MicroRNAs,stem cells and cancer stem cells

This review discusses the various regulatory charac-teristics of microRNAs that are capable of generating widespread changes in gene expression via post translational repression of many mRNA targets and control self-renewal, differentiation and division of cells. It controls the stem cell functions by controlling a wide range of pathological and physiological processes, including development, differentiation, cellular proliferation, programmed cell death, oncogenesis and metastasis. Through either mRNA cleavage or translational repression, miRNAs alter the expression of their cognate target genes; thereby modulating cellular pathways that affect the normal functions of stem cells, turning them into cancer stem cells, a likely cause of relapse in cancer patients. This present review further emphasizes the recent discoveries on the functional analysis of miRNAs in cancer metastasis and implications on miRNA based therapy using miRNA replacement or anti-miRNA technologies in specific cancer stem cells that are required to establish their efficacy in controlling tumorigenic potential and safe therapeutics.     

MicroRNAs in the tumor endothelium: Novel controls on the angioregulatory switchboard

Tumor angiogenesis facilitates tumor metastasis and allows malignant tissues to grow beyond a diffusion limited size. It is a complex process that requires endothelial cells to execute specific steps during different phases. miRNAs are small non-coding RNAs that act as molecular switches to redirect the expression profile of a cell. Evidence is emerging that miRNAs are important players in endothelial cell biology and tumor angiogenesis. In this review we summarize the available data of miRNA expression in the endothelium. In addition, we describe the current knowledge regarding the function of miRNAs in endothelial cell biology. Finally, we discuss the potential applications of miRNA based treatment strategies in angiostatic cancer therapy.     

An Integrative Meta-analysis of MicroRNAs in Hepatocellular Carcinoma

We aimed to shed new light on the roles of microRNAs （miRNAs） in liver cancer using an integrative in silico bioinformatics analysis. A new protocol for target prediction and functional analysis is presented and applied to the 26 highly differentially deregulated miRNAs in hepatocellular carcinoma. This framework comprises： （1） the overlap of prediction results by four out of five target prediction tools, including TargetScan, PicTar, miRanda, DIANA-microT and miRDB （combining machine-learning, alignment, interaction energy and statistical tests in order to minimize false positives）, （2） evidence from previous microarray analysis on the expression of these targets, （3） gene ontology （GO） and pathway enrichment analysis of the miRNA targets and their pathways and （4） linking these results to oncogenesis and cancer hallmarks. This yielded new insights into the roles of miRNAs in cancer hallmarks. Here we presented several key targets and hundreds of new targets that are significantly enriched in many new cancer-related hallmarks. In addition, we also revealed some known and new oncogenic pathways for liver cancer. These included the famous MAPK, TGFβ and cell cycle pathways. New insights were also provided into Wnt signaling, prostate cancer, axon guidance and oocyte meiosis pathways. These signaling and developmental pathways crosstalk to regulate stem cell transformation and implicate a role of miRNAs in hepatic stem cell deregulation and cancer development. By analyzing their complete interactome, we proposed new categorization for some of these miRNAs as either tumor-suppressors or oncomiRs with dual roles. Therefore some of these miRNAs may be addressed as therapeutic targets or used as therapeutic agents. Such dual roles thus expand the view of miRNAs as active maintainers of cellular homeostasis.     

MicroRNAs: critical regulators of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transition (MET) in cancer progression

MicroRNAs (miRNAs) are a class of small highly conserved RNAs that provide widespread expressional control through the translational repression of mRNA. MiRNAs have fundamental roles in the regulation of intracellular processes, and their importance during malignant transformation and metastasis is becoming increasingly well recognized. An important event in the metastatic cascade is epithelial to mesenchymal transition (EMT), a reversible phenotypic switch over, which endows malignant epithelial cells with the capacity to break free from one another and invade the surrounding stroma. Our understanding of EMT has been significantly improved by the characterization of miRNAs that influence the signalling pathways and downstream events that define EMT on a molecular level. Here, we detail the role of miRNAs in EMT, and in doing so demonstrate their importance in the early stages of the metastatic cascade; we discuss a significant body of data that suggest new opportunities for drug development, and we highlight critical knowledge gaps that remain to be addressed.     

Bedtime misalignment and progression of breast cancer

Disruption of circadian rhythms, which frequently occurs during night shift work, may be associated with cancer progression. The effect of chronotype (preference for behaviors such as sleep, work, or exercise to occur at particular times of day, with an associated difference in circadian physiology) and alignment of bedtime (preferred vs. habitual), however, have not yet been studied in the context of cancer progression in women with breast cancer. Chronotype and alignment of actual bedtime with preferred chronotype were examined using the Morningness–Eveningness Scale (MEQ) and sleep-wake log among 85 women with metastatic breast cancer. Their association with disease-free interval (DFI) was retrospectively examined using the Cox proportional hazards model. Median DFI was 81.9 months for women with aligned bedtimes (“going to bed at preferred bedtime”) (n?=?72), and 46.9 months for women with misaligned bedtimes (“going to bed later or earlier than the preferred bedtime”) (n?=?13) (log rank p?=?0.001). In a multivariate Cox proportional hazard model, after controlling for other significant predictors of DFI, including chronotype (morning type/longer DFI; HR?=?0.539, 95% CI?=?0.320–0.906, p?=?0.021), estrogen receptor (ER) status at initial diagnosis (negative/shorter DFI; HR?=?2.169, 95% CI?=?1.124–4.187, p?=?0.028) and level of natural-killer cell count (lower levels/shorter DFI; HR?=?1.641, 95% CI?=?1.000–2.695, p?=?0.050), misaligned bedtimes was associated with shorter DFI, compared to aligned bedtimes (HR?=?3.180, 95% CI?=?1.327–7.616, p?=?0.018). Our data indicate that a misalignment of bedtime on a daily basis, an indication of circadian disruption, is associated with more rapid breast cancer progression as measured by DFI. Considering the limitations of small sample size and study design, a prospective study with a larger sample is necessary to explore their causal relationship and underlying mechanisms.     

生物信息学预测植物miRNAs的方法

MicroRNA又称miRNA,是一类广泛存在于动植物体内、大小为21~25nt左右的内源性非编码单链小分子RNA。在植物体中,miRNA主要负责调控转录后基因的表达,在机体发育、生长和应答胁迫方面发挥着重要的调节作用。近年来,miRNA已成为分子生物学领域的研究热点。本文介绍了几种发现和研究miRNA的方法,重点阐述了生物信息学预测miRNA方法的流程和策略,并对各过程中采用的方法及信息学软件的优劣性进行比较和分析,为预测miRNA提供新的思路。     

microRNA序列和表达模式的多样性

microRNA(miRNA)在后生动植物细胞分化、生长发育、正常生理功能的维持、疾病的发生发展和转归中发挥重要功能.通常认为,已知miRNA对应的序列就是存储于miRBase数据库中相应的成熟miRNA序列.然而,人们忽视了miRNA序列长度和碱基的可变性,低估了来源于同一miRNA基因、非主要表达的miRNA的多样性及其功能的重要性.由于测序技术的快速发展和广泛使用,人们利用二代测序技术数据发现了miRNA序列和miRNA表达水平的多样性.基于miRNA序列和表达的多样性,本文介绍了miRNA序列5′端、3′端和内部的变异体、miRNA变异体的时空差异性表达和miRNA优势表达臂转换等方面近年来的研究进展.     

On the proportion of cancer stem cells in a tumour

It is now generally accepted that cancers contain a sub-population, the cancer stem cells (CSCs), which initiate and drive a tumour’s growth. At least until recently it has been widely assumed that only a small proportion of the cells in a tumour are CSCs. Here we use a mathematical model, supported by experimental evidence, to show that such an assumption is unwarranted. We show that CSCs may comprise any possible proportion of the tumour, and that the higher the proportion the more aggressive the tumour is likely to be.     

水稻MicroRNA的预测及实验验证

根据已报道水稻pre-miRNA的序列与结构信息,利用支持向量机（support vector machine, SVM）方法在miRNA前体上预测成熟区,产生一个模型——mature-SVM.它预测水稻成熟区的敏感性和特异性分别为86.7% 和100%;然后,用这个模型对从水稻基因组中筛选出的46.501条pre-miRNA进行成熟链预测,此外再根据miRNA的作用原理用blast程序所进一步的筛选,得到了127条pre-miRNA及成熟miRNA;除去其中已知的21条,最后得到106条候选的新的水稻miRNA. 从中随机挑取10条进行Northern验证,结果有4条miRNA得到确认.     

线粒体质量控制失调与恶性肿瘤发生和发展相关性的研究进展

线粒体活性氧增多、线粒体DNA突变和拷贝数改变、Ca~(2+)超载、凋亡异常等功能障碍与肿瘤发生、生长、侵袭、转移密切相关.随着研究的逐渐深入,人们认识到线粒体是个动态的细胞器,在生理、病理因素刺激下,经线粒体融合/分裂、线粒体自噬、线粒体生物合成以及线粒体分子伴侣和线粒体未折叠蛋白反应的协同调控,在细胞器和分子水平达到对线粒体及其蛋白质的质量控制,限制和延缓功能受损线粒体的积累和过度增多,维持线粒体数量、形态、功能和蛋白质量的动态平衡,保证细胞正常生命活动的进行,使其更好地适应环境.若线粒体及其蛋白的稳态调节能力下降或失衡,会导致受损线粒体的积累并引发细胞内环境的紊乱,影响线粒体功能的正常发挥,从而诱导正常细胞的恶性转化.     

外泌体内mircoRNAs在肝癌中的作用

外泌体是细胞间重要的信息交流介质,包含多种活性分子,如蛋白质、脂类、DNA和微RNA（microRNA, miRNA）等,外泌体可从供体细胞分泌后直接或间接作用于受体细胞,进而影响细胞之间的生命活动。更有意义的是,外泌体内的miRNAs可在血液中稳定存在,且当肿瘤发生时出现异常表达,进而参与肿瘤的发生发展,影响肿瘤患者生存及预后。近年大量研究报道显示,外泌体内miRNAs可作为肝癌诊断的新生物标志物及治疗肝癌的潜在靶标。本文就近年来外泌体内miRNAs在肝癌中的表达及其临床应用进行综述。     

MicroRNAs in cancer — from research to therapy

MicroRNAs (miRNAs) regulate target gene expression through translation repression or mRNA degradation. These non-coding RNAs are emerging as important modulators in cellular pathways, and they appear to play a key role in tumorigenesis. With increasing understanding of the miRNA target genes and the cellular behaviors influenced by them, modulating the miRNA activities may provide exciting opportunities for cancer therapy. Here the latest findings of which genes are targeted by each miRNA are reviewed, with particular emphasis on the deciphering of their possible mechanisms and the potential of miRNA-based cancer therapeutics.     

Dysregulation of axonal transport and motorneuron diseases

MNDs (motorneuron diseases) are neurodegenerative disorders in which motorneurons located in the motor cortex, in the brainstem and in the spinal cord are affected. These diseases in their inherited or sporadic forms are mainly characterized by motor dysfunctions, occasionally associated with cognitive and behavioural alterations. Although these diseases show high variability in onset, progression and clinical symptoms, they share common pathological features, and motorneuronal loss invariably leads to muscle weakness and atrophy. One of the most relevant aspect of these disorders is the occurrence of defects in axonal transport, which have been postulated to be either a direct cause, or a consequence, of motorneuron degeneration. In fact, due to their peculiar morphology and high energetic metabolism, motorneurons deeply rely on efficient axonal transport processes. Dysfunction of axonal transport is known to adversely affect motorneuronal metabolism, inducing progressive degeneration and cell death. In this regard, the understanding of the fine mechanisms at the basis of the axonal transport process and of their possible alterations may help shed light on MND pathological processes. In the present review, we will summarize what is currently known about the alterations of axonal transport found to be either causative or a consequence of MNDs.     

MicroRNAs and response to therapy in leukemia

A variety of epigenetic factors involved in leukemia pathogenesis. Among various epigenetic factors, microRNAs (miRNAs) have emerged as important players, which affect a sequence of cellular and molecular signaling pathways. Leukemia is known as progressive cancer, which is related to many health problems in the world. It has been shown that the destruction of the blood-forming organs could lead to abnormal effects on the proliferation and development of leukocytes and their precursors. Despite many attempts for approved effective and powerful therapies for patients with leukemia, finding and developing new therapeutic approaches are required. One of the important aspects of leukemia therapy, identification of underlying cellular and molecular mechanisms involved in the pathogenesis of leukemia. Several miRNAs (ie, miR-103, miR-101, mit-7, let-7i, miR-424, miR-27a, and miR-29c) and play major roles in response to therapy in patients with leukemia. miRNAs exert their effects by targeting a variety of targets, which are associated with response to therapy in patients with leukemia. It seems that more understanding about the roles of miRNAs in response to therapy in patients with leukemia could contribute to better treatment of patients with leukemia. Here, for the first time, we summarized various miRNAs, which are involved in response to therapy in the treatment patients with leukemia.     

GW小体在miRNA及细胞周期中的作用

GW小体（GW bodies,GWB）是利用自身免疫血清免疫标记蛋白GW182而鉴定的胞质聚集区,被认为是mRNA结构组分的储存中心和降解位点,是参与mRNA降解的浓缩的蛋白质.它与酵母菌中的胞质加工小体（cytoplasmic processing bodies,P-小体）蛋白具有同源性.它们的大小和数量随着细胞周期的不同而变化,且在S期和G,期体积最大,数量最多.GWB的破坏和降解使干扰小RNA（siRNA）和微RNA（miRNA）的功能减弱,且导入人的外源性的Argonaut蛋白也在GWB浓聚,说明RNAi功能可能与GWB存在着某些未知的联系.由于miRNA也参与调节细胞周期进程和细胞增殖,因此GWB不仅对miRNA的功能起关键作用,也与细胞的周期进程有很大联系.     

Regulatory MicroRNA Networks:Complex Patterns of Target Pathways for Disease-related and Housekeeping MicroRNAs

Blood-based micro RNA(mi RNA) signatures as biomarkers have been reported for various pathologies, including cancer, neurological disorders, cardiovascular diseases, and also infections. The regulatory mechanism behind respective mi RNA patterns is only partially understood. Moreover, ‘‘preserved' mi RNAs, i.e., mi RNAs that are not dysregulated in any disease,and their biological impact have been explored to a very limited extent. We set out to systematically determine their role in regulatory networks by defining groups of highly-dysregulated mi RNAs that contribute to a disease signature as opposed to preserved housekeeping mi RNAs. We further determined preferential targets and pathways of both dysregulated and preserved mi RNAs by computing multi-layer networks, which were compared between housekeeping and dysregulated mi RNAs. Of 848 mi RNAs examined across 1049 blood samples, 8 potential housekeepers showed very limited expression variations, while 20 mi RNAs showed highly-dysregulated expression throughout the investigated blood samples. Our approach provides important insights into mi RNAs and their role in regulatory networks. The methodology can be applied to systematically investigate the differences in target genes and pathways of arbitrary mi RNA sets.