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MicroRNAs (miRs) are small noncoding RNAs that play important roles in both physiological and pathological processes through post‐transcriptional regulation. The miR‐17‐92 cluster includes six individual members: miR‐17, miR‐18a, miR‐19a, miR‐19b‐1, miR‐20a, and miR‐92a‐1. The miR‐17‐92 cluster has been extensively studied and reported to broadly function in cancer biology, immunology, neurology, pulmonology, and cardiology. This review focuses on its roles in heart development and cardiac diseases. We briefly introduce the nature of the miR‐17‐92 cluster and its crucial roles in both normal development and the pathogenesis of various diseases. We summarize the recent progress in understanding the versatile roles of miR‐17‐92 during cardiac development, regeneration, and aging. Additionally, we highlight the indispensable roles of the miR‐17‐92 cluster in pathogenesis and therapeutic potential in cardiac birth defects and adult cardiac diseases. [ABSTRACT FROM AUTHOR]

miR-17-92 cluster encodes six micro RNAs (miRNAs) and plays a crucial role in the regulation of various cellular processes. Aberrant expression of this cluster may result in the onset of several diseases. Initially, the role of miR-17-92 cluster in tumorigenesis was discovered but recent research has also uncovered its role in other diseases. Members of the cluster may serve as potential biomarkers in the prognosis, diagnosis, and treatment of several diseases and their complications. In this article, we have reviewed the recent research carried out on the expression pattern of miR-17-92 cluster in non-communicable diseases i.e., obesity, cardiovascular diseases (CVD), kidney diseases (KD) and diabetes mellitus (DM). We examined miR-17-92 role in pathological processes and their potential importance as biomarkers. Each member of the cluster miR-17-92 was upregulated in obesity. miR-18a, miR-19b-3p, miR20a, and miR92a were significantly upregulated in CVD. An equal fraction of the cluster was dysregulated (upregulated and downregulated) in diabetes; however, miR-17-92 was downregulated in most studies on CKD. [ABSTRACT FROM AUTHOR]

MicroRNA (miRNA) biogenesis is tightly regulated to maintain distinct miRNA expression patterns. Almost half of mammalian miRNAs are generated from miRNA clusters, but this process is not well understood. We show here that Serine‐arginine rich splicing factor 3 (SRSF3) controls the processing of miR‐17‐92 cluster miRNAs in pluripotent and cancer cells. SRSF3 binding to multiple CNNC motifs downstream of Drosha cleavage sites within miR‐17‐92 is required for the efficient processing of the cluster. SRSF3 depletion specifically compromises the processing of two paralog miRNAs, miR‐17 and miR‐20a. In addition to SRSF3 binding to the CNNC sites, the SRSF3 RS‐domain is essential for miR‐17‐92 processing. SHAPE‐MaP probing demonstrates that SRSF3 binding disrupts local and distant base pairing, resulting in global changes in miR‐17‐92 RNA structure. Our data suggest a model where SRSF3 binding, and potentially its RS‐domain interactions, may facilitate an RNA structure that promotes miR‐17‐92 processing. SRSF3‐mediated increase in miR‐17/20a levels inhibits the cell cycle inhibitor p21, promoting self‐renewal in normal and cancer cells. The SRSF3‐miR‐17‐92‐p21 pathway operates in colorectal cancer, linking SRSF3‐mediated pri‐miRNA processing and cancer pathogenesis. Synopsis: SRSF3 binds to CNNC motifs within the miR‐17‐92 cluster and promotes the processing of specific cluster miRNAs. SRSF3 binding changes miR‐17‐92 structure, and this may impact miR‐17‐92 processing. Both SRSF3 binding to multiple positions within the miR‐17‐92 cluster RNA and the SRSF3 RS‐domain are required for the processing of cluster miRNAs.SHAPE‐MaP analyses demonstrate that SRSF3 binding to miR‐17‐92 alters its secondary structure.SRSF3‐mediated increase in miR‐17/20a levels promotes self‐renewal by inhibiting the cell cycle inhibitor p21 and marks advance colorectal cancer, linking SRSF3‐mediated pri‐miRNA processing to cancer pathogenesis. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cells (iPSCs) are promising cell sources for regenerative medicine and disease modeling. iPSCs are commonly established by introducing the defined reprogramming factors Oct4, Sox2, Klf4, and c-Myc. However, iPSC reprogramming efficiency remains low. Although recent studies have identified microRNAs that contribute to efficient reprogramming, the underlying molecular mechanisms are not completely understood. miR-17-92 is highly expressed in embryonic stem cells and may play an important role in regulating stem cell properties. Therefore, we examined the role of miR-17-92 in the induction of mouse iPSC production. c-Myc-mediated miR-17-92 upregulation increased reprogramming efficiency, whereas CRISPR/Cas9-based deletion of the miR-17-92 cluster decreased reprogramming efficiency. A combination of in silico and microarray analyses revealed that Pten and cyclin-dependent kinase inhibitor 1 (known as p21) are common target genes of miR-17 and miR-20a, which are transcribed from the miR-17-92 cluster. Moreover, miR-17-92 downregulated p21 in the early phase and PTEN in the mid-to-late phase of reprogramming. These downregulations were perturbed by introducing the 3′ UTR of PTEN and p21, respectively, suggesting that PTEN and p21 mRNAs are competing endogenous RNAs (ceRNA) against miR-17-92. Collectively, we propose that the c-Myc-mediated expression of miR-17-92 is involved in iPSC reprogramming through the phase-dependent inhibition of PTEN and p21 in a ceRNA manner, thus elucidating an underlying mechanism of iPSC reprogramming. [ABSTRACT FROM AUTHOR]

Gain of chromosome arm 13q is one of the most prevalent DNA copy number alterations associated with colorectal adenoma-to-carcinoma progression. The oncogenic miR-17-92 cluster, located at 13q, was found to be overexpressed in colorectal cancer and in adenomas harboring 13q gain. However, to what extent overexpression of this group of microRNAs actually drives progression to cancer remains to be resolved. Therefore, we aimed to clarify the role of miR-17-92 cluster in the progression from colorectal adenoma to carcinoma.The miR-17-92 cluster was overexpressed in human colorectal adenoma organoids without 13q gain and downstream effects on mRNA expression were investigated, along with functional consequences in vitro and in vivo.Comparison of mRNA sequencing results of organoids overexpressing miR-17-92 and cultures transduced with control vector revealed a miR-17-92 expression signature. This signature appeared to be enriched in an independent series of colorectal cancers and adenomas with 13q gain, confirming that miR-17-92 expression is associated with malignant progression. However, tumor-associated characteristics, such as increased proliferation rate, were not observed in miR-17-92 overexpressing adenoma organoids in vitro. In addition, subcutaneous injection of these organoids in immunodeficient mice was insufficient to cause tumor outgrowth.In conclusion, this study showed that miR-17-92 expression contributes to 13q gain-associated adenoma-to-carcinoma progression, however, this is insufficient to cause malignancy.

Induced pluripotent stem cells (iPSCs) are promising cell sources for regenerative medicine and disease modeling. iPSCs are commonly established by introducing the defined reprogramming factors Oct4, Sox2, Klf4, and c-Myc. However, iPSC reprogramming efficiency remains low. Although recent studies have identified microRNAs that contribute to efficient reprogramming, the underlying molecular mechanisms are not completely understood. miR-17-92 is highly expressed in embryonic stem cells and may play an important role in regulating stem cell properties. Therefore, we examined the role of miR-17-92 in the induction of mouse iPSC production. c-Myc-mediated miR-17-92 upregulation increased reprogramming efficiency, whereas CRISPR/Cas9-based deletion of the miR-17-92 cluster decreased reprogramming efficiency. A combination of in silico and microarray analyses revealed that Pten and cyclin-dependent kinase inhibitor 1 (known as p21) are common target genes of miR-17 and miR-20a, which are transcribed from the miR-17-92 cluster. Moreover, miR-17-92 downregulated p21 in the early phase and PTEN in the mid-to-late phase of reprogramming. These downregulations were perturbed by introducing the 3′ UTR of PTEN and p21, respectively, suggesting that PTEN and p21 mRNAs are competing endogenous RNAs (ceRNA) against miR-17-92. Collectively, we propose that the c-Myc-mediated expression of miR-17-92 is involved in iPSC reprogramming through the phase-dependent inhibition of PTEN and p21 in a ceRNA manner, thus elucidating an underlying mechanism of iPSC reprogramming.

MicroRNAs (miRNAs) are emerging as key controllers of T-cell differentiation and function. Their expression is dynamically regulated by extracellular signals such as costimulation and cytokine signals. miRNAs set thresholds for gene expression and optimize protein concentrations of genetic networks. Absence of individual miRNAs can lead to severe immune dysfunction. In this study, we review emerging principles and provide examples of important functions exerted by miRNAs. Although our understanding of miRNA function in T-cell differentiation is still rudimentary, the available evidence leaves no doubt that these small post-transcriptional regulators are indispensable for proper functioning of the immune system.

Abstract Background While vaccination remains the most effective method to control hepatitis B virus (HBV) infection, 5–10% of recipients exhibit non-responsiveness to the HB vaccine. Immunological analysis of strong, weak or absent protective antibody responses to the HB vaccine should provide insights into the mechanisms that contribute to non-responsiveness. Results We investigated the potential involvement of follicular helper T (Tfh) cells in the immune response to HB vaccine, and associations between the miR-17–92 cluster and Tfh cells. We recruited 12 adults who had completed the HB vaccination course during childhood. Following a booster dose of HB vaccine, hepatitis B surface antibody (HBsAb) titers, percentage of PD-1+ICOS+ circulating Tfh (cTfh) and plasma cells, and expression of miR-17–92 were assessed at baseline (before immunization) and after vaccination on days 7 and 14. Notably, the HBsAb level gradually increased after HB vaccination while the proportion of PD-1+ICOS+ cTfh cells was significantly increased on day 7 relative to baseline, so as plasma cells. Expression of miR-18a and miR-17 within the miR-17–92 cluster and HBsAb titers in CD4+ T cells were positively correlated with the PD-1+ICOS+ cTfh cells proportions after HB vaccination. Conclusions The increase in HBsAb titers was positively associated with expression of all the components of the miR-17–92 cluster except miR-19a. Our findings indicate that the miR-17–92 cluster contributes to antibody production, and miR-18a and miR-17 are involved in Tfh cells differentiation after HB vaccination.

High levels of miR-19 play an important role in malignant diseases of the hematopoietic system. Therefore the treatment with corresponding microRNA antagonists seems to be an interesting therapeutic approach. We found a significant increase of apoptosis in Jurkat cells which were transfected with a miR-19b inhibitor. The rise of apoptosis in transfected human monocuclear cells (MNCs) was significant as well, but the unspecific miRNA control induced apoptosis in MNCs to a similar extend. A closer look at the MNC subpopulations revealed higher specific apoptosis in B cells whereas T cell apoptosis was lower and induced by unspecific miRNA interference. [ABSTRACT FROM AUTHOR]

Background: Anxiety and depression are common symptoms in patients with coronary heart disease (CHD) after percutaneous coronary intervention (PCI). The 24-form Tai Chi may exert a protective function for CHD patients after PCI by improving anxiety and depression. Methods: Patients who received PCI after 1–4 days were randomly assigned to the 24-form Tai Chi group (TG) and the control group (CG). The differences in anxiety and depression, using the Medical Outcomes Study 36−item Short−Form Health Survey (SF-36), before and after an average of 10 months of Tai Chi intervention were compared in both groups to analyze the effects of Tai Chi on the emotion and the life quality of CHD patients. Meanwhile, the relative levels of miR-17-92 were measured by using real-time qPCR. The association between the relative levels of miR-17-92 and the anxiety and the depression of CHD patients after PCI was analyzed. Adjusted Cox models were used to explore the effect of Tai Chi exercise in CHD patients. Results: After 10 months of intervention, the changes in the anxiety subscale (P = 0.002), in the depression subscale (P = 0.008), and in the stress (P = 0.015) scores were higher in the TG group when compared to those of the CG group. The proportion of anxious (P = 0.045) and depressed subjects (P = 0.042) in the TG group was lower than that in the CG group. On the other hand, the increase in the SF-36 scores and in the relative levels of miR-17-92 was significantly higher in the TG group when compared with that of the CG group (P < 0.05). The serum level of miR-17-92 had a negative correlation with the anxiety, the depression, and the stress scores (P < 0.01). Conclusion: The 24-form Tai Chi improved the anxiety and the depression symptoms and upregulated the miR-17-92 levels in CHD patients after PCI. [ABSTRACT FROM AUTHOR]

Recent evidence has shown that the miR-17–92 cluster can function either as oncogene or tumor suppressor in human cancers. The function of miR-17–92 in subtypes of breast cancer remains largely unknown. The expression of miR-17–92 is elevated in triple negative breast cancer (TNBC) but reduced in estrogen receptor (ER)-positive breast cancer (ERPBC). We show that increased expression of miRNAs belonging to the miR-17–92 cluster is associated with poor outcome in TNBC, whereas the expression of miR-17–92 miRNAs is with good outcome in ERPBC. We show that ectopic expression of miR-17–92 inhibited cell growth and invasion of ER-positive and HER2-enriched cells. On the contrary, miR-17–92 expression enhanced cell growth and invasion of TNBC cells. Further, we found that miR-17–92 expression sensitized MCF7 cells to chemotherapeutic compounds, whereas it rendered SKBR3 cells resistant to them. We found that expression of ADORA1 was reduced by miR-17–92-expressing breast cancer cells, specifically in ERPBC. We observed an inverse correlation between the expression of ADORA1 and miR-17–92 in human breast cancer. Treatment with DPCPX, a selective ADORA1 antagonist, abolished the difference in the growth of control and miR-17–92 overexpressing MCF7 cells and identified ADORA1 as a key functional target of miR-17–92 in ERPBC. Furthermore, increased expression of ADORA1 in ERPBC is associated with a poor outcome. Our observations underscore the context-dependent role of miR-17–92 in breast cancer subtypes and suggest that miR-17–92 could serve as novel prognostic markers in breast cancer.

Background: Loss of the expression of thyroid differentiation markers such as sodium iodide symporter (NIS) and, consequently, radioiodine refractoriness is observed in aggressive papillary thyroid cancer and anaplastic thyroid cancer (ATC) that may harbor the BRAFV600E mutation. Activation of the BRAFV600E oncogene in thyroid follicular cells induces the expression of the miR-17-92 cluster that comprises seven mature microRNAs (miRNAs). miRNAs are a class of endogenous small RNAs (∼22 nt) that regulate gene expression post-transcriptionally. Indeed, miR-17-92 is overexpressed in ATC, and in silico prediction shows the potential targeting of thyroid transcription factors and tumor suppressor pathways. In this study, we aimed to investigate the role of the miR-17-92 cluster in thyroid cell differentiation and function. Methods:miR-17-92 silencing was performed using CRISPR/Cas9n-guided genomic editing of the miR-17-92 gene in the KTC2 ATC cell line, and miR-17-92 cluster or individual miRNAs were overexpressed in PCCl3 thyroid cells to evaluate the influence in thyroid cell differentiation and cell function. Results: In this study, we demonstrate that CRISPR/Cas9n gene editing of the miR-17-92 cluster results in promotion of thyroid follicular cell differentiation (NIS, thyroperoxidase, thyroglobulin, PAX8, and NKX2-1 expression) in the KTC2 ATC cell line and inhibits cell migration and proliferation by restoring transforming growth factor beta (TGF-β) signaling pathway responsiveness. Moreover, induction of the miR-17-92 cluster in normal thyroid follicular cells strongly impairs thyroid differentiation and induces a pro-oncogenic effect by blocking TGF-β signaling and increasing cell migration. Conclusions:miR-17-92 is a potent regulator of thyroid follicular cell differentiation, and CRISPR/Cas9n-mediated editing of the miR-17-92 gene efficiently blocks miR-17-92 expression in the KTC2 ATC cell line, resulting in improvement of thyroid differentiation. Thus, targeting miR-17-92 could provide a potential molecular approach to restoring thyroid cell differentiation and NIS expression in aggressive thyroid cancer. [ABSTRACT FROM AUTHOR]

miR-17-92 cluster was differentially expressed in cervical cancer, playing an important role in regulating cell proliferation, apoptosis, migration, and invasion. The purpose of this study was to investigate the association between polymorphisms (i.e., rs9588884, rs982873, and rs1813389) in the promoter of miR-17-92 and the risk of cervical squamous cell carcinoma (CSCC). The rs9588884 polymorphism was genotyped using a Taqman assay and the rs982873 and rs1813389 polymorphisms were genotyped using a polymerase chain reaction-restriction fragment length polymorphism method. The expression levels of miR-17-92 were determined using a quantitative PCR analysis. The rs9588884 GG genotype was associated with a reduced risk of CSCC in homozygote comparison (adjusted OR = 0.47, 95% CI, 0.30–0.75, P = 0.001), dominant model (adjusted OR = 0.67, 95% CI, 0.50–0.91, P = 0.01), and recessive model (adjusted OR = 0.57, 95% CI, 0.38–0.85, P = 0.01). The rs9588884 G allele was also associated with a reduced risk of CSCC in allele comparison (adjusted OR = 0.71, 95% CI, 0.58–0.88, P = 0.002). Moreover, patients with the rs9588884 GG genotype had lower levels of miR-20a compared with the rs9588884 CC genotype (P = 0.03). These findings indicate that the rs9588884 GG genotype was associated with lower levels of miR-20a and eventually related to the risk of CSCC in Chinese women. [ABSTRACT FROM AUTHOR]

Skeletal myogenesis is a highly coordinated process that involves cell proliferation, differentiation and fusion controlled by a complex gene regulatory network. The microRNA gene cluster miR-17–92 has been shown to be related to this process; however, the exact role of each cluster member remains unclear. Here, we show that miR-17 and miR-20a could effectively promote the differentiation of both C2C12 myoblasts and primary bovine satellite cells. In contrast, miR-18a might play a negative role in C2C12 cell differentiation, while miR-19 and miR-92a had little influence. Transcriptome and target analyses revealed that miR-17 could act on Ccnd2, Jak1 and Rhoc genes that are critical for cell proliferation and/or fusion. Notably, the addition of miR-19 could reverse the lethal effect of miR-17 and could thus facilitate the maturation of myotubes. Furthermore, by co-injecting the lentiviral shRNAs of miR-17 and miR-19 into mouse tibialis anterior muscles, we demonstrated the wound healing abilities of the two miRNAs. Our findings indicate that in combination with miR-19, miR-17 is a potent inducer of skeletal muscle differentiation. [ABSTRACT FROM AUTHOR]

Proper appetite, energy expenditure, and glucose and fat metabolisms are regulated by neurons in the arcuate nucleus (ARC) of mammalian hypothalamus. Studies have shown sex-specific difference in diet-induced obesity, but the underlying mechanisms remain unclear. Here, we show that microRNA (miRNA) miR-7 and miR-17-92 are expressed in proopiomelanocortin (POMC)-expressing neurons in the mouse ARC. Specific knockdown of miR-7 and knockout of miR-17-92 in POMC-expressing neurons aggravate diet-induced obesity only in females and males, respectively. Sex-differentially expressed genes are identified in the male and female ARC of wild-type adult mice using RNA sequencing. Interestingly, some target genes for miR-7 and miR-17-92 not only display sex-differential expression in the male and female ARC but also respond to high-fat diet treatment in miR-7 knockdown and miR-17-92 knockout mice. Our results demonstrate an important role of miRNAs in regulating sex-specific diet-induced obesity, likely through modulating expression of target genes that show sex-differential expression in the ARC of the hypothalamus. [ABSTRACT FROM AUTHOR]

Endothelial cell death is linked to vascular diseases such as atherosclerosis and tissue ischemia. miRNA-17-92 (miR-17–92) is a multiple functional oncogenic miRNA cluster which plays vital roles in tumor angiogenesis and tissue development. However, its role in regulation of endothelial cell ferroptosis remains unclear. In this study, we revealed that miR-17–92 protects endothelial HUVEC cells from erastin-induced ferroptosis. miR-17-92 overexpression significantly reduced erastin-induced growth inhibition and ROS generation of HUVEC cells. Furthermore, Zinc lipoprotein A20, a validated target of miR-17-92, was identified as a novel regulator of endothelial cell ferroptosis. Lentivirus mediated A20 overexpression increased ROS generation and enhanced erastin-induced ferroptosis, whereas A20 knockdown inhibited erastin-induced ferroptosis. Mechanistic studies revealed that erastin-induced ferroptosis is associated with GPX4 downregulation and ACSL4 upregulation. miR-17-92 overexpression or A20 inhibition increased the ACSL4 expression in HUVEC cells. A20 was identified to directly with and regulate ACSL4 expression by immunoprecipitation. It suggests that the A20-ACSL4 axis plays important roles in erastin-induced endothelial ferroptosis. In conclusion, this study revealed a novel mechanism through which miR-17-92 protects endothelial cells from erastin-induced ferroptosis by targeting the A20-ACSL4 axis. • miR-17-92 protects endothelial cells from erastin-induced ferroptosis. • Zinc lipoprotein A20 is identified as a novel regulator of ferroptosis. • A20 regulates ACSL4 by their directly interaction in endothelial cells. • miR-17-92 targets the A20-ACSL4 axis in endothelial cells. [ABSTRACT FROM AUTHOR]

Emerging evidence has shown that noncoding RNAs, particularly microRNAs (miRNAs), contribute to the pathogenesis of mood and anxiety disorders, although the molecular mechanisms are poorly understood. Here, we show that altered levels of miR-17-92 in adult hippocampal neural progenitors have a significant impact on neurogenesis and anxiety- and depression-related behaviors in mice. miR-17-92 deletion in adult neural progenitors decreases neurogenesis in the dentate gyrus, while its overexpression increases neurogenesis. miR-17-92 affects neurogenesis by regulating genes in the glucocorticoid pathway, especially serum- and glucocorticoid-inducible protein kinase-1 (Sgk1). miR-17-92 knockout mice show anxiety- and depression-like behaviors, whereas miR-17-92 overexpressing mice exhibit anxiolytic and antidepression-like behaviors. Furthermore, we show that miR-17-92 expression in the adult mouse hippocampus responds to chronic stress, and miR-17-92 rescues proliferation defects induced by corticosterone in hippocampal neural progenitors. Our study uncovers a crucial role for miR-17-92 in adult neural progenitors through regulation of neurogenesis and anxiety- and depression-like behaviors.

An important event in the unfolded protein response (UPR) is activation of the endoplasmic reticulum (ER) kinase PERK. The PERK signalling branch initially mediates a prosurvival response, which progresses to a proapoptotic response upon prolonged ER stress. However, the molecular mechanisms of PERK-mediated cell death are not well understood. Here we show that expression of the primary miR-17-92 transcript and mature miRNAs belonging to the miR-17-92 cluster are decreased during UPR. We found that miR-17-92 promoter reporter activity was reduced during UPR in a PERK-dependent manner. Furthermore, we show that activity of the miR-17-92 promoter is repressed by ectopic expression of ATF4 and NRF2. Promoter deletion analysis mapped the region responding to UPR-mediated repression to a site in the proximal region of the miR-17-92 promoter. Hypericin-mediated photo-oxidative ER damage reduced the expression of miRNAs belonging to the miR-17-92 cluster in wild-type but not in PERK-deficient cells. Importantly, ER stress-induced apoptosis was inhibited upon miR-17-92 overexpression in SH-SY5Y and H9c2 cells. Our results reveal a novel function for ATF4 and NRF2, where repression of the miR-17-92 cluster plays an important role in ER stress-mediated apoptosis. Mechanistic details are provided for the potentiation of cell death via sustained PERK signalling mediated repression of the miR-17-92 cluster.

T follicular helper (Tfh) cells are critically involved in the establishment of potent antibody responses against infectious pathogens, such as viruses and bacteria, but their dysregulation may also result in aberrant antibody responses that frequently coincide with autoimmune diseases or allergies. The fate and identity of Tfh cells is tightly controlled by gene regulation on the transcriptional and posttranscriptional level. Here, we provide deeper insights into the posttranscriptional mechanisms that regulate Tfh cell differentiation, function, and plasticity through the actions of RNA-binding proteins (RBPs) and small endogenously expressed regulatory RNAs called microRNAs (miRNAs). The Roquin family of RBPs has been shown to dampen spontaneous activation and differentiation of naïve CD4+ T cells into Tfh cells, since CD4+ T cells with Roquin mutations accumulate as Tfh cells and provide inappropriate B cell help in the production of autoantibodies. Moreover, Regnase-1, an endoribonuclease that regulates a set of targets, which strongly overlaps with that of Roquin, is crucial for the prevention of autoantibody production. Interestingly, both Roquin and Regnase-1 proteins are cleaved and inactivated after TCR stimulation by the paracaspase MALT1. miRNAs are expressed in naïve CD4+ T cells and help preventing spontaneous differentiation into effector cells. While most miRNAs are downregulated upon T cell activation, several miRNAs have been shown to regulate the fate of these cells by either promoting (e.g., miR-17–92 and miR-155) or inhibiting (e.g., miR-146a) Tfh cell differentiation. Together, these different aspects highlight a complex and dynamic regulatory network of posttranscriptional gene regulation in Tfh cells that may also be active in other T helper cell populations, including Th1, Th2, Th17, and Treg.

Non-coding RNAs that are small in size, called microRNAs (miRNAs), exert a consequence in neutralizing gene activity after transcription. The nervous system is a massively expressed organ, and an expanding body of research reveals the vital functions that miRNAs play in the brain's growth and neural activity. The significant benefit of miRNAs on the development of the central nervous system is currently shown through new scientific methods that concentrate on targeting and eradicating vital miRNA biogenesis pathways the elements involving Dicer and DGCR8. Modulation of miRNA has been associated with numerous essential cellular processes on neural progenitors, like differentiation, proliferation, and destiny determination. Current research discoveries that emphasize the significance of miRNAs in the complex process of brain development are included in this book. The miRNA pathway plays a major role in brain development, its operational dynamics, and even diseases. Recent studies on miRNA-mediated gene regulation within neural discrepancy, the circadian period and synaptic remodeling are signs of this. We also discussed how these discoveries may affect our comprehension of the fundamental processes behind brain diseases, highlighting the novel therapeutic opportunities miRNAs provide for treating various human illnesses., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Abstract: The aim of this study was to investigate the association of genetic polymorphisms in the promoter region of miR‐17‐92 with systemic lupus erythematosus (SLE). The gene polymorphism was analysed using SNaPshot in 312 SLE patients and 396 controls. Relative expression of miR‐17‐92 was measured by quantitative real‐time PCR. Association was found between rs9515692 and a decreased risk of SLE (CT vs CC: OR = 0.65, 95%CI, 0.46‐0.92, P = .014; CT+TT vs CC: OR = 0.64, 95%CI, 0.46‐0.90, P = .009; T vs C: OR = 0.69, 95%CI, 0.52‐0.92, P = .010, respectively). Haplotype analysis showed that C‐G‐G, C‐A‐A haplotypes were associated with an increased SLE risk (OR=4.46, 95%CI, 2.17‐9.17, P < 0.001; OR=2.33, 95%CI, 1.44‐3.76, P < 0.001, respectively). T allele and CT+TT genotypes in rs9515692 were associated with decreased risk of anti‐dsDNA in SLE (CT+TT vs CC: OR = 0.42, 95%CI = 0.24‐0.72, P = .002; T vs A: OR = 0.49, 95%CI = 0.31‐0.79, P = .003). Moreover, rs9515692 CT+TT genotypes had a higher level of miR‐17 as compared to CC genotype (P = .017). These findings suggest that the rs9515692 CT+TT genotypes were a protective factor for the susceptibility of SLE, probably by increasing the expression of miR‐17. [ABSTRACT FROM AUTHOR]

T follicular helper (Tfh) cells are critically involved in the establishment of potent antibody responses against infectious pathogens, such as viruses and bacteria, but their dysregulation may also result in aberrant antibody responses that frequently coincide with autoimmune diseases or allergies. The fate and identity of Tfh cells is tightly controlled by gene regulation on the transcriptional and posttranscriptional level. Here, we provide deeper insights into the posttranscriptional mechanisms that regulate Tfh cell differentiation, function, and plasticity through the actions of RNA-binding proteins (RBPs) and small endogenously expressed regulatory RNAs called microRNAs (miRNAs). The Roquin family of RBPs has been shown to dampen spontaneous activation and differentiation of naïve CD4+ T cells into Tfh cells, since CD4+ T cells with Roquin mutations accumulate as Tfh cells and provide inappropriate B cell help in the production of autoantibodies. Moreover, Regnase-1, an endoribonuclease that regulates a set of targets, which strongly overlaps with that of Roquin, is crucial for the prevention of autoantibody production. Interestingly, both Roquin and Regnase-1 proteins are cleaved and inactivated after TCR stimulation by the paracaspase MALT1. miRNAs are expressed in naïve CD4+ T cells and help preventing spontaneous differentiation into effector cells. While most miRNAs are downregulated upon T cell activation, several miRNAs have been shown to regulate the fate of these cells by either promoting (e.g., miR-17–92 and miR-155) or inhibiting (e.g., miR-146a) Tfh cell differentiation. Together, these different aspects highlight a complex and dynamic regulatory network of posttranscriptional gene regulation in Tfh cells that may also be active in other T helper cell populations, including Th1, Th2, Th17, and Treg. [ABSTRACT FROM AUTHOR]

The fundamental function of ribonucleic acids is to transfer genetic information from DNA to protein during translation process, however, this is not the only way connecting active RNA sequences with essential biological processes. Up until now, many RNA subclasses of different size, structure, and biological function were identified. Among them, there are non-coding single-stranded microRNAs (miRNAs). This subclass comprises RNAs of 19-25 nucleotides in length that modulate the activity of well-defined coding RNAs and play a crucial role in many physiological and pathological processes. miRNA genes are located both in exons, introns, and also within non-translated regions. Several miRNAs that are transcribed from the adjacent miRNA genes are called cluster. One of the largest ones is miR-17-92 cluster known as OncomiR-1 due to its strong link to oncogenesis. Six miRNAs from the OncomiR-1 have been shown to play important roles in various physiological cellular processes but also through inhibition of cell death in many cancer-relevant processes. Due to the origin and similarity of the sequence, miR-17-92 cluster and paralogs, miR-106b-25 and miR-106a-363 clusters were defined. Here we discuss the oncogenic function of those miRNA subgroups found in many types of cancers, including brain tumors. [ABSTRACT FROM AUTHOR]

MicroRNAs associated with the mir‐17‐92 cluster are crucial regulators of the mammalian cell cycle, as they inhibit transcription factors related to the E2F family that tightly control decision‐making events for a cell to commit for active cellular proliferation. Intriguingly, in many solid cancers, these mir‐17‐92 cluster members are overexpressed, whereas in some hematopoietic cancers they are down‐regulated. Our proposed model of the Myc/E2F/mir‐17‐92 network demonstrates that the differential expression pattern of mir‐17‐92 in different cell types can be conceived due to having a contrasting E2F dynamics induced by mir‐17‐92. The model predicts that by explicitly altering the mir‐17‐92‐related part of the network, experimentally it is possible to control cellular proliferation in a cell type‐dependent manner for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Wound healing is a complex and dynamic process that involves a series of cellular and molecular events. Mesenchymal stem cells (MSCs) and their exosomes (MSC-Exos) have crucial functions in cutaneous wound healing. MiR-17–92 is a multifunctional microRNA (miRNA) cluster that plays vital roles in tissue development and tumor angiogenesis. This study aimed to explore the function of miR-17.92 in wound healing as a component of MSC-Exos. Human MSCs were cultured in serum-free medium, and exosomes were collected by ultracentrifugation. The levels of miR-17–92 in MSCs and MSC-Exos were determined by quantitative real-time polymerase chain reaction. MSC-Exos were topically applied to full-thickness excision wounds in the skin of miR-17–92 knockout (KO) and wild-type (WT) mice. The proangiogenic and antiferroptotic effects of MSC-Exos overexpressing miR-17–92 were assayed by evaluating the relative levels of angiogenic and ferroptotic markers. MiRNA-17–92 was found to be highly expressed in MSCs and enriched in MSC-Exos. Moreover, MSC-Exos promoted the proliferation and migration of human umbilical vein endothelial cells in vitro. KO of miR-17–92 effectively attenuated the promotion of wound healing by MSC-Exos. Furthermore, exosomes derived from miR-17–92-overexpressing human umbilical cord-derived MSCs accelerated cell proliferation, migration, angiogenesis, and enhanced against erastin-induced ferroptosis in vitro. miR-17–92 plays a key role in the protective effects of MSC-Exos against erastin-induced ferroptosis in HUVECs These findings suggest that miR-17–92 participates in the repair ability of MSC-Exos and that miR-17–92-overexpressing exosomes may represent a new strategy for cutaneous wound repair. • Mesenchymal stem cells (MSCs) and its exosomes (MSC-Exos) have crucial functions in cutaneous wound healing. • MiR-17–92 is a multifunctional microRNA (miRNA) cluster that plays vital roles in tissue development and tumour angiogenesis. • MSC-exosomal miR-17–92 promotes wound healing by inducing angiogenesis and inhibiting ferroptosis. Additionally, MiR-17–92 is a multifunctional microRNA (miRNA) cluster that plays vital roles in tissue development and tumour angiogenesis. [ABSTRACT FROM AUTHOR]

miR-17-92 cluster are overexpressed in hematological malignancies including chronic myeloid leukemia (CML). However, their roles and mechanisms that regulate BCR-ABL induced leukemogenesis remain unclear. In this study, we demonstrated that genomic depletion of miR-17-92 inhibited the BCR-ABL induced leukemogenesis by using a mouse model of transplantation of BCR-ABL transduced hematopoietic stem cells. Furthermore, we identified that miR-19b targeted A20 (TNFAIP3). A20 overexpression results in inactivation of NF-κB activity including decrease of phosphorylation of P65 and IκBα, leads to induce apoptosis and inhibit proliferation and cycle in CML CD34 + cells. Thus we proved that miR-17-92 is a critical contributor to CML leukemogenesis via targeting A20 and activation of NF-κB signaling. These findings indicate that miR-17-92 will be important resources for developing novel treatment strategies of CML and better understanding long-term disease control. [ABSTRACT FROM AUTHOR]

Aims: The miR-17-92 cluster and the HDAC9 gene are involved in inflammatory, apoptotic, and angiogenic processes that are activated in the vulnerable carotid plaque. The aim of this research was to determine whether expression of one or more of the miRs of the miR-17-92 cluster and/or HDAC9 expression could represent biomarkers for patients with unstable atherosclerotic carotid plaques. Materials and Methods: Plasma levels of miRs and HDAC9 expression in peripheral blood were analyzed by real-time PCR in patients with histologically classified stable or unstable plaques. Results: No differences were observed between the two groups. Discussion and Conclusions: Levels of the miR-17-92 cluster in plasma and HDAC9 gene expression in peripheral blood cannot be considered appropriate biomarkers to identify patients with unstable plaques at risk of rupture. [ABSTRACT FROM AUTHOR]

Ｏｂｊｅｃｔｉｖｅ　Ｔｏ ｅｘｐｌｏｒｅ ｔｈｅ ｅｆｆｅｃｔ ａｎｄ ｍｅｃｈａｎｉｓｍ ｏｆ ｏｖｅｒ⁃ｅｘｐｒｅｓｓｉｏｎ ｏｆ ｍｉＲ⁃１７⁃９２ ｇｅｎｅ ｃｌｕｓｔｅｒ ｏｎ ｔｈｅ ｂｉｏｌｏｇｉｃａｌ ｃｈａｒａｃｔｅｒｉｓｔｉｃｓ ｏｆ ｐｒｏｓｔａｔｅ ｃａｎｃｅｒ ｃｅｌｌｓ． Ｍｅｔｈｏｄｓ　ＤＵ１４５ ｃｅｌｌｓ ｗｅｒｅ ｔｒａｎｓｆｅｃｔｅｄ ｗｉｔｈ ｍｉＲ⁃１７⁃９２ ｇｅｎｅ ｅｘｐｒｅｓｓｉｏｎ ｐｌａｓｍｉｄ ａｎｄ ｃｌｏｎｅｓ ｗｉｔｈ ｓｔａｂｌｅ ｅｃｔｏｐｉｃ ｍｉＲ⁃１７⁃９２ ｏｖｅｒｅｘｐｒｅｓｓｉｏｎ ｗｅｒｅ ｅｓｔａｂｌｉｓｈｅｄ． Ｔｈｅ ｃｅｌｌ ｖｉａｂｉｌｉｔｉｅｓ ｏｆ ＤＵ１４５⁃１７⁃９２ ａｎｄ ＤＵ１４５⁃ｃｏｎｔｒｏｌ ｃｅｌｌｓ ｗｅｒｅ ｍｏｎｉｔｏｒｅｄ ｂｙ ｘＣＥＬＬｉｇｅｎｃｅ ｓｙｓｔｅｍ． Ｃｅｌｌ ｐｒｏｌｉｆｅｒａｔｉｏｎ ａｎｄ ａｐｏｐｔｏｓｉｓ ｗｅｒｅ ａｎａｌｙｚｅｄ ｂｙ Ｋｉ⁃６７ ａｎｄ ｔｅｒｍｉｎａｌ ｄｅｏｘｙｎｕｃｌｅｏｔｉｄｙｌ ｔｒａｎｓｆｅｒａｓｅ ｄＵＴＰ ｎｉｃｋ ｅｎｄ ｌａｂｅｌｉｎｇ （ＴＵＮＥＬ） ａｓｓａｙ． Ｃｅｌｌ ｃｙｃｌｅ ｗａｓ ｄｅｔｅｃｔｅｄ ｂｙ ｆｌｏｗ ｃｙｔｏｍｅｔｒｙ． Ｅｘｐｒｅｓｓｉｏｎ ｌｅｖｅｌｓ ｏｆ ｐｒｏｔｅｉｎｓ ｉｎｖｏｌｖｅｄ ｉｎ ａｐｏｐｔｏｓｉｓ ａｎｄ Ａｋｔ ｐａｔｈｗａｙ ｗｅｒｅ ｄｅｔｅｒｍｉｎｅｄ ｂｙ ｗｅｓｔｅｒｎ ｂｌｏｔｔｉｎｇ． Ｒｅｓｕｌｔｓ　ｘＣＥＬＬｉｇｅｎｃｅ ＲＴＣＡ ａｒｒａｙ ｄａｔａ ｓｈｏｗｅｄ ｔｈａｔ ｔｈｅ ｇｒｏｗｔｈ ｒａｔｅ ｏｆ ＤＵ１４５⁃１７⁃９２ ｃｅｌｌｓ ｗａｓ ｓｉｇｎｉｆｉｃａｎｔｌｙ ｈｉｇｈｅｒ ｔｈａｎ ｔｈａｔ ｏｆ ＤＵ１４５⁃ｃｏｎｔｒｏｌ ｃｅｌｌｓ ａｆｔｅｒ ２４ ｈ ｏｆ ｓｅｅｄｉｎｇ （Ｐ＜０．０１）． Ｔｈｅ Ｋｉ⁃６７⁃ｐｏｓｉｔｉｖｅ ｒａｔｅｓ ｏｆ ｔｈｅ ＤＵ１４５⁃ｃｏｎｔｒｏｌ ｇｒｏｕｐ ａｔ ２４， ４８ ａｎｄ ７２ ｈｏｕｒｓ ｗｅｒｅ （５６．５７±１．６８）％， （８５．４８±０．２６）％ ａｎｄ （９０．８５±２．０８）％， ｒｅｓｐｅｃｔｉｖｅｌｙ． Ｗｈｉｌｅ ｔｈｅ Ｋｉ⁃６７ ｐｏｓｉｔｉｖｅ ｒａｔｅｓ ｏｆ ｔｈｅ ＤＵ１４５⁃１７⁃９２ ｇｒｏｕｐ ａｔ ｔｈｅ ｄｅｓｉｒｅｄ ｔｉｍｅ ｐｏｉｎｔｓ ｗｅｒｅ （７３．６４±０．６８）％， （９３．４３±１．２３）％ ａｎｄ （９７．３６±０．８６）％， ｒｅｓｐｅｃｔｉｖｅｌｙ， ｗｉｔｈ ａ ｓｔａｔｉｓｔｉｃａｌｌｙ ｓｉｇｎｉｆｉｃａｎｔ ｄｉｆｆｅｒｅｎｃｅ ａｔ ２４ ｈｏｕｒｓ （Ｐ＜０．０１）． Ｔｈｅ ｐｅｒｃｅｎｔａｇｅｓ ｏｆ ａｐｏｐｔｏｔｉｃ ｃｅｌｌｓ ｏｆ ｔｈｅ ＤＵ１４５⁃ｃｏｎｔｒｏｌ ｇｒｏｕｐ ａｔ ２４， ４８ ａｎｄ ７２ ｈｏｕｒｓ ｗｅｒｅ （６．７６±０．０９）％， （１４．５１±０．８６）％ ａｎｄ （２０．７３±１．６４）％， ｒｅｓｐｅｃｔｉｖｅｌｙ， ｗｈｉｌｅ ｔｈｅ ａｐｏｐｔｏｔｉｃ ｐｅｒｃｅｎｔａｇｅｓ ｏｆ ｔｈｅ ＤＵ１４５⁃１７⁃９２ ｇｒｏｕｐ ｗｅｒｅ （１．８６±０．１５）％， （７．９０±０．４０）％ ａｎｄ （４．９２±０．４８）％， ｒｅｓｐｅｃｔｉｖｅｌｙ． Ｔｈｅ ｐｅｒｃｅｎｔａｇｅｓ ｏｆ ａｐｏｐｔｏｔｉｃ ｃｅｌｌｓ ｏｆ ｔｈｅ ＤＵ１４５⁃ｃｏｎｔｒｏｌ ｇｒｏｕｐ ａｔ ｄｉｆｆｅｒｅｎｔ ｔｉｍｅ ｗｅｒｅ ｓｉｇｎｉｆｉｃａｎｔｌｙ ｈｉｇｈｅｒ ｔｈａｎ ｔｈｏｓｅ ｏｆ ＤＵ１４５⁃１７⁃９２ ｇｒｏｕｐ （Ｐ＜０．０１ ｆｏｒ ａｌｌ）． Ｔｈｅ ｒｅｓｕｌｔ ｏｆ ｗｅｓｔｅｒｎ ｂｌｏｔｔｉｎｇ ｓｈｏｗｅｄ ｔｈａｔ ｔｈｅ ｐｒｏｔｅｉｎ ｅｘｐｒｅｓｓｉｏｎ ｌｅｖｅｌｓ ｏｆ Ｂｃｌ⁃２ ｉｎｔｅｒａｃｔｉｎｇ ｍｅｄｉａｔｏｒ ｏｆ ｃｅｌｌ ｄｅａｔｈ （ＢＩＭ） ａｎｄ ｐｈｏｓｐｈａｔａｓｅ ａｎｄ ｔｅｎｓｉｎ ｈｏｍｏｌｏｇ ｄｅｌｅｔｅｄ ｏｎ ｃｈｒｏｍｏｓｏｍｅ ｔｅｎ （ＰＴＥＮ） ｉｎ ＤＵ１４５⁃ｃｏｎｔｒｏｌ ｃｅｌｌｓ ｗｅｒｅ ０．８３±０．００ ａｎｄ ０．９１±０．００， ｒｅｓｐｅｃｔｉｖｅｌｙ， ｓｉｇｎｉｆｉｃａｎｔｌｙ ｈｉｇｈｅｒ ｔｈａｎ ０．１６±０．００ ａｎｄ ０．１３±０．００ ｏｆ ＤＵ１４５⁃１７⁃９２ ｃｅｌｌｓ （ｂｏｔｈ Ｐ ＜０．０１）． Ｏｖｅｒｅｘｐｒｅｓｓｉｏｎ ｏｆ ｍｉＲ１７⁃９２ ｉｎｄｕｃｅｄ ｔｈｅ ｐｈｏｓｐｈｏｒｙｌａｔｉｏｎ ｏｆ ｐｒｏｔｅｉｎ ｋｉｎａｓｅ Ｂ （Ａｋｔ） ａｔ Ｓｅｒ４７３ ｗｈｉｌｅ ｎｏ ａｐｐｒｅｃｉａｂｌｅ ｅｆｆｅｃｔ ｏｎ ｔｈｅ ｐｈｏｓｐｈｏｒｙｌａｔｉｏｎ ｏｆ Ａｋｔ ａｔ Ｔｈｒ３０８． Ｔｈｅ ｐｈｏｓｐｈｏｒｙｌａｔｅｄ ｌｅｖｅｌ ｏｆ ｅｘｔｒａｃｅｌｌｕｌａｒ ｒｅｇｕｌａｔｅｄ ｐｒｏｔｅｉｎ ｋｉｎａｓｅｓ （ＥＲＫ） ｉｎ ＤＵ１４５⁃ｃｏｎｔｒｏｌ ｃｅｌｌｓ ｗａｓ ０．２１±０．０１， ｓｉｇｎｉｆｉｃａｎｔｌｙ ｌｏｗｅｒ ｔｈａｎ ０．７２±０．０１ ｏｆ ＤＵ１４５⁃１７⁃９２ ｃｅｌｌｓ （Ｐ＜０．０１）． Ｃｏｎｃｌｕｓｉｏｎｓ　Ｏｖｅｒｅｘｐｒｅｓｓｉｏｎ ｏｆ ｍｉＲ⁃１７⁃９２ ｇｅｎｅ ｐｌａｙｓ ａ ｐｉｖｏｔａｌ ｒｏｌｅ ｉｎ ｇｒｏｗｔｈ， ｐｒｏｌｉｆｅｒａｔｉｏｎ， ａｐｏｐｔｏｓｉｓ ａｎｄ ｃｅｌｌ ｃｙｃｌｅ ｏｆ ＤＵ１４５ ｃｅｌｌｓ ｔｈｒｏｕｇｈ ｄｏｗｎ⁃ｒｅｇｕｌａｔｉｏn ｏｆ ａｐｏｐｔｏｔｉｃ ｐｒｏｔｅｉｎ ＢＩＭ ａｎｄ ｔｕｍｏｒ ｓｕｐｐｒｅｓｓｏｒ ＰＴＥＮ ａｎｄ ａｃｔｉｖａｔｉｏｎ ｏｆ Ａｋｔ ａｎｄ ＥＲＫ ｓｉｇｎａｌｉｎｇ ｐａｔｈｗａｙ. [ABSTRACT FROM AUTHOR]

Background A variety of cancers are associated with the expression of the oncogenic miR-17-92 cluster (Oncomir-1) and tumor suppressor miR-143-5p/miR-145-5p. Epidermal skin cancer has not been investigated for the expression of miR-17-92 and miR-143-145 clusters, despite being extensively studied regarding global microRNA profiles. The goal of this study was to investigate the expression and possible correlation of expression of miR17-92 and miR-143-145 cluster members in epidermal skin cancer. Methods We evaluated punch biopsies from patients with cutaneous squamous cell carcinoma (cSCC, n = 15) and basal cell carcinoma (BCC, n = 16), along with control specimens from non-lesional epidermal skin (n = 16). Expression levels of the miR17-92 cluster (including miR-17-5p, miR-17-3p, miR-18a-3p, miR-18a-5p, miR-19a-3p, miR-19a-5p, miR-19b-3p, miR-19b-1-5p, miR-20a-3p, miR-20a-5p, miR-92a-3p, and miR-92a-5p) and the tumor-suppressive cluster miR-143-145 (including miR-143-5p and miR-145-5p) were detected by quantitative real-time reverse transcriptase polymerase chain reaction. Results We noted a highly significant increased expression of the miR-17-92 members miR-17-5p, miR-18a-5p, miR19a-3p, and miR-19b-3p and tumor suppressor miR-143-5p (p < 0.01) in cSCC. miR-145-5p had a significantly decreased expression (p < 0.05) for in BCC. A correlation analysis revealed multiple correlating miRNA-pairs within and between the investigated clusters. Conclusion This study marks the first evidence for the participation of members of the miR-17-92 cluster in cSCC and miR-143-145 cluster in BCC. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have gradually been recognized as regulators of embryonic development; however, relatively few miRNAs have been identified that regulate cardiac development. A series of recent papers have established an essential role for the miRNA-17-92 (miR-17-92) cluster of miRNAs in the development of the heart. Previous research has shown that the Friend of Gata-2 (FOG-2) is critical for cardiac development. To investigate the possibility that the miR-17-92 cluster regulates FOG-2 expression and inhibits proliferation in mouse embryonic cardiomyocytes we initially used bioinformatics to analyze 3’ untranslated regions (3’UTR) of FOG-2 to predict the potential of miR-17-92 to target it. We used luciferase assays to demonstrate that miR-17-5p and miR-20a of miR-17-92 interact with the predicted target sites in the 3’UTR of FOG-2. Furthermore, RT-PCR and Western blot were used to demonstrate the post-transcriptional regulation of FOG-2 by miR-17-92 in embryonic cardiomyocytes from E12.5-day pregnant C57BL/6J mice. Finally, EdU cell assays together with the FOG-2 rescue strategy were employed to evaluate the effect of proliferation on embryonic cardiomyocytes. We first found that the miR-17-5p and miR-20a of miR-17-92 directly target the 3’UTR of FOG-2 and post-transcriptionally repress the expression of FOG-2. Moreover, our findings demonstrated that over-expression of miR-17-92 may inhibit cell proliferation via post-transcriptional repression of FOG-2 in embryonic cardiomyocytes. These results indicate that the miR-17-92 cluster regulates the expression of FOG-2 protein and suggest that the miR-17-92 cluster might play an important role in heart development.

Overexpression of the miR-17-92 cluster is a key oncogenic event in various cancer types. The oncogenic effect of the miR-17-92 cluster is enhanced by cooperation between its members in targeting tumor-suppressive proteins and pathways such as PTEN and TGFβ signaling. However, in the case of miR-19a and miR-19b, these have been shown to have a preponderant role in the cluster’s oncogenicity. Important studies have revealed the influence of the Myc proto-oncogene family in the transcriptional regulation of miR-17-92. Recent findings show that other oncogenic signaling pathways, such as those of Notch and Sonic Hedgehog, activate miR-17-92 in cancer. Notwithstanding, another layer of complexity has been added by the influence of the relevant primary miR-17-92 tertiary structure during processing to mature miRNA. In this review, we attempt to integrate current transcriptional and post-transcriptional knowledge to enhance our global understanding of the coordinated up-regulation of miR-17-92 in cancer.

MiR-17-92 cluster contributes to the regulation of mammalian development, aging and tumorigenesis. The functional roles of miR-17-92 in pancreatic beta-cells are largely unknown. In this study, we found that conditional deletion of miR-17-92 in mouse pancreatic beta-cells ( miR-17-92βKO ) significantly reduces glucose tolerance and the first phase of insulin secretion, despite normal ad libitum fed and fasting glucose levels. Proliferation is down-regulated in pancreatic beta-cells after deleting miR-17-92 . MiR-17-92βKO mice show higher phosphatase and tensin homologue (PTEN) and lower phosphorylated AKT in islets. Under high fat diet challenge for 16 weeks, miR-17-92βKO mice lose compensation and exhibit higher glucose levels, and lower insulin secretion. Collectively, these data suggest that miR-17-92 is a critical contributor to molecular mechanisms regulating glucose-stimulated insulin secretion and pancreatic beta-cell adaptation under metabolic stress. [ABSTRACT FROM AUTHOR]

Background: Neural stem/precursor cells (NSCs) are of particular interest because of their potential application in cell therapy for brain damage. However, most brain injury cases are followed with neuroinflammatory stress, which affects the lineage selection of grafted NSCs by promoting astrocytogenesis, thus hampering the potential for neural replacement. The present study investigated the role of miR-17-92 in protecting against detrimental effects of neuroinflammation on NSC differentiation in cell therapy.Methods: NSCs were treated with conditioned medium from lesioned astrocytes with/without neutralizing antibodies of leukemia inhibitory factor (LIF) or/and ciliary neurotrophic factor (CNTF), respectively. Afterward, the levels of p-STAT3 and p-JAK2 were determined by western blotting while expression of glial fibrillary acidic protein (GFAP) and β-tubulin III was assessed by immunostaining. The activation of JAK-STAT pathway and cell differentiation were also evaluated after we overexpressed miR-17-92 in NSCs under different neuroinflammatory conditions. After the transplantation of miR-17-92-overexpressing NSCs into injured mouse cortex, PH3, nestin, GFAP, and NeuN were analyzed by immunostaining. In addition, motor coordination of mice was evaluated by rotarod test.Results: Conditioned medium from lesioned astrocytes activated JAK-STAT pathway and facilitated astrocytic differentiation in NSCs while neutralizing antibodies of LIF and CNTF remarkably attenuated such effects. miR-17-92 cluster repressed the expression of multiple proteins including GP130, CNTFR, JAK2, and STAT3 in JAK-STAT pathway. Overexpression of miR-17-92 in NSCs systematically blocked the activation of JAK-STAT pathway mediated by LIF and CNTF, which facilitated neuronal differentiation in vitro. Furthermore, miR-17-92 increased neuronal generation of grafted NSCs and reduced astrogliosis, which resulted in the improvement of motor coordination of brain-injured mice.Conclusions: Our results suggest that miR-17-92 promotes neuronal differentiation of grafted NSCs under neuroinflammatory condition via inhibition of multiple proteins in JAK-STAT pathway. [ABSTRACT FROM AUTHOR]

Summary Emerging evidence has shown that noncoding RNAs, particularly microRNAs (miRNAs), contribute to the pathogenesis of mood and anxiety disorders, although the molecular mechanisms are poorly understood. Here, we show that altered levels of miR-17-92 in adult hippocampal neural progenitors have a significant impact on neurogenesis and anxiety- and depression-related behaviors in mice. miR-17-92 deletion in adult neural progenitors decreases neurogenesis in the dentate gyrus, while its overexpression increases neurogenesis. miR-17-92 affects neurogenesis by regulating genes in the glucocorticoid pathway, especially serum- and glucocorticoid-inducible protein kinase-1 (Sgk1). miR-17-92 knockout mice show anxiety- and depression-like behaviors, whereas miR-17-92 overexpressing mice exhibit anxiolytic and antidepression-like behaviors. Furthermore, we show that miR-17-92 expression in the adult mouse hippocampus responds to chronic stress, and miR-17-92 rescues proliferation defects induced by corticosterone in hippocampal neural progenitors. Our study uncovers a crucial role for miR-17-92 in adult neural progenitors through regulation of neurogenesis and anxiety- and depression-like behaviors. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Ovarian cancer treatments are often impeded by drug resistance. It has been proposed that microRNA (miRNA) expression patterns may play a role in drug resistance among ovarian cancers. The present study investigated the relationship between resistance to the cancer drug paclitaxel and miRNA expression. MATERIALS AND METHODS: We compared the expression patterns of miRNA genes in paclitaxel-sensitive (SKOV3) and paclitaxel-resistant (SKOV3-TR30) cell lines. RESULTS: Expression of the miR-134 gene cluster was found to be significantly lower in the paclitaxel-resistant cell line than in the paclitaxel-sensitive cell line, while the expression of the miR-17-92 gene cluster was significantly higher in the paclitaxel-resistant cells. An analysis of miRNA target gene protein expression revealed that several targets of miR-17-92 were significantly altered between the two cell types. CONCLUSIONS: The higher expression of miR-17-92 and lower expression of mi-134 and the associated alterations of target gene expression may be associated with the drug-resistant nature of some ovarian cancers. [ABSTRACT FROM AUTHOR]

The miR-17–92 cluster is a prototypical example of a polycistronic miRNA gene. Recently, miR-17–92 has emerged as a pleiotropic regulator in immune system. Its loss or deregulation leads to defects in lymphocyte development and response, and lymphoma development. Although the six individual miRNAs of the cluster are expressed together from the same primary transcript, their relative abundance, functional contributions and interactions vary in different cellular contexts. [ABSTRACT FROM AUTHOR]

MicroRNAs are short single-stranded RNAs that regulate target gene expression by binding to complementary sites in the 3′ untranslated region (UTR) of their mRNA targets. The polycistronic miR-17-92 cluster, which encodes miR-17 , miR-18a , miR-19a , miR-20a , miR-19b , and miR-92a , was previously shown to be overexpressed in multiple types of cancer. In this study, target gene prediction algorithms were used to predict potential targets of the miR-17-92 cluster. WEE1, a kinase that inhibits cell cycle progression, was identified as a possible target of five of the six miRNAs in the cluster. Luciferase reporter assays were used to determine that miR-17 , miR-20a , and miR-18a specifically target nucleotides 465–487 of the 3′ UTR of WEE1 , whereas miR-19a and miR-19b exert control on WEE1 by targeting nucleotides 1069–1091. A negative correlation was determined between endogenous miR-17 or miR-19a expression and endogenous WEE1 protein expression in the same panel of cell lines. We conclude that WEE1 is a valid target of the miR-17-92 cluster in leukemia. [ABSTRACT FROM AUTHOR]

The overexpression of microRNA cluster miR-17-92 has been implicated in development of solid tumors and hematological malignancies. The role of miR-17-92 in lymphomagenesis has been extensively investigated; however, because of the developmental defects caused by miR-17-92 dysregulation, its ability to drive tumorigenesis has remained undetermined until recently. Here we demonstrate that overexpression of miR-17-92 in a limited number of hematopoietic cells is sufficient to cause B cell malignancies. In sum, our study provides a novel and physiologically relevant model that exposes the potent ability of miR-17-92 to act as a driver of tumorigenesis. [ABSTRACT FROM AUTHOR]

Gain of chromosome arm 13q is one of the most prevalent DNA copy number alterations associated with colorectal adenoma-to-carcinoma progression. The oncogenic miR-17-92 cluster, located at 13q, was found to be overexpressed in colorectal cancer and in adenomas harboring 13q gain. However, to what extent overexpression of this group of microRNAs actually drives progression to cancer remains to be resolved. Therefore, we aimed to clarify the role of miR-17-92 cluster in the progression from colorectal adenoma to carcinoma. The miR-17-92 cluster was overexpressed in human colorectal adenoma organoids without 13q gain and downstream effects on mRNA expression were investigated, along with functional consequences in vitro and in vivo. Comparison of mRNA sequencing results of organoids overexpressing miR-17-92 and cultures transduced with control vector revealed a miR-17-92 expression signature. This signature appeared to be enriched in an independent series of colorectal cancers and adenomas with 13q gain, confirming that miR-17-92 expression is associated with malignant progression. However, tumor-associated characteristics, such as increased proliferation rate, were not observed in miR-17-92 overexpressing adenoma organoids in vitro. In addition, subcutaneous injection of these organoids in immunodeficient mice was insufficient to cause tumor outgrowth. In conclusion, this study showed that miR-17-92 expression contributes to 13q gain-associated adenoma-to-carcinoma progression, however, this is insufficient to cause malignancy. [ABSTRACT FROM AUTHOR]

Transfection of human oral squamous carcinoma cells (clone E10) with mimics for unexpressed miR-20b or miR-363-5p, encoded by the miR-106a-363 cluster (miR-20b, miR-106a, miR-363-3p, or miR-363-5p), caused 40-50% decrease in proliferation. Transfection with mimics for miR-18a or miR-92a, encoded by the miR-17-92 cluster (all members being expressed in E10 cells), had no effect on proliferation. In contrast, mimic for the sibling miRNA-19a yielded about 20% inhibition of proliferation. To investigate miRNA involvement profiling of miRNA transcriptomes were carried out using deoxyoligonucleotide microarrays. In transfectants for miR-19a, or miR-20b or miR-363-5p most differentially expressed miRNAs exhibited decreased expression, including some miRNAs encoded in paralogous miR-17-92-or miR-106b-25 cluster. Only in cells transfected with miR-19a mimic significantly increased expression of miR-20b observed-about 50-fold as judged by qRT-PCR. Further studies using qRT-PCR showed that transfection of E10 cells with mimic for miRNAs encoded by miR-17-92 - or miR-106a-363 - or the miR-106b-25 cluster confirmed selective effect on expression on sibling miRNAs. We conclude that high levels of miRNAs encoded by the miR-106a-363 cluster may contribute to inhibition of proliferation by decreasing expression of several sibling miRNAs encoded by miR-17-92 or by the miR-106b-25 cluster. The inhibition of proliferation observed in miR-19a-mimic transfectants is likely caused by the miR-19a-dependent increase in the levels of miR-20b and miR-106a. Bioinformatic analysis of differentially expressed miRNAs from miR-106a, miR-20b and miR-363-5p transfectants, but not miR-92a transfectants, yielded significant associations to "Cellular Growth and Proliferation" and "Cell Cycle." Western blotting results showed that levels of affected proteins to differ between transfectants, suggesting that different anti-proliferative mechanisms may operate in these transfectants. [ABSTRACT FROM AUTHOR]

Highlights: [•] miR-17-5p functions as a pro-proliferative miRNA in gastric cancer. [•] SOCS6 was demonstrated to be a direct target of miR-17-5p. [•] SOCS6 exerted an opposite function with miR-17-5p in gastric cancer. [•] miR-17-5p acts as a pro-proliferative factor by repressing SOCS6 in gastric cancer. [Copyright &y& Elsevier]