MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in S��zary syndrome

Sézary syndrome (SS) is an incurable leukemic variant of cutaneous T-cell lymphoma and its pathogenesis is still unknown. Diagnosis/prognosis may strongly ameliorate the management of SS individuals. Here, we profiled the expression of 470 microRNAs (miRNAs) in a cohort of 22 SS patients, and we identified 45 miRNAs differentially expressed between SS and controls. Using predictive analysis, a list of 19 miRNAs, including miR-21, miR-214, miR-486, miR-18a, miR-342, miR-31 and let-7 members were also found. Moreover, we defined a signature of 14 miRNAs including again miR-21, potentially able to discriminate patients with unfavorable and favorable outcome. We validated our data for miR-21, miR-214 and miR-486 by qRT-PCR, including an additional set of array-independent SS cases. In addition, we also provide an in vitro evidence for a contribution of miR-214, miR-486 and miR-21 to apoptotic resistance of CTCL cell line.     

IFN-α Regulates Blimp-1 Expression via miR-23a and miR-125b in Both Monocytes-Derived DC and pDC

Type I interferon (IFN-I) have emerged as crucial mediators of cellular signals controlling DC differentiation and function. Human DC differentiated from monocytes in the presence of IFN-α (IFN-α DC) show a partially mature phenotype and a special capability of stimulating CD4+ T cell and cross-priming CD8+ T cells. Likewise, plasmacytoid DC (pDC) are blood DC highly specialized in the production of IFN-α in response to viruses and other danger signals, whose functional features may be shaped by IFN-I. Here, we investigated the molecular mechanisms stimulated by IFN-α in driving human monocyte-derived DC differentiation and performed parallel studies on peripheral unstimulated and IFN-α-treated pDC. A specific miRNA signature was induced in IFN-α DC and selected miRNAs, among which miR-23a and miR-125b, proved to be negatively associated with up-modulation of Blimp-1 occurring during IFN-α-driven DC differentiation. Of note, monocyte-derived IFN-α DC and in vitro IFN-α-treated pDC shared a restricted pattern of miRNAs regulating Blimp-1 expression as well as some similar phenotypic, molecular and functional hallmarks, supporting the existence of a potential relationship between these DC populations. On the whole, these data uncover a new role of Blimp-1 in human DC differentiation driven by IFN-α and identify Blimp-1 as an IFN-α-mediated key regulator potentially accounting for shared functional features between IFN-α DC and pDC.     

The expanding role of miR-302–367 in pluripotency and reprogramming

MicroRNA (miRNA) has been shown to be essential for regulating cell fate and pluripotency; however, our knowledge of miRNA function in stem cells is incomplete due to experimental limitations and difficulties in identifying their physiological targets. Recent studies implicated hESC-expressed miRNAs (miR?302–367 and miR?371–373 clusters) in regulating BMP signaling and promoting pluripotency, suggesting that low levels of BMP signaling may promote pluripotency by preventing neural induction. A comprehensive list of miR?302–367 targets recently identified by genome-wide approaches suggests a number of additional cellular processes and signaling pathways whose regulation by miR?302–367 may promote pluripotency and reprogramming, such as cell cycle, epigenetic changes, metabolism and vesicular transfer.     

Targeting PKCε by miR-143 regulates cell apoptosis in lung cancer

Non-small cell lung cancer (NSCLC) is one of the most common causes for lung cancer and cancer-related death. The imbalance between cell proliferation and apoptosis was suggested to play an important role in cancer pathogenesis and PKCε is one of the widely recognized targets. Here, we demonstrate that miR-143 is aberrantly downregulated in NSCLC tissue and negatively correlates with expression of PKCε. We show that miR-143 specifically targets the 3′-UTR of PKCε and regulates its expression. Treatment with miR-143 inhibitor mimics cell proliferation and apoptosis imbalance in NSCLC, while inhibition of PKCε can reverse it. Our findings suggest that targeting PKCε overexpression in NSCLC should be beneficial for lung cancer therapy.     

The role of miR-2∼13∼71 cluster in resistance to deltamethrin in Culex pipiens pallens

Excessive and continuous application of deltamethrin has resulted in the development of deltamethrin resistance among mosquitoes, which becomes a major obstacle for mosquito control. In a previous study, differentially expressed miRNAs between deltamethrin-susceptible (DS) strain and deltamethrin-resistant (DR) strain using illumina sequencing in Culex pipiens pallens were identified. In this study, we applied RNAi and the Centers for Disease Control and Prevention (CDC) bottle bioassay to investigate the relationship between miR-2∼13∼71 cluster (miR-2, miR-13 and miR-71) and deltamethrin resistance. We used quantitative real-time PCR (qRT-PCR) to measure expression levels of miR-2∼13∼71 clusters. MiR-2∼13∼71 cluster was down regulated in adult female mosquitoes from the DR strain and played important roles in deltamethrin resistance through regulating target genes, CYP9J35 and CYP325BG3. Knocking down CYP9J35 and CYP325BG3 resulted in decreased mortality of DR mosquitoes. This study provides the first evidence that miRNA clusters are associated with deltamethrin resistance in mosquitoes. Moreover, we investigated the regulatory networks formed between miR-2∼13∼71 cluster and its target genes, which provide a better understanding of the mechanism involved in deltamethrin resistance.     

Potential role of miR-214 in β-catenin gene expression within hepatocellular carcinoma

Molecular Biology Reports - MicroRNAs (miRNAs) are important gene regulators whose dysregulations can be involved in tumorigenesis. β-catenin, the main agent in the Wnt/β-catenin pathway,...     

miR-155研究进展

microRNAs(miRNAs)是进化上保守且广泛存在于真核生物中的一类非编码单链小RNA,大小约为19-25个核苷酸,主要通过抑制靶基因的表达或翻译来发挥转录后调控作用。miR-155是microRNAs家族中的重要成员,由于其具有多功能的特点而颇受关注,人们对其开展了广泛而又深刻的研究。大量研究结果表明miR-155的功能广泛,它参与机体造血细胞的发育分化、免疫细胞的发育分化、炎症反应、免疫应答、肌肉发育以及脂肪分化等许多生物过程,并在肝癌、淋巴癌、乳腺癌、胰腺癌和肺癌等多种癌组织或细胞株中呈现高表达,与肿瘤的发生、侵袭和转移密切相关,而且,随着研究的不断深入,mi R-155极有可能成为一个新的肿瘤标志物以及肿瘤基因治疗的新靶点。miR-155在各种生命过程中扮演着无可替代的角色,并在相关信号通路的调节中发挥着不可或缺的作用,是个典型的重要的多功能miRNA。就miR-155的主要特点以及相关功能研究进展予以综述,旨在讨论miR-155在机体生命活动中发挥的重要作用,为多种疾病的治疗提供新思路和新方法。     

miR-29b inhibits TGF-β1-induced cell proliferation in articular chondrocytes

Transforming growth factor β1 (TGF-β1) is a known regulator of chondrocyte proliferation and promotes cartilage repair in osteoarthritis (OA). microRNA-29b-3p (miR-29b-3p) is downregulated by TGF-β1 and overexpressed in OA cartilage. However, the ability of miR-29b-3p to mediate the chondrocyte pro-proliferative effects of TGF-β1 is not yet understood. This current study aimed to investigate the effect of miR-29b-3p on TGF-β1-induced cell proliferation in murine articular chondrocytes. The stimulation of chondrocytes by TGF-β1 for 24 h resulted in the downregulation of miR-29b-3p expression. The ratio of G0/G1 phase cells decreased in response to TGF-β1 whereas the ratio of S phase cells was increased. Consistent with this observation, miR-29b-3p overexpression inhibited TGF-β1’s ability to promote the ratio of S phase cells and downregulate the ratio of G0/G1 phase cells. These findings suggest that the downregulation of miR-29b-3p is a likely requirement for TGF-β1-mediated proliferation of murine articular chondrocytes. Furthermore, implying that miR-29b-3p expression may be involved in reduced chondrocyte proliferation in OA.     

miR-146a suppresses the sensitivity to interferon-α in hepatocellular carcinoma cells

Background

Interferon-based (IFN-based) therapy is effective in the treatment of advanced hepatocellular carcinoma (HCC). However, the issue of resistance to this therapy remains to be solved. The aim of this study was to identify microRNAs (miRNAs) that govern the sensitivity to IFN-α in HCC cells.

Methods

miRNA microarray analysis using IFN-α-resistant clones of PLC/PRF/5 (PLC-Rs) and their parental cells (PLC-P) was conducted. Changes in the anti-cancer effects of IFN-α were studied after gain-of-function and loss-of-function of the candidate miRNA.

Results

miR-146a expression was significantly higher in PLC-Rs than in PLC-P. miR-146a decreased the sensitivity to IFN-α through the suppression of apoptosis. Further experiments showed that miR-146a-related resistance to IFN-α was mediated through SMAD4.

Conclusions

The results indicated that miR-146a regulated the sensitivity of HCC cells to the cytotoxic effects of IFN-α through SMAD4, suggesting that this miRNA could be suitable for prediction of the clinical response and potential therapeutic target in HCC patients on IFN-based therapy.     

miR-142-3p enhances FcεRI-mediated degranulation in mast cells

Mast cells are immune cells derived from hematopoietic progenitors. When they are activated by stimuli, they immediately release granule-associated mediators, leading to allergic inflammation. Several factors controlling mediator release have been identified; however, little is known whether microRNAs (miRNAs) are involved in this process. miRNAs are a small class of non-coding RNAs that negatively regulate gene expression. In this study, we investigated the relationship between miRNAs and degranulation in LAD2 cells, a human mast cell line. We demonstrated that silencing of Dicer, a key enzyme of miRNA biogenesis, attenuates degranulation, indicating that miRNAs are involved in mast cell degranulation. We furthermore discovered that the overexpression of miR-142-3p enhances FcεRI-mediated degranulation and that miR-142-3p rescues the reduction of degranulation by silencing Dicer. Similar effects were observed in bone marrow-derived mast cells obtained miR-142-3p-deficient mice. Our studies suggest that miR-142-3p is a potential therapeutic target in pathological conditions caused by mast cells, such as mastocytosis and allergies.     

miR-146a suppresses the sensitivity to interferon-α in hepatocellular carcinoma cells

Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (OSE) and in epithelial ovarian tumors. Most notably, OSE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-κB) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to IκB degradation and activation of NF-κB. NF-κB activation was confirmed by nuclear localization of NF-κB p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-κB signaling attenuated LPS-induced TNFα plus increased doubling time in both cell lines. Contradictory to reports using human OSE cell lines, inhibition of NF-κB signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to OSE-derived cancers, inhibition of NF-κB does not sensitize GCTs to TRAIL or cisplatin.