phenotypic switches of vascular smooth muscle cells (VSMCs) play a key role in the pathogenesis of different vascular diseases (Alexander and Owens 2012). Gain-of-function studies showed that overexpression
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of miR-23b inhibited VSMC proliferation and migration, whereas the opposite effect was obtained with the in vitro inhibition of miR-23b (Iaconetti, De Rosa et al. 2015). It also has been demonstrated that miR-23b can significantly promote the expression of VSMC marker genes such as smooth muscle α-actin (ACTA2) and
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smooth muscle myosin heavy chain (MYH11). The effect of miR-23b on VSMCs is mediated, at least in part, by targeting SMAD3, Urokinase-type Plasminogen Activator (uPA, PLAU) and FOXO4, key regulators of VSMC physiology (Iaconetti, De Rosa et al. 2015). Hence, miR-23b is a critical factor for normal vascular function. Several studies have shown that miR-23b is up-regulated by laminar flow (Wang, Garmire et al. 2010; Hergenreider, Heydt et al. 2012). MAPKs, which are linked to mitogenic growth factor activation and SMAD signaling, mediate shear-induced miR23b expression, while miR-23b provides negative feedback regulation of shear-induced MAPK activation (He, Li et al. 2012). Growth arrest of vascular endothelial cells (ECs) induced by pulsatile shear (PS) flow is important for flow regulation of ECs (Lin, Hsu et al. 2000). The increased
ACCEPTED MANUSCRIPT expression of miR-23b by shear stress inhibits cell cycle progression of ECs by indirectly blocking phosphorylation of the retinoblastoma protein and by reducing E2F1 expression (Wang, Garmire et al. 2010). MiR-23b was also induced by the flow-dependent transcription factor KLF2 (Hergenreider, Heydt et al. 2012), which is a critical regulator of endothelial gene expression patterns induced by atheroprotective flow (Boon and Horrevoets 2009). Moreover, pulsatile shear flow-induced and KLF2 mediated
expression of miR-23b
regulates the cyclin-dependent kinase-activating kinase (CAK) complex, which is composed of CDK7 and cyclin H (CCNH) to exert anti-proliferative effects on ECs. The KLF2-dependent elevation of miR-23b in
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response to pulsatile shear flow suppresses CCNH, which impairs the integrity and activity of the CAK complex
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and reduces the activities of CDK2 and CDK4 (Wang, Nguyen et al. 2014). While pulsatile shear flow regulates
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the miR-23b/CAK pathway to exert anti-proliferative effects on ECs, oscillatory shear flow has little effect on the miR-23b/CAK pathway and hence does not cause EC growth arrest (Wang, Nguyen et al. 2014). These studies revealed that miR-23b is an important shear flow-dependent regulator of vascular cell growth and
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regulation.
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2.2 Control of virus infection by miR-23b levels.
Because of their principal roles as post-transcriptional regulators, miRNAs are key effector molecules in the
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complicated interaction network between virus and host (Kurzynska-Kokorniak, Jackowiak et al. 2009), and indeed miR-23B also performs important biological roles in virus infection (Fig. 2). For example, Ouda and
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colleagues demonstrated that the expression of miR-23b is induced during viral infection by the innate immune response, which is mediated by Toll-like receptors (TLRs) and the retinoic acid inducible gene I (RIG-I)-like receptor (RLR). These receptors normally activate the type I interferon (IFN) system to produce antiviral
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proteins that inhibit various steps of viral replication and facilitate the subsequent activation of acquired immune responses. Activation of RLR signaling by rhinovirus infection upregulates miR-23b to attenuate
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expression of the very low density lipoprotein receptor (VLDLR) used for viral entry (Ouda, Onomoto et al. 2011). Furthermore, enterovirus 71 (EV71) infection downregulates the expression of miR-23b, because
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otherwise miR-23b would inhibit EV71 replication by suppressing EV71 VPl protein (Wen, Dai et al. 2013). Other studies showed that the expression of miR-23b is upregulated during infection with either influenza A virus (Makkoch, Poomipak et al. 2015) or Epstein-Barr virus (Imig, Motsch et al. 2011). Although the exact roles of miR-23b in virus infections remain to be further studied, it is evident that modulations in this miRNA has important functions in regulating both cellular and viral responses after infection. The miR-23b/uPA(PLAU) pathway may be important for the effects of the oncogenic human papillomaviruses HPV-16 in provoking the development of cervical cancer (Au Yeung, Tsang et al. 2011). Cervical cancer involves inactivation of p53 (TP53) by the viral oncoprotein E6. The loss of p53 prevents activation of miR-23b expression through a p53 binding site in the promoter of the MIR23B gene on chromosome 9 (Au Yeung, Tsang et al. 2011). Moreover, miR-23b is often downregulated in HPV-associated cervical cancer and the
ACCEPTED MANUSCRIPT upregulation of uPA (PLAU) due to reduced expression of miR-23b instigates cell migration as a key step towards metastasis and invasiveness (Duffy, Maguire et al. 1999) and may represent a prognostic indicator of cervical cancer (Riethdorf, Riethdorf et al. 1999).
2.3 Role of miR-23b as a metastatic suppressor miRNA
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Investigations of variety of different tumors has shown that down-regulation of miR-23b promotes cancer
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progression, suggesting that it may act as a tumor suppressor consistent with a number of recent studies on
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the role of miR-23b loss of function in cancer (Table 1) Prostate cancer
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Several reports have shown that the expression of miR-23b is down-regulated in metastatic, castrationresistant tumors compared to primary prostate cancer and benign tissue, while elevated expression of miR-23b is associated with higher survival rates in prostate cancer patients. In contrast, high levels of miR-23b directly
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attenuates several proto-oncogenes, including SRC kinase, AKT, PRDX3 and RAC1, and overexpression of miR-23b inhibits proliferation, migration, invasion, cell cycle arrest, and apoptosis in prostate cancer(He, Zhu et
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al. 2012; Ishteiwy, Ward et al. 2012; Majid, Dar et al. 2012). These findings are generally consistent with the importance of p53 function during prostate tumorigenesis (Downing, Russell et al. 2003) and that a p53 binding
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site is necessary for miR-23b expression, as discussed above (Au Yeung, Tsang et al. 2011).
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Bladder cancer
Similar to its cancer-protective role in prostate cancer, miR-23b functions as a tumor suppressor and may
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contribute to metastasis in bladder cancer patients (Chiyomaru, Seki et al. 2015). One mechanism by which miR-23b suppresses bladder tumors is by inhibiting expression of the c-Met oncogene (MET), which activates
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multiple signal transduction pathways, including RAS, PI3K-AKT, STAT and WNT/β-catenin(Monga, Mars et al. 2002; O'Brien, Tang et al. 2004). Another mechanism that miR-23b may employ is its ability to block Zeb1 (Majid, Dar et al. 2013), one of the crucial regulators of the epithelial-to-mesenchymal transition (EMT) (Sayan, Griffiths et al. 2009). Consistent with these findings, over-expression of miR-23b in bladder cancer cells inhibits cell proliferation, impairs colony formation, induces a G0/G1 cell cycle arrest and forces apoptosis, while blocking cell migration and invasion (Majid, Dar et al. 2013). Breast Cancer Beyond prostate and bladder, miR-23b regulates focal adhesion, cell spreading, cell-cell junctions and the formation of lamellipodia in breast cancer. In this cancer type, presences of miR-23b reduces cell motility and invasion, by altering cytoskeletal dynamics by suppressing the PAK2 gene. Inhibition of miR-23b increases cell
ACCEPTED MANUSCRIPT migration and metastasis in vivo breast cancer models, and low miR-23b expression correlates with the clinical development of metastases in breast cancer patients (Pellegrino, Stebbing et al. 2013). Direct effects on tumor growth are also evident, because overexpression of miR-23b in a bone marrow–derived metastatic human breast cancer induces a dormant phenotype by suppressing MARCKS, which encodes a protein that promotes cell cycle progression and motility (Ono, Kosaka et al. 2014). Angiogenesis is also controlled by miR-23b, based on the observation that miR-23b is linked to the mechanism of action for docosahexaenoic acid (DHA), a natural compound with anticancer and anti-angiogenesis activity. Overexpression of miR-23b decreases the
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expression of two key pro-angiogenic target genes (uPA/PLAU, AMOTL1), while significantly inhibiting tube
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formation by endothelial cells (Hannafon, Carpenter et al. 2015). Importantly, this same study also suggests
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that transfer of miR-23b and other microRNAs by exosomes may account for the anti-angiogenic action of DHA in recipient endothelial cells (Hannafon, Carpenter et al. 2015). This finding suggests that miR-23b is both a
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tumor-intrinsic suppressor and a paracrine inhibitor of vascularization. Gastro-intestinal cancer
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Another key role for miR-23b-3p was revealed by its ability to inhibit autophagy mediated by ATG12 and HMGB2 in gastric cancer cells that sensitized these cells to chemotherapy (An, Zhang et al. 2015). Its tumor-
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suppressive effects on gastric cancer progression may also involve inhibition of Ets1 and the Notch2 receptor as part of a reciprocal regulatory feedback loop in gastric carcinogenesis (Huang, Ping et al. 2015). Down-
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regulation of miR-23b in human colon cancer results in activation of multiple metastasis-related cellular patwhays, including tumor growth, invasion and angiogenesis. The mechanisms involves modulation of a cohort of pro-metastatic targets, including FZD7 , MAP3K1, PAK2, TGFβR2 , RRAS2 or uPA/PLAU (Zhang,
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Hao et al. 2011).
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Glioma
Expression of miR-23b expression is silenced by methylation and induction of miR-23b expression exerts cell
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growth-inhibitory effects in glioma cels. This growth inhibition is linked to down-regulation of HMGA2, which results in cell cycle arrest (Geng, Luo et al. 2012). In addition, overexpression of miRNA-23b in glioma cells directly suppresses mitochondrial transcription factor A (TFAM) resulting inhibition of proliferation, as well as cell migration and colony formation. In contrast, overexpression of TFAM had opposite effects as expected and significantly enhanced these same biological processes (Jiang, Yang et al. 2013). Furthermore, miRNA-23b controls the activity of the PI3K/Akt signaling pathway (Jiang, Yang et al. 2013), which is critical for cell proliferation and migration, and the expression of invasion-related proteins MMP2, MMP9 and protein tyrosine kinase 2 beta (PYK2/PTK2B) (Loftus, Ross et al. 2012; Jiang, Yang et al. 2013). Taken together, the biological processes targeted by miR-23b are similar to those described for other tumors, although the proposed targets are different.
ACCEPTED MANUSCRIPT Other cancers Ectopic expression of miR-23b significantly inhibits ovarian cancer cell proliferation and tumorigenicity by down-regulating the expression of RUNX2, and its expression level may be a potential prognostic marker that is inversely related to epithelial ovarian cancer (Li, Liu et al. 2014). This anti-tumor activity of miR23B, which may be directly depend on activation by p53, is analogous to the anti-tumor activity of miR-34, which is activated by p53 and prevents RUNX2 activation osteosarcoma (van der Deen, Taipaleenmaki et al. 2013).
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Furthermore, overexpression of miR-23b suppresses the translation urokinase-type plasminogen activator
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(uPA/PLAU) and c-Met(MET), and decreases migration and proliferation of hepatocellular carcinoma cells (Salvi, Sabelli et al. 2009). Furthermore, similar to observations in gastric cancer discussed above, miR-23b
pancreatic cancer cells to irradiation (Wang, Zhang et al. 2013).
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2.4 Role of miR-23b as an oncogenic miRNA
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suppresses expression of the autophagy regulator ATG12 that decreases autophagic activity and sensitizes
Although the role of miR-23b as a tumor suppressor has been well established, many studies demonstrated
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that it can also act as oncogenic miRNA (Table. 2). In an univariate survival analysis of ovarian carcinoma, high levels of miR-23b were associated with poor progression-free survival and this unfavorable diagnosis may
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be related to low expression of tumor suppressor PTEN, which is a validated target of miR-23b (Vaksman, Trope et al. 2014). Downregulation of PTEN by miR-23b promotes prostate cancer cell proliferation in vitro
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(Tian, Fang et al. 2013). Other studies on the regulation of miR-23b indicate that tumor growth factors EGF and TNFα, as well as Her2/neu, induce expression of miR-23b via the NF-κB signaling pathway in breast
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cancer. Suppression of miR-23b activity results in the up-regulation of the tumor suppressor Nischarin (NISCH) and decreased of tumor growth and metastasis in vivo (Jin, Wessely et al. 2013). Analysis of 160 Chinese
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gastric cancer patients revealed that miR-23a and miR-23b expression were both higher in gastric cancer patients with shorter overall survival (Ma, Dai et al. 2014). Consistent with the idea that miR-23b has oncogenic activity depending on the biological context, recent studies on miR-23b revealed reciprocal repression
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reflecting feedback control between TUSC7 and miR-23b. In this regulatory pathway, TUSC7 blocks and miR23b promotes cell growth. The results of this study also established that TUSC7 is a p53-regulated tumor suppressor that acts in part by repressing miR-23b in gastric cancer (Qi, Xu et al. 2015). Even though evidence in glioblastoma discussed above indicates that miR-23b is a tumor suppressive miRNA, miR-23b may also have oncogenic properties by enhancing glioma survival and invasion. The latter effects of miR-23B are mediated by VHL via suppression of HIF-1α (HIF1A)/VEGF and β-catenin(CTNNB1)/TCF4 signaling (Chen, Han et al. 2012). Other studies obtained similar results by showing that inhibition of miR-23b in glioma cell lines and orthotopic tumor mouse models results in a reduction in tumor malignancy, a mechanism that at least in part may operate by downregulation of HIF-1α, β-catenin, MMP2, MMP9, VEGF and ZEB1, as well as increased expression of VHL and E-cadherin (CDH1) (Chen, Zhang et al. 2014).
ACCEPTED MANUSCRIPT 2.5 Control of cell differentiation by miR-23B and its role in regenerative medicine Several studies have examined the role of miRNAs in chondrogenic differentiation of mesenchymal stem cells (MSCs) that are critical for successful cartilage regeneration (Kobayashi, Lu et al. 2008; McAlinden, Varghese et al. 2013). Complementary to its role in suppressing cell growth, miR-23b induces chondrocyte differentiation by inhibiting the expression of Protein Kinase A catalytic subunit B (PRKACB) and phosphorylation of CREB, which are downstream targets of Protein Kinase A in synovial fluid-derived mesenchymal stem cells.
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Furthermore, miRNA-23b also appears to maintain cartilage homeostasis by inhibiting extracellular matrix
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breakdown by MMPs (Ham, Lee et al. 2014) (Table 3).
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Consistent with a general role of suppressing cell growth and promoting a differentiated phenotype, miR-23b is highly expressed in differentiated keratinocytes and represents a differentiation biomarker for human skin (Hildebrand, Rutze et al. 2011). Upregulation of miR-23b also occurs during myogenic differentiation (Dmitriev,
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Barat et al. 2013) and bone regeneration (Palmieri, Pezzetti et al. 2008). In myoblasts, transcription factor PITX2C promotes cell proliferation by downregulating several microRNAs including miR-23b, which represses
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the expression of cyclin D1 (CCND1) and cyclin D2 (CCND2) genes. Interestingly, this PITX2C-microRNA pathway controls cell proliferation of early-activated satellite cells, enhances the number of Myf5+ satellite cells
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and promotes their commitment to a myogenic cell fate (Lozano-Velasco, Vallejo et al. 2015) (Table 3). Downregulation of miR-23b may contribute to activation of the TGF-β1 (TGFB1)/SMAD3 signaling pathway during
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the termination stage of liver regeneration (Yuan, Dong et al. 2011) (Table 3). Furthermore, miR-23b promotes neurogenic differentiation by targeting hairy/enhancer of split protein (HES1), which is a bHLH transcriptional repressor functioning in neuronal differentiation (Kimura, Kawasaki et al. 2004). Taken together, the cell growth
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suppressive activity of miR-23b during development and tumorigenesis is accompanied by its ability to control
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differentiation of multiple cell lineages.
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2.6 Association of miR-23b with autoimmune disease and thyroid function Beyond the role of miR23b as a developmentally important and cancer-related and miRNA that can either block tumorigenic or enhance metastatic properties of cells depending on the biological context, miR-23b is also associated with immune responses. For example, miR-23b regulates the inflammatory cytokine interleukin-17 (IL17), and other cytokines in many immune processes, including expression of tumor necrosis factor-α (TNF) and interleukin-1β (IL1B)–mediated activation of transcription factor nuclear factor κB (NFκB/NFKB1). As is the case in other molecular pathways described above, miR-23b participates in a feedback loop that regulates the inflammatory response and is disrupted in autoimmune diseases (Zhu, Pan et al. 2012) (Table 3). Furthermore, treatment of thyroid follicular cells with Thyroid Stimulating Hormone (TSH) induces entry into S phase of the cell cycle and is associated with up-regulation of miR-23b. This stimulation of
ACCEPTED MANUSCRIPT cell cycle progression is achieved by miR-23b dependent inhibition of TGF-β/Smad3 signaling (Leone, D'Angelo et al. 2012) (Table 3). These studies provide further evidence for the broad utilization of the regulatory potential of miR-23b in diverse biological processes.
2.7 Parasite infection
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Because miR-23b controls immune responses through effects on the NFkB-pathway, it is perhaps not
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surprising that expression of this miRNA is modulated during infection by Cryptosporidium parvum, which is a protozoan parasite that infects the gastrointestinal epithelium and causes diarrheal disease worldwide. Studies
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by Rui Zhou and colleagues identified a panel of miRNAs, including miR-23b, that are transcriptionally activated by NFkB/p65 (NKFB1) in human cholangiocytes in response to C. parvum infection. (Zhou, Hu et al.
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2009). Furthermore, miR-23b is among a subset of miRNA genes that is trans-activated by promoter binding of STAT3 during Toxoplasma gondii infection. Importantly, functional inhibition of selected STAT3-binding miRNAs in human macropahges increased apoptosis of host cells (Cai, Chen et al. 2013). These findings
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collectively indicate that miR-23b forms part of a regulatory network with NFkB and STAT3 that may be
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relevant to the regulation of epithelial anti-microbial defenses in general. 3. Conclusion
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During the last years, the development of different high throughput miRNA profiling technologies has revealed that miR-23B expression is modulated in many different diseases, including normal growth and differentiation
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during development, cancer, cardiovascular disease, as well as virus infection, autoimmune disease and parasite infection. In these diverse biological process and diseases, miR-23b targets many different mRNAs of
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different genes that form negative feedback loops. Of particular note are its epigenetic suppression by DNA methylation, as well as its activation by p53, NFkB and STAT3 in different contexts, and its ability to control cell
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growth and differentiation through effects on multiple signaling pathways. The next challenge will be to modulate levels of miR-23b in animal models of different diseases and apply loss-of-function and gain-offunction approaches to evaluate the biological importance of miR-23b in vivo and to translate the in vivo results to the clinical management of miR-23b controlled diseases through diagnosis, treatment, and prognosis.
Disclosure: This work was supported by Natural Science Foundation of Hubei Province of China. Grant 2017CFB470. None of the authors acknowledge any conflict of interest in connection with this submission.
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Ishteiwy, R. A., T. M. Ward, et al. (2012). "The microRNA -23b/-27b cluster suppresses the metastatic phenotype of castration-resistant prostate cancer cells." PloS one 7(12): e52106. Jiang, J., J. Yang, et al. (2013). "TFAM is directly regulated by miR-23b in glioma." Oncology reports 30(5): 2105-2110. Jin, L., O. Wessely, et al. (2013). "Prooncogenic factors miR-23b and miR-27b are regulated by Her2/Neu, EGF, and TNFalpha in breast cancer." Cancer research 73(9): 2884-2896. Kimura, H., H. Kawasaki, et al. (2004). "Mouse microRNA-23b regulates expression of Hes1 gene in P19 cells." Nucleic acids symposium series(48): 213-214. Kobayashi, T., J. Lu, et al. (2008). "Dicer-dependent pathways regulate chondrocyte proliferation and differentiation." Proceedings of the National Academy of Sciences of the United States of America 105(6): 1949-1954. Kurzynska-Kokorniak, A., P. Jackowiak, et al. (2009). "Human- and virus-encoded microRNAs as potential targets of antiviral therapy." Mini reviews in medicinal chemistry 9(8): 927-937. Leone, V., D. D'Angelo, et al. (2012). "Thyrotropin regulates thyroid cell proliferation by up-regulating miR-23b and miR29b that target SMAD3." The Journal of clinical endocrinology and metabolism 97(9): 3292-3301. Li, W., Z. Liu, et al. (2014). "MicroRNA-23b is an independent prognostic marker and suppresses ovarian cancer progression by targeting runt-related transcription factor-2." FEBS letters 588(9): 1608-1615. Lin, K., P. P. Hsu, et al. (2000). "Molecular mechanism of endothelial growth arrest by laminar shear stress." Proceedings of the National Academy of Sciences of the United States of America 97(17): 9385-9389. Loftus, J. C., J. T. Ross, et al. (2012). "miRNA expression profiling in migrating glioblastoma cells: regulation of cell migration and invasion by miR-23b via targeting of Pyk2." PloS one 7(6): e39818. Lozano-Velasco, E., D. Vallejo, et al. (2015). "A Pitx2-MicroRNA Pathway Modulates Cell Proliferation in Myoblasts and Skeletal-Muscle Satellite Cells and Promotes Their Commitment to a Myogenic Cell Fate." Molecular and cellular biology 35(17): 2892-2909. Ma, G., W. Dai, et al. (2014). "Upregulation of microRNA-23a/b promotes tumor progression and confers poor prognosis in patients with gastric cancer." International journal of clinical and experimental pathology 7(12): 8833-8840. Majid, S., A. A. Dar, et al. (2012). "miR-23b represses proto-oncogene Src kinase and functions as methylation-silenced tumor suppressor with diagnostic and prognostic significance in prostate cancer." Cancer research 72(24): 64356446. Majid, S., A. A. Dar, et al. (2013). "MicroRNA-23b functions as a tumor suppressor by regulating Zeb1 in bladder cancer." PloS one 8(7): e67686. Makkoch, J., W. Poomipak, et al. (2015). "Human microRNAs profiling in response to influenza A viruses (subtypes pH1N1, H3N2, and H5N1)." Experimental biology and medicine. McAlinden, A., N. Varghese, et al. (2013). "Differentially expressed microRNAs in chondrocytes from distinct regions of developing human cartilage." PloS one 8(9): e75012. Miska, E. A. (2005). "How microRNAs control cell division, differentiation and death." Current opinion in genetics & development 15(5): 563-568. Monga, S. P., W. M. Mars, et al. (2002). "Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes." Cancer research 62(7): 2064-2071. O'Brien, L. E., K. Tang, et al. (2004). "ERK and MMPs sequentially regulate distinct stages of epithelial tubule development." Developmental cell 7(1): 21-32. Ono, M., N. Kosaka, et al. (2014). "Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells." Science signaling 7(332): ra63. Ouda, R., K. Onomoto, et al. (2011). "Retinoic acid-inducible gene I-inducible miR-23b inhibits infections by minor group rhinoviruses through down-regulation of the very low density lipoprotein receptor." The Journal of biological chemistry 286(29): 26210-26219. Palmieri, A., F. Pezzetti, et al. (2008). "Peptide-15 changes miRNA expression in osteoblast-like cells." Implant dentistry 17(1): 100-108. Park, S. M. and M. E. Peter (2008). "microRNAs and death receptors." Cytokine & growth factor reviews 19(3-4): 303-311. Pellegrino, L., J. Stebbing, et al. (2013). "miR-23b regulates cytoskeletal remodeling, motility and metastasis by directly targeting multiple transcripts." Nucleic acids research 41(10): 5400-5412.
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Qi, P., M. D. Xu, et al. (2015). "Reciprocal repression between TUSC7 and miR-23b in gastric cancer." International journal of cancer. Journal international du cancer 137(6): 1269-1278. Riethdorf, L., S. Riethdorf, et al. (1999). "Urokinase gene expression indicates early invasive growth in squamous cell lesions of the uterine cervix." The Journal of pathology 189(2): 245-250. Salvi, A., C. Sabelli, et al. (2009). "MicroRNA-23b mediates urokinase and c-met downmodulation and a decreased migration of human hepatocellular carcinoma cells." The FEBS journal 276(11): 2966-2982. Sayan, A. E., T. R. Griffiths, et al. (2009). "SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer." Proceedings of the National Academy of Sciences of the United States of America 106(35): 14884-14889. Tian, L., Y. X. Fang, et al. (2013). "Four microRNAs promote prostate cell proliferation with regulation of PTEN and its downstream signals in vitro." PloS one 8(9): e75885. Vaksman, O., C. Trope, et al. (2014). "Exosome-derived miRNAs and ovarian carcinoma progression." Carcinogenesis 35(9): 2113-2120. van der Deen, M., H. Taipaleenmaki, et al. (2013). "MicroRNA-34c inversely couples the biological functions of the runtrelated transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma." J Biol Chem 288(29): 21307-21319. Wang, K. C., L. X. Garmire, et al. (2010). "Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth." Proceedings of the National Academy of Sciences of the United States of America 107(7): 32343239. Wang, K. C., P. Nguyen, et al. (2014). "MicroRNA-23b regulates cyclin-dependent kinase-activating kinase complex through cyclin H repression to modulate endothelial transcription and growth under flow." Arteriosclerosis, thrombosis, and vascular biology 34(7): 1437-1445. Wang, P., J. Zhang, et al. (2013). "MicroRNA 23b regulates autophagy associated with radioresistance of pancreatic cancer cells." Gastroenterology 145(5): 1133-1143 e1112. Wen, B. P., H. J. Dai, et al. (2013). "MicroRNA-23b inhibits enterovirus 71 replication through downregulation of EV71 VPl protein." Intervirology 56(3): 195-200. Yuan, B., R. Dong, et al. (2011). "Down-regulation of miR-23b may contribute to activation of the TGF-beta1/Smad3 signalling pathway during the termination stage of liver regeneration." FEBS letters 585(6): 927-934. Zhang, H., Y. Hao, et al. (2011). "Genome-wide functional screening of miR-23b as a pleiotropic modulator suppressing cancer metastasis." Nature communications 2: 554. Zhou, Q., R. Gallagher, et al. (2011). "Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23~27~24 clusters." Proceedings of the National Academy of Sciences of the United States of America 108(20): 8287-8292. Zhou, R., G. Hu, et al. (2009). "NF-kappaB p65-dependent transactivation of miRNA genes following Cryptosporidium parvum infection stimulates epithelial cell immune responses." PLoS pathogens 5(12): e1000681. Zhu, S., W. Pan, et al. (2012). "The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-alpha." Nature medicine 18(7): 1077-1086.
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ACCEPTED MANUSCRIPT Table.1 Overview of miR-23b acting as a metastatic suppressor miRNA
metastasis suppressors that might serve as novel biomarkers and therapeutic agents
Rac1
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Target Src kinase Akt PRDX3
(He, Zhu et al. 2012) (Ishteiwy, Ward et al. 2012) (Chiyomaru, Seki et al. 2015)
inhibit cancel cell proliferation, migration, invasion and impair colony formation induce G0/G1 cell cycle arrest and apoptosis
Zeb1
(Majid, Dar et al. 2013)
a central role in cytoskeletal dynamics reduce cell motility and invasion
PAK2
(Pellegrino, Stebbing et al. 2013)
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Breast Cancer
Reference
c-Met
repress cancer cell proliferation, migration and invasion
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bladder cancer
Function Inhibit proliferation, colony formation, migration and invasion trigger G0/G1 cell cycle arrest and apoptosis suppress the response of PRDX3 expression to hypoxic condition
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Tumor types prostate cancer
PLAU AMOTL1
(Hannafon, Carpenter et al. 2015)
contribute to the induction of dormancy in disseminated breast cancer cells
MARCKS
(Ono, Kosaka et al. 2014)
inhibit autophagy sensitize gastric cancer cells to chemotherapy act as a prognostic factor for overall survival suppress tumor progression affect tumor sphere ultra-structure in gastric cancer cells
ATG12 HMGB2
(An, Zhang et al. 2015)
Notch2 receptor Ets1 FZD7 MAP3K1
(Huang, Ping et al. 2015)
induce cancer cell cycle arrest inhibit cancel cell proliferation
HMGA2
(Geng, Luo et al. 2012)
Inhibit the proliferation, cell cycle progression, migration and colony formation in glioma cells
TFAM PI3K/Akt
Inhibit glioma cell migration and invasion
Pyk2
(Loftus, Ross et al. 2012)
ovarian cancer
Inhibit cancer cell proliferation and tumorigenicity a potential prognostic marker
RUNX2
(Li, Liu et al. 2014)
hepatocellular
decrease cancer cells migration and proliferation
uPA
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digestive tract cancer
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inhibit tube formation by endothelial cells anticancer and anti-angiogenesis
glioma
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mediate multiple steps of metastasis, including tumor growth, invasion and angiogenesis
(Zhang, Hao et al. 2011)
(Jiang, Yang et al. 2013)
(Salvi, Sabelli
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et al. 2009)
ATG12
(Wang, Zhang et al. 2013)
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decrease autophagic activity sensitize pancreatic cancer cells to irradiation
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pancreatic cancer
c-Met
ACCEPTED MANUSCRIPT Table.2 Overview of miR-23b acting as an oncogenic miRNA Function high levels of miR-23b was associated with poor progression-free survival
Target PTEN
prostate cancer
promote prostate cancer cell proliferation
PTEN
breast cancer
increase tumour growth and metastasis
Nischarin
gastric cancer
promote cancer cell growth in gastric cancer
glioma
increase tumor survival promote tumor malignancy
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Tumor types ovarian carcinoma
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TUSC7 VHL E-cadherin
Reference (Vaksman, Trope et al. 2014) (Tian, Fang et al. 2013) (Jin, Wessely et al. 2013) (Qi, Xu et al. 2015) (Chen, Han et al. 2012) (Chen, Zhang et al. 2014)
ACCEPTED MANUSCRIPT Table.3 Regulation and role of miR-23b in some other pathologic and biological process
Function
Target
Reference
IL-17
Up/down regulation down
suppress IL-17−, TNF-a− or IL-1b–induced NF-kB activation and inflammatory cytokine expression repress autoimmune inflammation
TAB3 IKK-α TAB2
(Leone, D'Angelo et al. 2012)
human goiters
TSH
up
promotes thyroid cell growth
smad3
(Leone, D'Angelo et al. 2012)
induce chondrocyte differentiation
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Chondrogenic differentiation
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Factor
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Diseases and process inflammatory autoimmune diseases
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maintain a cartilage phenotype by inhibiting matrix breakdown
PRKACB p-CREB MMPs
Pitx2
down
increases cell proliferation in myoblasts enhance Myf5+ satellite cells and promote their commitment to a myogenic cell fate
cyclin D1 cyclin D2
liver regeneration
TGF-b1
down
down-regulation of miR-23b may contribute to activation of the TGF-b1/Smad3 signalling pathway during the termination stage of liver regeneration
Smad3
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myoblast differentiation
(Ham, Lee et al. 2014)
(LozanoVelasco, Vallejo et al. 2015) (Yuan, Dong et al. 2011)
ACCEPTED MANUSCRIPT Abbreviates list MicroRNAs
C9orf3
Chromosome 9 Open Reading Frame 3
pri-miRNAs
primary miRNA
pre-miRNAs
precursor miRNAs
miRISC
miRNA-induced silencing complex
ECs
endothelial cells
VSMCs
vascular smooth muscle cells
ACTA2
smooth muscle α-actin
MYH11
myosin heavy chain
uPA / PLAU
Urokinase-type Plasminogen Activator
SMAD
Mothers against dpp
pulsatile shear E2F transcription factor 1
KLF2
Kruppel like factor 2
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E2F1
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PS
mitogen activated kinase-like protein
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MAPK
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miRNAs
cyclin-dependent kinase-activating kinase
CCNH
cyclin H
CDK
Cyclin-dependent kinase
TLRs
Toll-like receptors
RIG-I
retinoic acid inducible gene I
RLR
retinoic acid inducible gene I like receptor
IFN
interferon
VLDLR
very low density lipoprotein receptor
EV71
enterovirus 71
TP53
tumor protein p53
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CAK
HPV
Human papillomavirus
SRC
non-receptor tyrosine kinase
AKT
serine-threonine protein kinase
PRDX3
peroxiredoxin 3
ACCEPTED MANUSCRIPT Rac family small GTPase 1
MET
c-Met oncogene
RAS
resistance to audiogenic seizures
PI3K
Phosphatidylinositol-4,5-bisphosphate 3-kinase
STAT
signal transducer and activator of transcription
WNT
protein Wnt-2
Zeb1
zinc finger E-box binding homeobox 1
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RAC1
epithelial-to-mesenchymal transition
PAK2
p21 (RAC1) activated kinase 2
MARCKS
myristoylated alanine rich protein kinase C substrate
DHA
haloalkane dehalogenase autophagy related 12
HMGB2
high mobility group box 2
Ets1
transcription factor Ets
FZD7
frizzled class receptor 7
MAP3K1
mitogen-activated protein kinase kinase kinase 1
TGFβR2
transforming growth factor beta receptor 2
RRAS2
RAS related 2
HMGA2
high mobility group AT-hook 2
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ATG12
mitochondrial transcription factor A
MMP
matrix metalloproteinase
PYK2/PTK2B
protein tyrosine kinase 2 beta
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TFAM
RUNX2
runt related transcription factor 2
p53
CG33336 gene product from transcript CG33336-R
PTEN
phosphatase and tensin homolog
EGF
epidermal growth factor
TNFα
tumor necrosis factor alpha
Her2
hairy-related 2
CR
angiomotin like 1
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AMOTL1
IP
EMT
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neuraminidase
NF-κB
nuclear factor of kappa light polypeptide gene enhancer in B cells
TUSC7
Nischarin tumor suppressor candidate 7 von Hippel-Lindau tumor suppressor
HIF-1α
hypoxia inducible factor 1 alpha subunit
VEGF
vascular endothelial growth factor precursor
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VHL
catenin beta 1
TCF4
transcription factor 4
CDH1
cadherin 1
MSCs
mesenchymal stem cells
PRKACB
Protein Kinase A catalytic subunit B
CREB
cAMP responsive element binding protein
PITX2C
paired-like homeodomain 2
CCND
cyclin D
Myf5
myogenic factor 5
HES1
hairy/enhancer of split protein
bHLH
basic helix-loop-helix
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CTNNB1
interleukin
TSH
Thyroid Stimulating Hormone
DNA
Deoxyribonucleic acid
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NISCH
Wei Wang, Yuji Wang, Weijun Liu, Andre J. van Wijnen PII: DOI: Reference:
S0378-1119(17)30931-9 doi:10.1016/j.gene.2017.10.085 GENE 42306
To appear in:
Gene
Received date: Accepted date:
29 September 2017 31 October 2017
Please cite this article as: Wei Wang, Yuji Wang, Weijun Liu, Andre J. van Wijnen , Regulation and biological roles of the multifaceted miRNA-23b (MIR23B). The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Gene(2017), doi:10.1016/j.gene.2017.10.085
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ACCEPTED MANUSCRIPT Regulation and biological roles of the multifaceted miRNA-23b (MIR23B) Wei Wang 1,2, Yuji Wang2,3, Weijun Liu1 , Andre J.van Wijnen2 * 1
Department of Orthopeadics, Pu Ai Hospital, Tongji Medical College, Huazhong University of Science and
Technology, Hubei, China. 2
Department of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905,
Department of Orthopaedics, Changzhou No. 2 People’s Hospital, Nanjing Medical University, 29 Xinglong
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USA
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Alley, Jiangsu, China.
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* Correspondence to:
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Andre J. van Wijnen, Ph.D. Department of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
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Tel: 507-293-2105 Fax: 507-284-5075 Email: [email protected]
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Running headline: Biological control by miR-23b
ACCEPTED MANUSCRIPT ABSTRACT MicroRNAs (miRNAs) are important short endogenous non-coding RNAs that have critical biological roles by acting as post-transcriptional regulators of gene expression. Chromosomal region 9q22.32 encodes the miR23b/27b/24-1 cluster and produces miR-23b, which is a pleiotropic modulator in many developmental processes and pathological conditions. Expression of miR-23b is actively suppressed and induced in response to many different stimuli. We discuss the biological functions and transcriptional regulation of this multifaceted
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miRNA in different tumor types, during development, upon viral infection, as well as in various clinical disorders,
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immune responses, as well as cardiovascular and thyroid functions. The combined body of work suggests that miR-23b expression is modulated by a diverse array of stimuli in cells from different lineages and participates
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in multiple gene regulatory feedback loops. Elevation of miR-23b levels appears to instruct cells to limit their proliferative and migratory potential, while promoting the acquisition of specialized phenotypes or protection
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from invading viruses and parasites. In contrast, loss of miR-23b can deregulate normal tissue homeostasis by removing constraints on cell cycle progression and cell motility. Collectively, the findings on miR-23b indicate that it is a very potent post-transcriptional regulator of growth and differentiation during development, multiple
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cancers and other biological processes. Understanding the regulation and activity of miR-23b has significant diagnostic value in many biological disorders and may identify cellular pathways that are amenable to
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therapeutic intervention.
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Key words: non-coding RNA, cancer, tumor, transcriptional control
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1. Introduction
MicroRNAs have emerged as a major class of gene expression modulators linked to a wide range of biological
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processes, such as cellular proliferation, differentiation and apoptosis (Miska 2005; Park and Peter 2008). Many members of this class of single-stranded short non-coding RNAs are evolutionarily conserved and endogenously generated from chromosomal loci interspersed throughout the genome. Mature miRNA forms are about 22 nucleotides in length on average. Some precursor miRNAs are either encoded in the introns of regular protein-coding host genes, while others are derived from unique long non-coding transcripts encoding one or more miRNAs (miRNA genes or clusters). As is the case for protein coding mRNAs, miRNA genes are transcribed by RNA polymerase II in the nucleus. This review focuses on miR-23b (MIR23B) which is encoded by a long non-coding RNA transcript referred to as Chromosome 9 Open Reading Frame 3 (C9orf3) in human and RIKEN cDNA 2010111I01 gene (2010111I01Rik) in mouse that also contain the miR-27b (MIR27B) and miR-24-1 (MIR24-1).
ACCEPTED MANUSCRIPT The generation of miR-26b and other miRNAs from long precursors is a multistage process that takes place first in the nucleus and then moves to the cytoplasm (Bartel 2004; Ha and Kim 2014). Long primary miRNA transcripts (pri-miRNAs) like C9ORF3 are cleaved by the RNase III enzyme Drosha into ~70 nt stem-loop precursor miRNAs (pre-miRNAs). Pre-miRNAs are exported from the nucleus into the cytoplasm via Exportin-5 and cleaved by a Dicer containing protein complex into a miRNA duplex (~19–24 nucleotides). This duplex is composed of a guide RNA sequence (e.g., miR-23b) and the passenger RNA that together facilitate a miRNAinduced silencing complex (miRISC) in which miR-23b interacts with complementary sequences in its target
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mRNAs, while the passenger strand is typically degraded. Most miRNAs have tens if not hundreds of target
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genes, and many protein-encoding genes (>60%) have one or more predicted miRNA binding sites. Therefore,
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miRNAs constitute one of the largest and most important classes of gene regulatory molecules (Ha and Kim 2014). Of these, miR-23b is a particularly potent pleiotropic modulator in different diseases and disorders. Recent advances necessitate a critical appraisal of how this multifaceted miRNA is transcriptionally controlled
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and affects both normal and disease related cellular signaling pathways and gene regulatory networks.
2.1 Regulation of cardiovascular cells by miR-23b
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2. The regulation and functional role of miR-23b in different diseases
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Expression of miR23b is highly elevated in many vascularized tissues and play critical roles in cardiovascular development, angiogenesis, cardiac ischemia and endothelial cells (ECs) homeostasis (Bang, Fiedler et al.
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2012) (Fig 1). Recent studies have shown that miR-23b enhance angiogenesis by promoting angiogenic signaling by targeting Sprouty2 and Sema6A proteins, which exert antiangiogenic activity (Zhou, Gallagher et
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al. 2011). Phenotypic switches of vascular smooth muscle cells (VSMCs) play a key role in the pathogenesis of different vascular diseases (Alexander and Owens 2012). Gain-of-function studies showed that overexpression
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of miR-23b inhibited VSMC proliferation and migration, whereas the opposite effect was obtained with the in vitro inhibition of miR-23b (Iaconetti, De Rosa et al. 2015). It also has been demonstrated that miR-23b can significantly promote the expression of VSMC marker genes such as smooth muscle α-actin (ACTA2) and
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smooth muscle myosin heavy chain (MYH11). The effect of miR-23b on VSMCs is mediated, at least in part, by targeting SMAD3, Urokinase-type Plasminogen Activator (uPA, PLAU) and FOXO4, key regulators of VSMC physiology (Iaconetti, De Rosa et al. 2015). Hence, miR-23b is a critical factor for normal vascular function. Several studies have shown that miR-23b is up-regulated by laminar flow (Wang, Garmire et al. 2010; Hergenreider, Heydt et al. 2012). MAPKs, which are linked to mitogenic growth factor activation and SMAD signaling, mediate shear-induced miR23b expression, while miR-23b provides negative feedback regulation of shear-induced MAPK activation (He, Li et al. 2012). Growth arrest of vascular endothelial cells (ECs) induced by pulsatile shear (PS) flow is important for flow regulation of ECs (Lin, Hsu et al. 2000). The increased
ACCEPTED MANUSCRIPT expression of miR-23b by shear stress inhibits cell cycle progression of ECs by indirectly blocking phosphorylation of the retinoblastoma protein and by reducing E2F1 expression (Wang, Garmire et al. 2010). MiR-23b was also induced by the flow-dependent transcription factor KLF2 (Hergenreider, Heydt et al. 2012), which is a critical regulator of endothelial gene expression patterns induced by atheroprotective flow (Boon and Horrevoets 2009). Moreover, pulsatile shear flow-induced and KLF2 mediated
expression of miR-23b
regulates the cyclin-dependent kinase-activating kinase (CAK) complex, which is composed of CDK7 and cyclin H (CCNH) to exert anti-proliferative effects on ECs. The KLF2-dependent elevation of miR-23b in
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response to pulsatile shear flow suppresses CCNH, which impairs the integrity and activity of the CAK complex
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and reduces the activities of CDK2 and CDK4 (Wang, Nguyen et al. 2014). While pulsatile shear flow regulates
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the miR-23b/CAK pathway to exert anti-proliferative effects on ECs, oscillatory shear flow has little effect on the miR-23b/CAK pathway and hence does not cause EC growth arrest (Wang, Nguyen et al. 2014). These studies revealed that miR-23b is an important shear flow-dependent regulator of vascular cell growth and
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2.2 Control of virus infection by miR-23b levels.
Because of their principal roles as post-transcriptional regulators, miRNAs are key effector molecules in the
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complicated interaction network between virus and host (Kurzynska-Kokorniak, Jackowiak et al. 2009), and indeed miR-23B also performs important biological roles in virus infection (Fig. 2). For example, Ouda and
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colleagues demonstrated that the expression of miR-23b is induced during viral infection by the innate immune response, which is mediated by Toll-like receptors (TLRs) and the retinoic acid inducible gene I (RIG-I)-like receptor (RLR). These receptors normally activate the type I interferon (IFN) system to produce antiviral
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proteins that inhibit various steps of viral replication and facilitate the subsequent activation of acquired immune responses. Activation of RLR signaling by rhinovirus infection upregulates miR-23b to attenuate
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expression of the very low density lipoprotein receptor (VLDLR) used for viral entry (Ouda, Onomoto et al. 2011). Furthermore, enterovirus 71 (EV71) infection downregulates the expression of miR-23b, because
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otherwise miR-23b would inhibit EV71 replication by suppressing EV71 VPl protein (Wen, Dai et al. 2013). Other studies showed that the expression of miR-23b is upregulated during infection with either influenza A virus (Makkoch, Poomipak et al. 2015) or Epstein-Barr virus (Imig, Motsch et al. 2011). Although the exact roles of miR-23b in virus infections remain to be further studied, it is evident that modulations in this miRNA has important functions in regulating both cellular and viral responses after infection. The miR-23b/uPA(PLAU) pathway may be important for the effects of the oncogenic human papillomaviruses HPV-16 in provoking the development of cervical cancer (Au Yeung, Tsang et al. 2011). Cervical cancer involves inactivation of p53 (TP53) by the viral oncoprotein E6. The loss of p53 prevents activation of miR-23b expression through a p53 binding site in the promoter of the MIR23B gene on chromosome 9 (Au Yeung, Tsang et al. 2011). Moreover, miR-23b is often downregulated in HPV-associated cervical cancer and the
ACCEPTED MANUSCRIPT upregulation of uPA (PLAU) due to reduced expression of miR-23b instigates cell migration as a key step towards metastasis and invasiveness (Duffy, Maguire et al. 1999) and may represent a prognostic indicator of cervical cancer (Riethdorf, Riethdorf et al. 1999).
2.3 Role of miR-23b as a metastatic suppressor miRNA
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Investigations of variety of different tumors has shown that down-regulation of miR-23b promotes cancer
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progression, suggesting that it may act as a tumor suppressor consistent with a number of recent studies on
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the role of miR-23b loss of function in cancer (Table 1) Prostate cancer
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Several reports have shown that the expression of miR-23b is down-regulated in metastatic, castrationresistant tumors compared to primary prostate cancer and benign tissue, while elevated expression of miR-23b is associated with higher survival rates in prostate cancer patients. In contrast, high levels of miR-23b directly
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attenuates several proto-oncogenes, including SRC kinase, AKT, PRDX3 and RAC1, and overexpression of miR-23b inhibits proliferation, migration, invasion, cell cycle arrest, and apoptosis in prostate cancer(He, Zhu et
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al. 2012; Ishteiwy, Ward et al. 2012; Majid, Dar et al. 2012). These findings are generally consistent with the importance of p53 function during prostate tumorigenesis (Downing, Russell et al. 2003) and that a p53 binding
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Bladder cancer
Similar to its cancer-protective role in prostate cancer, miR-23b functions as a tumor suppressor and may
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contribute to metastasis in bladder cancer patients (Chiyomaru, Seki et al. 2015). One mechanism by which miR-23b suppresses bladder tumors is by inhibiting expression of the c-Met oncogene (MET), which activates
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multiple signal transduction pathways, including RAS, PI3K-AKT, STAT and WNT/β-catenin(Monga, Mars et al. 2002; O'Brien, Tang et al. 2004). Another mechanism that miR-23b may employ is its ability to block Zeb1 (Majid, Dar et al. 2013), one of the crucial regulators of the epithelial-to-mesenchymal transition (EMT) (Sayan, Griffiths et al. 2009). Consistent with these findings, over-expression of miR-23b in bladder cancer cells inhibits cell proliferation, impairs colony formation, induces a G0/G1 cell cycle arrest and forces apoptosis, while blocking cell migration and invasion (Majid, Dar et al. 2013). Breast Cancer Beyond prostate and bladder, miR-23b regulates focal adhesion, cell spreading, cell-cell junctions and the formation of lamellipodia in breast cancer. In this cancer type, presences of miR-23b reduces cell motility and invasion, by altering cytoskeletal dynamics by suppressing the PAK2 gene. Inhibition of miR-23b increases cell
ACCEPTED MANUSCRIPT migration and metastasis in vivo breast cancer models, and low miR-23b expression correlates with the clinical development of metastases in breast cancer patients (Pellegrino, Stebbing et al. 2013). Direct effects on tumor growth are also evident, because overexpression of miR-23b in a bone marrow–derived metastatic human breast cancer induces a dormant phenotype by suppressing MARCKS, which encodes a protein that promotes cell cycle progression and motility (Ono, Kosaka et al. 2014). Angiogenesis is also controlled by miR-23b, based on the observation that miR-23b is linked to the mechanism of action for docosahexaenoic acid (DHA), a natural compound with anticancer and anti-angiogenesis activity. Overexpression of miR-23b decreases the
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expression of two key pro-angiogenic target genes (uPA/PLAU, AMOTL1), while significantly inhibiting tube
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formation by endothelial cells (Hannafon, Carpenter et al. 2015). Importantly, this same study also suggests
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that transfer of miR-23b and other microRNAs by exosomes may account for the anti-angiogenic action of DHA in recipient endothelial cells (Hannafon, Carpenter et al. 2015). This finding suggests that miR-23b is both a
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tumor-intrinsic suppressor and a paracrine inhibitor of vascularization. Gastro-intestinal cancer
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Another key role for miR-23b-3p was revealed by its ability to inhibit autophagy mediated by ATG12 and HMGB2 in gastric cancer cells that sensitized these cells to chemotherapy (An, Zhang et al. 2015). Its tumor-
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suppressive effects on gastric cancer progression may also involve inhibition of Ets1 and the Notch2 receptor as part of a reciprocal regulatory feedback loop in gastric carcinogenesis (Huang, Ping et al. 2015). Down-
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regulation of miR-23b in human colon cancer results in activation of multiple metastasis-related cellular patwhays, including tumor growth, invasion and angiogenesis. The mechanisms involves modulation of a cohort of pro-metastatic targets, including FZD7 , MAP3K1, PAK2, TGFβR2 , RRAS2 or uPA/PLAU (Zhang,
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Hao et al. 2011).
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Glioma
Expression of miR-23b expression is silenced by methylation and induction of miR-23b expression exerts cell
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growth-inhibitory effects in glioma cels. This growth inhibition is linked to down-regulation of HMGA2, which results in cell cycle arrest (Geng, Luo et al. 2012). In addition, overexpression of miRNA-23b in glioma cells directly suppresses mitochondrial transcription factor A (TFAM) resulting inhibition of proliferation, as well as cell migration and colony formation. In contrast, overexpression of TFAM had opposite effects as expected and significantly enhanced these same biological processes (Jiang, Yang et al. 2013). Furthermore, miRNA-23b controls the activity of the PI3K/Akt signaling pathway (Jiang, Yang et al. 2013), which is critical for cell proliferation and migration, and the expression of invasion-related proteins MMP2, MMP9 and protein tyrosine kinase 2 beta (PYK2/PTK2B) (Loftus, Ross et al. 2012; Jiang, Yang et al. 2013). Taken together, the biological processes targeted by miR-23b are similar to those described for other tumors, although the proposed targets are different.
ACCEPTED MANUSCRIPT Other cancers Ectopic expression of miR-23b significantly inhibits ovarian cancer cell proliferation and tumorigenicity by down-regulating the expression of RUNX2, and its expression level may be a potential prognostic marker that is inversely related to epithelial ovarian cancer (Li, Liu et al. 2014). This anti-tumor activity of miR23B, which may be directly depend on activation by p53, is analogous to the anti-tumor activity of miR-34, which is activated by p53 and prevents RUNX2 activation osteosarcoma (van der Deen, Taipaleenmaki et al. 2013).
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Furthermore, overexpression of miR-23b suppresses the translation urokinase-type plasminogen activator
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(uPA/PLAU) and c-Met(MET), and decreases migration and proliferation of hepatocellular carcinoma cells (Salvi, Sabelli et al. 2009). Furthermore, similar to observations in gastric cancer discussed above, miR-23b
pancreatic cancer cells to irradiation (Wang, Zhang et al. 2013).
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2.4 Role of miR-23b as an oncogenic miRNA
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suppresses expression of the autophagy regulator ATG12 that decreases autophagic activity and sensitizes
Although the role of miR-23b as a tumor suppressor has been well established, many studies demonstrated
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that it can also act as oncogenic miRNA (Table. 2). In an univariate survival analysis of ovarian carcinoma, high levels of miR-23b were associated with poor progression-free survival and this unfavorable diagnosis may
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be related to low expression of tumor suppressor PTEN, which is a validated target of miR-23b (Vaksman, Trope et al. 2014). Downregulation of PTEN by miR-23b promotes prostate cancer cell proliferation in vitro
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(Tian, Fang et al. 2013). Other studies on the regulation of miR-23b indicate that tumor growth factors EGF and TNFα, as well as Her2/neu, induce expression of miR-23b via the NF-κB signaling pathway in breast
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cancer. Suppression of miR-23b activity results in the up-regulation of the tumor suppressor Nischarin (NISCH) and decreased of tumor growth and metastasis in vivo (Jin, Wessely et al. 2013). Analysis of 160 Chinese
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gastric cancer patients revealed that miR-23a and miR-23b expression were both higher in gastric cancer patients with shorter overall survival (Ma, Dai et al. 2014). Consistent with the idea that miR-23b has oncogenic activity depending on the biological context, recent studies on miR-23b revealed reciprocal repression
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reflecting feedback control between TUSC7 and miR-23b. In this regulatory pathway, TUSC7 blocks and miR23b promotes cell growth. The results of this study also established that TUSC7 is a p53-regulated tumor suppressor that acts in part by repressing miR-23b in gastric cancer (Qi, Xu et al. 2015). Even though evidence in glioblastoma discussed above indicates that miR-23b is a tumor suppressive miRNA, miR-23b may also have oncogenic properties by enhancing glioma survival and invasion. The latter effects of miR-23B are mediated by VHL via suppression of HIF-1α (HIF1A)/VEGF and β-catenin(CTNNB1)/TCF4 signaling (Chen, Han et al. 2012). Other studies obtained similar results by showing that inhibition of miR-23b in glioma cell lines and orthotopic tumor mouse models results in a reduction in tumor malignancy, a mechanism that at least in part may operate by downregulation of HIF-1α, β-catenin, MMP2, MMP9, VEGF and ZEB1, as well as increased expression of VHL and E-cadherin (CDH1) (Chen, Zhang et al. 2014).
ACCEPTED MANUSCRIPT 2.5 Control of cell differentiation by miR-23B and its role in regenerative medicine Several studies have examined the role of miRNAs in chondrogenic differentiation of mesenchymal stem cells (MSCs) that are critical for successful cartilage regeneration (Kobayashi, Lu et al. 2008; McAlinden, Varghese et al. 2013). Complementary to its role in suppressing cell growth, miR-23b induces chondrocyte differentiation by inhibiting the expression of Protein Kinase A catalytic subunit B (PRKACB) and phosphorylation of CREB, which are downstream targets of Protein Kinase A in synovial fluid-derived mesenchymal stem cells.
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Furthermore, miRNA-23b also appears to maintain cartilage homeostasis by inhibiting extracellular matrix
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breakdown by MMPs (Ham, Lee et al. 2014) (Table 3).
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Consistent with a general role of suppressing cell growth and promoting a differentiated phenotype, miR-23b is highly expressed in differentiated keratinocytes and represents a differentiation biomarker for human skin (Hildebrand, Rutze et al. 2011). Upregulation of miR-23b also occurs during myogenic differentiation (Dmitriev,
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Barat et al. 2013) and bone regeneration (Palmieri, Pezzetti et al. 2008). In myoblasts, transcription factor PITX2C promotes cell proliferation by downregulating several microRNAs including miR-23b, which represses
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the expression of cyclin D1 (CCND1) and cyclin D2 (CCND2) genes. Interestingly, this PITX2C-microRNA pathway controls cell proliferation of early-activated satellite cells, enhances the number of Myf5+ satellite cells
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and promotes their commitment to a myogenic cell fate (Lozano-Velasco, Vallejo et al. 2015) (Table 3). Downregulation of miR-23b may contribute to activation of the TGF-β1 (TGFB1)/SMAD3 signaling pathway during
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the termination stage of liver regeneration (Yuan, Dong et al. 2011) (Table 3). Furthermore, miR-23b promotes neurogenic differentiation by targeting hairy/enhancer of split protein (HES1), which is a bHLH transcriptional repressor functioning in neuronal differentiation (Kimura, Kawasaki et al. 2004). Taken together, the cell growth
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suppressive activity of miR-23b during development and tumorigenesis is accompanied by its ability to control
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differentiation of multiple cell lineages.
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2.6 Association of miR-23b with autoimmune disease and thyroid function Beyond the role of miR23b as a developmentally important and cancer-related and miRNA that can either block tumorigenic or enhance metastatic properties of cells depending on the biological context, miR-23b is also associated with immune responses. For example, miR-23b regulates the inflammatory cytokine interleukin-17 (IL17), and other cytokines in many immune processes, including expression of tumor necrosis factor-α (TNF) and interleukin-1β (IL1B)–mediated activation of transcription factor nuclear factor κB (NFκB/NFKB1). As is the case in other molecular pathways described above, miR-23b participates in a feedback loop that regulates the inflammatory response and is disrupted in autoimmune diseases (Zhu, Pan et al. 2012) (Table 3). Furthermore, treatment of thyroid follicular cells with Thyroid Stimulating Hormone (TSH) induces entry into S phase of the cell cycle and is associated with up-regulation of miR-23b. This stimulation of
ACCEPTED MANUSCRIPT cell cycle progression is achieved by miR-23b dependent inhibition of TGF-β/Smad3 signaling (Leone, D'Angelo et al. 2012) (Table 3). These studies provide further evidence for the broad utilization of the regulatory potential of miR-23b in diverse biological processes.
2.7 Parasite infection
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Because miR-23b controls immune responses through effects on the NFkB-pathway, it is perhaps not
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surprising that expression of this miRNA is modulated during infection by Cryptosporidium parvum, which is a protozoan parasite that infects the gastrointestinal epithelium and causes diarrheal disease worldwide. Studies
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by Rui Zhou and colleagues identified a panel of miRNAs, including miR-23b, that are transcriptionally activated by NFkB/p65 (NKFB1) in human cholangiocytes in response to C. parvum infection. (Zhou, Hu et al.
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2009). Furthermore, miR-23b is among a subset of miRNA genes that is trans-activated by promoter binding of STAT3 during Toxoplasma gondii infection. Importantly, functional inhibition of selected STAT3-binding miRNAs in human macropahges increased apoptosis of host cells (Cai, Chen et al. 2013). These findings
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collectively indicate that miR-23b forms part of a regulatory network with NFkB and STAT3 that may be
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relevant to the regulation of epithelial anti-microbial defenses in general. 3. Conclusion
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During the last years, the development of different high throughput miRNA profiling technologies has revealed that miR-23B expression is modulated in many different diseases, including normal growth and differentiation
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during development, cancer, cardiovascular disease, as well as virus infection, autoimmune disease and parasite infection. In these diverse biological process and diseases, miR-23b targets many different mRNAs of
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different genes that form negative feedback loops. Of particular note are its epigenetic suppression by DNA methylation, as well as its activation by p53, NFkB and STAT3 in different contexts, and its ability to control cell
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growth and differentiation through effects on multiple signaling pathways. The next challenge will be to modulate levels of miR-23b in animal models of different diseases and apply loss-of-function and gain-offunction approaches to evaluate the biological importance of miR-23b in vivo and to translate the in vivo results to the clinical management of miR-23b controlled diseases through diagnosis, treatment, and prognosis.
Disclosure: This work was supported by Natural Science Foundation of Hubei Province of China. Grant 2017CFB470. None of the authors acknowledge any conflict of interest in connection with this submission.
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ACCEPTED MANUSCRIPT Table.1 Overview of miR-23b acting as a metastatic suppressor miRNA
metastasis suppressors that might serve as novel biomarkers and therapeutic agents
Rac1
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Target Src kinase Akt PRDX3
(He, Zhu et al. 2012) (Ishteiwy, Ward et al. 2012) (Chiyomaru, Seki et al. 2015)
inhibit cancel cell proliferation, migration, invasion and impair colony formation induce G0/G1 cell cycle arrest and apoptosis
Zeb1
(Majid, Dar et al. 2013)
a central role in cytoskeletal dynamics reduce cell motility and invasion
PAK2
(Pellegrino, Stebbing et al. 2013)
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Breast Cancer
Reference
c-Met
repress cancer cell proliferation, migration and invasion
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bladder cancer
Function Inhibit proliferation, colony formation, migration and invasion trigger G0/G1 cell cycle arrest and apoptosis suppress the response of PRDX3 expression to hypoxic condition
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Tumor types prostate cancer
PLAU AMOTL1
(Hannafon, Carpenter et al. 2015)
contribute to the induction of dormancy in disseminated breast cancer cells
MARCKS
(Ono, Kosaka et al. 2014)
inhibit autophagy sensitize gastric cancer cells to chemotherapy act as a prognostic factor for overall survival suppress tumor progression affect tumor sphere ultra-structure in gastric cancer cells
ATG12 HMGB2
(An, Zhang et al. 2015)
Notch2 receptor Ets1 FZD7 MAP3K1
(Huang, Ping et al. 2015)
induce cancer cell cycle arrest inhibit cancel cell proliferation
HMGA2
(Geng, Luo et al. 2012)
Inhibit the proliferation, cell cycle progression, migration and colony formation in glioma cells
TFAM PI3K/Akt
Inhibit glioma cell migration and invasion
Pyk2
(Loftus, Ross et al. 2012)
ovarian cancer
Inhibit cancer cell proliferation and tumorigenicity a potential prognostic marker
RUNX2
(Li, Liu et al. 2014)
hepatocellular
decrease cancer cells migration and proliferation
uPA
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digestive tract cancer
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inhibit tube formation by endothelial cells anticancer and anti-angiogenesis
glioma
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mediate multiple steps of metastasis, including tumor growth, invasion and angiogenesis
(Zhang, Hao et al. 2011)
(Jiang, Yang et al. 2013)
(Salvi, Sabelli
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et al. 2009)
ATG12
(Wang, Zhang et al. 2013)
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decrease autophagic activity sensitize pancreatic cancer cells to irradiation
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pancreatic cancer
c-Met
ACCEPTED MANUSCRIPT Table.2 Overview of miR-23b acting as an oncogenic miRNA Function high levels of miR-23b was associated with poor progression-free survival
Target PTEN
prostate cancer
promote prostate cancer cell proliferation
PTEN
breast cancer
increase tumour growth and metastasis
Nischarin
gastric cancer
promote cancer cell growth in gastric cancer
glioma
increase tumor survival promote tumor malignancy
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Tumor types ovarian carcinoma
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TUSC7 VHL E-cadherin
Reference (Vaksman, Trope et al. 2014) (Tian, Fang et al. 2013) (Jin, Wessely et al. 2013) (Qi, Xu et al. 2015) (Chen, Han et al. 2012) (Chen, Zhang et al. 2014)
ACCEPTED MANUSCRIPT Table.3 Regulation and role of miR-23b in some other pathologic and biological process
Function
Target
Reference
IL-17
Up/down regulation down
suppress IL-17−, TNF-a− or IL-1b–induced NF-kB activation and inflammatory cytokine expression repress autoimmune inflammation
TAB3 IKK-α TAB2
(Leone, D'Angelo et al. 2012)
human goiters
TSH
up
promotes thyroid cell growth
smad3
(Leone, D'Angelo et al. 2012)
induce chondrocyte differentiation
CR
Chondrogenic differentiation
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Factor
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Diseases and process inflammatory autoimmune diseases
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maintain a cartilage phenotype by inhibiting matrix breakdown
PRKACB p-CREB MMPs
Pitx2
down
increases cell proliferation in myoblasts enhance Myf5+ satellite cells and promote their commitment to a myogenic cell fate
cyclin D1 cyclin D2
liver regeneration
TGF-b1
down
down-regulation of miR-23b may contribute to activation of the TGF-b1/Smad3 signalling pathway during the termination stage of liver regeneration
Smad3
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myoblast differentiation
(Ham, Lee et al. 2014)
(LozanoVelasco, Vallejo et al. 2015) (Yuan, Dong et al. 2011)
ACCEPTED MANUSCRIPT Abbreviates list MicroRNAs
C9orf3
Chromosome 9 Open Reading Frame 3
pri-miRNAs
primary miRNA
pre-miRNAs
precursor miRNAs
miRISC
miRNA-induced silencing complex
ECs
endothelial cells
VSMCs
vascular smooth muscle cells
ACTA2
smooth muscle α-actin
MYH11
myosin heavy chain
uPA / PLAU
Urokinase-type Plasminogen Activator
SMAD
Mothers against dpp
pulsatile shear E2F transcription factor 1
KLF2
Kruppel like factor 2
IP CR US
ED
E2F1
AN
PS
mitogen activated kinase-like protein
M
MAPK
T
miRNAs
cyclin-dependent kinase-activating kinase
CCNH
cyclin H
CDK
Cyclin-dependent kinase
TLRs
Toll-like receptors
RIG-I
retinoic acid inducible gene I
RLR
retinoic acid inducible gene I like receptor
IFN
interferon
VLDLR
very low density lipoprotein receptor
EV71
enterovirus 71
TP53
tumor protein p53
AC
CE
PT
CAK
HPV
Human papillomavirus
SRC
non-receptor tyrosine kinase
AKT
serine-threonine protein kinase
PRDX3
peroxiredoxin 3
ACCEPTED MANUSCRIPT Rac family small GTPase 1
MET
c-Met oncogene
RAS
resistance to audiogenic seizures
PI3K
Phosphatidylinositol-4,5-bisphosphate 3-kinase
STAT
signal transducer and activator of transcription
WNT
protein Wnt-2
Zeb1
zinc finger E-box binding homeobox 1
T
RAC1
epithelial-to-mesenchymal transition
PAK2
p21 (RAC1) activated kinase 2
MARCKS
myristoylated alanine rich protein kinase C substrate
DHA
haloalkane dehalogenase autophagy related 12
HMGB2
high mobility group box 2
Ets1
transcription factor Ets
FZD7
frizzled class receptor 7
MAP3K1
mitogen-activated protein kinase kinase kinase 1
TGFβR2
transforming growth factor beta receptor 2
RRAS2
RAS related 2
HMGA2
high mobility group AT-hook 2
CE
PT
ED
M
AN
ATG12
mitochondrial transcription factor A
MMP
matrix metalloproteinase
PYK2/PTK2B
protein tyrosine kinase 2 beta
AC
TFAM
RUNX2
runt related transcription factor 2
p53
CG33336 gene product from transcript CG33336-R
PTEN
phosphatase and tensin homolog
EGF
epidermal growth factor
TNFα
tumor necrosis factor alpha
Her2
hairy-related 2
CR
angiomotin like 1
US
AMOTL1
IP
EMT
ACCEPTED MANUSCRIPT neu
neuraminidase
NF-κB
nuclear factor of kappa light polypeptide gene enhancer in B cells
TUSC7
Nischarin tumor suppressor candidate 7 von Hippel-Lindau tumor suppressor
HIF-1α
hypoxia inducible factor 1 alpha subunit
VEGF
vascular endothelial growth factor precursor
IP
VHL
catenin beta 1
TCF4
transcription factor 4
CDH1
cadherin 1
MSCs
mesenchymal stem cells
PRKACB
Protein Kinase A catalytic subunit B
CREB
cAMP responsive element binding protein
PITX2C
paired-like homeodomain 2
CCND
cyclin D
Myf5
myogenic factor 5
HES1
hairy/enhancer of split protein
bHLH
basic helix-loop-helix
PT
ED
M
AN
US
CR
CTNNB1
interleukin
TSH
Thyroid Stimulating Hormone
DNA
Deoxyribonucleic acid
CE
IL
AC
T
NISCH