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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: 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]

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]

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]

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]

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]

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]

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]

Human gastric cancers contain a population of gastric cancer stem cells (GCSCs) that can undergo self-renewal and multipotent differentiation. GCSCs can be enriched with EpCAM+/CD44+ gastric cancer cells. However, the underlying mechanisms controlling the balance of GCSC self-renewal and differentiation remain to be explored. Because miRNAs can regulate cancer cell fates, we compared miRNA expression in tumorspheric cancer cells enriched with GCSCs and more differentiated cells. We found that the miR-17-92 cluster members miR-19b, miR-20a and miR-92a were gradually reduced during the differentiation of GCSCs. Therefore, we speculated that miR-17-92 members might regulate the self-renewal ability of GCSCs. By downregulating miR-19b, miR-20a and miR-92a in EpCAM+/CD44+ GCSCs, or overexpressing them in EpCAM2/CD442 non-GCSC populations, we found that miR-19b, miR-20a and miR-92a could sustain the self-renewal function of GCSCs. Furthermore, we found that miR-19b, miR-20a and miR-92a could also promote the proliferation of gastric cancer cells miR-17-92 targeted the E2F1 and HIPK1 proteins, which suppressed Wnt-β-catenin signaling. A real-time PCR analysis of miR-19b, miR-20a and miR-92a expression in 97 gastric cancer specimens suggested that miR- 92a could be used as an independent prognostic factor in gastric cancer. This study showed that several members of the miR-17-92 cluster, miR-19b, miR-20a and miR-92a, might play important roles in the development of gastric cancer stem cells and that miR-92a has the potential to be used as a predictive prognostic marker in gastric cancer. [ABSTRACT FROM AUTHOR]

Micro RNAs (mi RNAs) 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. mi RNAs set thresholds for gene expression and optimize protein concentrations of genetic networks. Absence of individual mi RNAs can lead to severe immune dysfunction. In this study, we review emerging principles and provide examples of important functions exerted by mi RNAs. Although our understanding of mi RNA 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 FROM AUTHOR]

Abstract: MicroRNA (miR) are emerging as important gene expression regulators often involved in a variety of pathogenesis such as cancers and autoimmunity. Signal transducers and activators of transcription (STAT) proteins are the principle signaling proteins for many cytokines and growth factors, thereby play a critical role in regulating immune cell homeostasis, differentiation and cellular functions. In this review, we discuss recent advances in the field demonstrating active interactions between STATs and miRs, with our primary focus on the promotion and inhibition of immune cells and cancer. Additionally, we review the reciprocal regulations between STATs and miR, and discuss how we can use this knowledge in the context of diseases. For example, recent findings related to STAT1 and miR-155 support the presence of a positive feedback loop of miR-155 and STAT1 in response to inflammatory signals or infection. STAT3 is known to play critical roles in tumorigenesis and cancer-induced immunosuppression. There is a growing body of evidence demonstrating that STAT3 directly activates miR-21, one of miRs that promote cancer cell survival and proliferation. While some miRs directly regulate STATs, there are findings demonstrating indirect STAT regulation by miRs also mediate important biological mechanisms. Therefore, further research is warranted to elucidate significant contributions made by direct and indirect miR–STAT mechanisms. As we learn more about miR pathways, we gain the opportunity to manipulate them in cancer cells to slow down growth or increase their susceptibility anti-tumor immunity. [Copyright &y& Elsevier]

Abstract: Osteosarcoma (OS) is the common histological form of primary bone cancer and one of the leading aggressive cancers in children under age fifteen. Although several genetic predisposing conditions have been associated with OS the understanding of its molecular etiology is limited. Here, we show that microRNAs (miRNAs) at the chr.14q32 locus are significantly downregulated in osteosarcoma compared to normal bone tissues. Bioinformatic predictions identified that a subset of 14q32 miRNAs (miR-382, miR-369-3p, miR-544 and miR-134) could potentially target cMYC transcript. The physical interaction between these 14q32 miRNAs and cMYC was validated using reporter assays. Further, restoring expression of these four 14q32 miRNAs decreased cMYC levels and induced apoptosis in Saos2 cells. We also show that exogenous expression of 14q32 miRNAs in Saos2 cells significantly downregulated miR-17–92, a transcriptional target of cMYC. The pro-apoptotic effect of 14q32 miRNAs in Saos2 cells was rescued either by overexpression of cMYC cDNA without the 3′UTR or with miR-17–92 cluster. Further, array comparative genomic hybridization studies showed no DNA copy number changes at 14q32 locus in OS patient samples suggesting that downregulation of 14q32 miRNAs are not due to deletion at this locus. Together, our data support a model where the deregulation of a network involving 14q32 miRNAs, cMYC and miR-17–92 miRNAs could contribute to osteosarcoma pathogenesis. [Copyright &y& Elsevier]

Abstract: MicroRNAs (miRNAs) are an abundant class of small non-coding RNAs (ncRNAs) that function to regulate gene expression at the post-transcriptional level. Although their functions were originally described during normal development, miRNAs have emerged as integral components of the oncogenic and tumor suppressor network, regulating nearly all cellular processes altered during tumor formation. In particular, mir-17-92, a miRNA polycistron also known as oncomir-1, is among the most potent oncogenic miRNAs. Genomic amplification and elevated expression of mir-17-92 were both found in several human B-cell lymphomas, and its enforced expression exhibits strong tumorigenic activity in multiple mouse tumor models. mir-17-92 carries out pleiotropic functions during both normal development and malignant transformation, as it acts to promote proliferation, inhibit differentiation, increase angiogenesis, and sustain cell survival. Unlike most protein coding genes, mir-17-92 is a polycistronic miRNA cluster that contains multiple miRNA components, each of which has a potential to regulate hundreds of target mRNAs. This unique gene structure of mir-17-92 may underlie the molecular basis for its pleiotropic functions in a cell type- and context-dependent manner. Here we review the recent literature on the functional studies of mir-17-92 and highlight its potential impacts on the oncogene network. These findings on mir-17-92 indicate that miRNAs are integrated components of the molecular pathways that regulate tumor development and tumor maintenance. [Copyright &y& Elsevier]

Aurora kinase A (AURKA) is an essential mitotic serine/threonine kinase and its abnormal expression is observed in many malignancies, yet the exact role for AURKA in tumorigenesis still remains elusive. Here, through a transcription factor array, we show that the transcription activity of E2F1 was increased by AURKA overexpression. Meanwhile, the E2F1 protein level was found to be upregulated and a correlation between AURKA and E2F1 expression was observed in cancer specimens. Further analysis revealed that AURKA increased E2F1 protein stability by inhibiting proteasome-dependent degradation of this protein. Additionally, a microRNA cluster, miR-17-92, was found to be upregulated upon AURKA overexpression, and this stimulation was largely repressed by E2F1 knockdown. Chromatin immunoprecipitation further demonstrated that AURKA enhanced E2F1 occupancy to the promoter of the miR- 17- 92 cluster. These data reveal a novel link between AURKA and microRNAs via the regulation of E2F1, providing new clues for understanding the role of AURKA in tumorigenesis. [ABSTRACT FROM AUTHOR]

All-trans retinoic acid is a potent promoter of cellular differentiation processes, which is used in cancer therapy. Glioblastoma spheroid cultures are enriched in tumor-initiating cells, and provide a model to test new treatment options in vitro. We investigated the molecular mechanisms of response to exposure to differentiation-promoting conditions in such cultures. Microarray analyses of five independent cultures showed that after induction of differentiation, inhibitors of transforming growth factor-β/bone morphogenetic protein, Wnt/β-catenin and IGF signaling were upregulated, whereas expression of several microRNAs decreased, particularly that of the miR-17-92 cluster. In primary astrocytic gliomas (n=82), expression of several members of miR-17-92 was significantly higher relative to those of normal brain (n=8) and significantly increased with tumor grade progression (P<0.05). A high-level amplification of the miR-17-92 locus was detected in one glioblastoma specimen. Transfection of inhibitors of miR-17-92 induced increased apoptosis and decreased cell proliferation in glioblastoma spheroids. Mir-17-92 inhibition was also associated with increased messenger RNA (mRNA) and/or protein expression of CDKN1A, E2F1, PTEN and CTGF. The CTGF gene was shown to be a target of miR-17-92 in glioblastoma spheroids by luciferase reporter assays. Our results suggest that miR-17-92 and its target CTGF mediate effects of differentiation-promoting treatment on glioblastoma cells through multiple regulatory pathways. [ABSTRACT FROM AUTHOR]

The discovery of microRNAs (miRNAs) has revealed a new layer of gene expression regulation that affects many normal and pathologic biological systems. Among the malignancies affected by the dysregulation of miRNAs, there are cancers of lymphoid origin in which miRNAs are thought to have tumor suppressive or tumor promoting activities, depending on the nature of their specific targets. In the last four to five years, the experimental field that provided the deepest insights into the in vivo biology of miRNAs is that of mouse modeling, in which transgenic and knockout animals mimic over-expression or down-regulation, respectively, of specific miRNAs involved in human leukemia/lymphoma. This review discusses recent advances in our understanding of lymphoid malignancies based on the natural and engineered mouse models of three different miRNAs: miR-15a/16-1 cluster, miR-155, and miR-17-92 cluster. [ABSTRACT FROM AUTHOR]

Recent studies have revealed the importance of multiple microRNAs (miRNAs) in promoting tumorigenesis, among which mir-17-92/Oncomir-1 exhibits potent oncogenic activity. Genomic amplification and elevated expression of mir-17-92 occur in several human B-cell lymphomas, and enforced mir-17-92 expression in mice cooperates with c-myc to promote the formation of B-cell lymphomas. Unlike classic protein-coding oncogenes, mir-17-92 has an unconventional gene structure, where one primary transcript yields six individual miRNAs. Here, we functionally dissected the individual components of mir-17-92 by assaying their tumorigenic potential in vivo. Using the Eμ1/4-myc model of mouse B-cell lymphoma, we identified miR-19 as the key oncogenic component of mir-17-92, both necessary and sufficient for promoting c-myc-induced lymphomagenesis by repressing apoptosis. The oncogenic activity of miR-19 is at least in part due to its repression of the tumor suppressor Pten. Consistently, miR-19 activates the Akt?"mTOR (mammalian target of rapamycin) pathway, thereby functionally antagonizing Pten to promote cell survival. Our findings reveal the essential role of miR-19 in mediating the oncogenic activity of mir-17-92, and implicate the functional diversity of mir-17-92 components as the molecular basis for its pleiotropic effects during tumorigenesis. [ABSTRACT FROM AUTHOR]

Abstract: Whole-genome microRNA and gene expression analyses were used to monitor changes during retinoic acid induced differentiation of neuroblasts in vitro. Interestingly, the entire miR-17 family was over-represented among the down-regulated miRNA. The implications of these changes are considerable, as target gene prediction suggests that the miR-17 family is involved in the regulation of the mitogen-activated protein kinase (MAPK) signaling pathway, synaptic plasticity and other markers of neuronal differentiation. Significantly, many of the target responses predicted by changes in miRNA expression were supported by the observed changes in gene expression. As expected, markers of neuronal differentiation such as anti-apoptotic protein B-cell lymphoma 2 (BCL2), myocyte enhancer factor-2D (MEF2D) and zipper protein kinase (MAP3K12; aka ZPK/MUK/DLK) were each up-regulated in response to differentiation. The expression of these genes was also reduced in response to miR-17 and miR-20a transfection, and more specifically they were also shown to contain functional miRNA recognition elements for members of the miR-17 family by reporter gene assay. This suggests that the miR-17 family have an integral role in fine-tuning the pathways involved in the regulation of neuronal differentiation. [Copyright &y& Elsevier]

Abstract: MicroRNAs constitute a family of small RNA species that regulate translation and stability of mRNA. This additional layer of epigenetic regulation has escaped discovery until recently, and introduces another level between mRNA expression profiling and proteomics. Since microRNAs are involved in regulating most, if not all cellular processes, their involvement in oncogenesis was anticipated. Indeed, soon after their discovery, microRNAs were found to act as tumor suppressor genes by blocking the translation of oncogenes and act as oncogenes by inhibiting the translation of tumor suppressor genes. Here we review the most recent attempts aiming to analyze the functional roles of microRNAs in neuroblastoma, the most devastating solid tumor in childhood. [Copyright &y& Elsevier]

The NK-like family of homeobox genes includes TLX1, TLX3 and NKX2-5, which are ectopically activated in distinct subsets of T-cell acute lymphoblastic leukemia (T-ALL) cells. Here we analysed their effect on the miR-17-92 cluster overexpressed in several types of cancer, including T-ALL. The pri-miR-17-92 polycistron encodes micro-RNAs (miRNAs), which decrease E2F1 protein expression, regulating proliferation and/or apoptosis. Quantification of pri-miR-17-92 in T-ALL cell lines suggested an implication of the NK-like homeodomain proteins in transcriptional regulation. Lentiviral-mediated overexpression of NKX2-5 in the T-ALL cell line MOLT-4 consistently resulted in increased miR-17-92 pri-miRNA levels and decreased amounts of E2F1 protein. Induction of apoptosis by treating miR17-92 or E2F1 transduced T-ALL cells with etoposide led to reduced or enhanced cell viability, respectively. Furthermore, analysis of pri-miR-17-92 in T-ALL patients indicated elevated expression in those bearing TLX1/3 positive cells. These data support an activatory effect of NK-like homeodomain proteins on pri-miR-17-92 expression and concomitantly reduced E2F1 protein levels, thereby enhancing survival of leukemic T-cells. [ABSTRACT FROM AUTHOR]

Abstract: PTPRO is often silenced by DNA hypermethylation in primary human tumors and cancer cell lines and functions as a tumor suppressor. Here we show that PTPRO is a target of E2F1. In addition, the microRNA cluster miR-17-92, another target of E2F1, participates in PTPRO regulation. PTPRO mRNA was up-regulated during S phase in synchronized HeLa cells and in vitro PTPRO promoter activity is high in early S phase while the PTPRO 3′UTR reporter activity is low in late S phase. This study provides evidence that the PTPRO gene is co-regulated by both E2F1 and miR-17-92. [Copyright &y& Elsevier]

Abstract: The miR-17-92 locus encodes a cluster of 7 microRNAs transcribed as a single primary transcript. It can accelerate c-Myc induced B cell lymphoma development and is highly expressed in many tumors, including lung tumors. However, the role of miR-17-92 in development has not been well studied. From analysis of microRNAs during lung development, expression of the miR-17-92 cluster is high at early stages, but declines as development proceeds. We used the mouse surfactant protein C (Sftpc) promoter to over-express the cluster in embryonic lung epithelium. Transgenic lungs have a very abnormal lethal phenotype. They contain numerous proliferative epithelial cells that retain high levels of Sox9, a marker of distal progenitors. The differentiation of proximal epithelial cells was also inhibited. Furthermore, a significant increase in the number of neuroendocrine cell clusters was observed in the lungs of dead transgenic pups. We identify a tumor suppressor, Rbl2 which belongs to the Rb family, as a new target for miR-17-5p. Together, these studies suggest that mir-17-92 normally promotes the high proliferation and undifferentiated phenotype of lung epithelial progenitor cells. [Copyright &y& Elsevier]

MicroRNAs (miRs) are non-coding master regulators of transcriptome that could act as tumor suppressors (TSs) or oncogenes (oncomiRs). We aimed to systematically investigate the relevance of miRs as prognostic biomarkers in primary glioblastoma multiforme (GBM) treated with postoperative radio(chemo)therapy (PORT). For hypothesis generation, tumor miR expression by Agilent 8x15K human microRNA microarrays and survival data from 482 GBM patients of The Cancer Genome Atlas (TCGA cohort) were analyzed using Cox-PH models. Expression of candidate miRs with prognostic relevance (miR-221/222; miR-17-5p, miR-18a, miR-19b) was validated by qRT-PCR using Taqman technology on an independent validation cohort of GBM patients (n = 109) treated at Heidelberg University Hospital (HD cohort). In TCGA, 50 miRs showed significant association with survival. Among the top ranked prognostic miRs were members of the two miR families miR-221/222 and miR-17-92. Loss of miR-221/222 was correlated with improved prognosis in both cohorts (TCGA, HD) and was an independent prognostic marker in a multivariate analysis considering demographic characteristics (age, sex, Karnofsky performance index (KPI)), molecular markers (O-6-methylguanine-DNA methyltransferase (MGMT) methylation, IDH mutation status) and PORT as co-variables. The prognostic value of miR-17-92 family members was ambiguous and in part contradictory by direct comparison of the two cohorts, thus warranting further validation in larger prospective trials. [ABSTRACT FROM AUTHOR]

Numerous molecular factors disrupt the correctness of the cell cycle process leading to the development of cancer due to increased cell proliferation. Among known causative factors of such process is abnormal gene expression. Nowadays in the light of current knowledge such alterations are frequently considered in the context of mRNA–miRNA correlation. One of the molecular factors with potential value in tumorigenesis is the feedback loop between MYC and E2F genes in which miR-17-5p and miR-20a from the miR-17-92 cluster are involved. The current literature shows that overexpression of the members of the OncomiR-1 are involved in the development of many solid tumors. In the present work, we investigated the expression of components of the MYC/E2F/miR-17-92 network and their closely related elements including members of MYC and E2F families and miRNAs from two paralogs of miR-17-92: miR-106b-25 and miR-106a-363, in the most common brain tumors of childhood, pilocytic astrocytoma (PA), WHO grade 1; ependymoma (EP), WHO grade 2; and medulloblastoma (MB), WHO grade 4. We showed that the highest gene expression was observed in the MYC family for MYCN and in the E2F family for E2F2. Positive correlation was observed between the gene expression and tumor grade and type, with the highest expression being noted for medulloblastomas, followed by ependymomas, and the lowest for pilocytic astrocytomas. Most members of miR-17-92, miR-106a-363 and miR-106b-25 clusters were upregulated and the highest expression was noted for miR-18a and miR-18b. The rest of the miRNAs, including miR-19a, miR-92a, miR-106a, miR-93, or miR-25 also showed high values. miR-17-5p, miR-20a obtained a high level of expression in medulloblastomas and ependymomas, while close to the control in the pilocytic astrocytoma samples. miRNA expression also depended on tumor grade and histology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The functional effect of a specific miRNA is tightly linked to the transcriptome, thus having the potential to elicit distinct outcomes in different cellular states. Our recent discovery of a dual role of the miR-17-92 cluster, which shifts from oncogene to tumor suppressor during lymphoma progression, exemplifies the spatiotemporal plasticity of miRNAs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The miR-17-92 gene cluster, with its six different mature microRNAs (miRNAs), has an established oncogenic function. However, the oncogenic contribution of each individual miRNA in the cluster has not been assigned. Two studies published in the December 15, 2009, issue of Genes & Development by Mu and colleagues (pp. 2806-2811) and Olive and colleagues (pp. 2839-2849) dissected the miR-17-92 cluster to its individual miRNA components and identified their relative contributions to oncogenic transformation in mouse model systems. [ABSTRACT FROM AUTHOR]