miR-181在免疫系统中的研究进展

介绍miR-181家族成员在免疫系统功能和作用的研究进展。miR-181是一个重要的免疫系统调控因子,涉及到B细胞、T细胞等免疫细胞的增殖分化,生物体免疫应答、免疫耐受以及炎症反应等生理过程的变化,同时miR-181与白血病,红斑狼疮等免疫系统疾病的发生和发展存在一定的关系。对miR-181家族成员在免疫系统中的功能与作用、存在问题以及未来的研究发展趋势做一综述,以期为免疫系统疾病提供新的治疗策略。     

miR-181在人类疾病中的研究进展

miRNA-181是一个进化中极其保守的明星分子.在人类基因组中,miR-181家族成员包括miR-181a-1、miR-181a-2、miR-181b-2、miR-181b-2、miR-181c和miR-181d.miR-181最早是在小鼠B淋巴细胞中发现其特异高表达,且能调控早期造血系统的形成,从而引起了人们的关注.miR-181在小鼠胸腺、脑、肺等器官中高表达,骨髓和脾脏中也可检测到它的存在,而在造血前体细胞中低表达.其中,miR-181a被认为参与B细胞的分化成熟过程.其后,大量研究证实miR-181是一个重要的基因表达调控因子,功能涉及生物体免疫、炎症,细胞周期调控、细胞凋亡及分化等病理生理过程.另一方面miR-181在多种肿瘤中表达异常,包括白血病、神经母细胞瘤、神经胶质瘤等,但其功能及调控机制不太清楚.本文就miR-181分子的基因结构、基因表达与调控、生物学功能以及与疾病发生的相关性作一综述.     

miR-143在脂肪细胞分化和脂类代谢中的作用

miR-143是内源性非编码的RNA,在细胞的分化、发育、增殖、脂肪代谢及疾病产生等许多生物学过程中具有重要作用。miR-143与脂类代谢密切相关,主要通过与靶基因的相互作用,影响脂肪的分化,甘油三酯的合成等。针对miR-143合成、预测的靶基因以及靶基因的调控机制方面进行综述,阐述miR-143在脂肪代谢中的作用,以便为相关疾病的诊断、治疗方面提供新思路。     

miRNA调控成肌分化的研究进展

成肌分化过程包括成肌细胞的增殖,然后分化为肌细胞,最后融合形成肌管;microRNA(miRNA)是一类在转录后水平调控基因表达的微小非编码RNA,它通过靶向靶基因mRNA的3'UTR,抑制其翻译或诱导其降解。已有研究表明,miRNA在成肌分化中起重要调控作用。根据表达方式的不同,分为肌肉特异表达的miRNA,有miR-1,miR-133,miR-206,miR-208,miR-499和miR-486;和非肌肉特异表达的miRNA,其中miR-27,miR-29,miR-128,miR-199a和miR-431在成肌分化过程中具有重要的调控功能。另外,阐述了几个与miRNA相互作用从而调控成肌分化的lncRNA的功能。通过介绍两类miRNA的靶基因及调控机制,阐述了最新的研究进展。     

microRNAs调控骨骼肌分化的分子机制

microRNA（miRNA）是一大类广泛存在于真核细胞当中的长度约22nt的内源性单链非编码RNA,通过与靶基因mRNA的3’非翻译区（3’untranslated region,3’UTR）结合在转录后水平调控靶基因的表达。miRNA作为调控基因表达的重要分子在骨骼肌分化调控中的作用越来越受到关注,阐明miRNA在骨骼肌增殖与分化中的作用机制具有重要的理论意义,同时也可为骨骼肌相关疾病的治疗提供新的思路。文章总结了miRNA,尤其是miR-1、miR-133和miR-206等肌肉特异性miRNA,在调控骨骼肌分化过程中作用机制的研究进展,以便于进一步工作的开展。     

miR-20b-5p在肿瘤及其他疾病中的生物学功能

miRNAs是一类非编码的小RNA分子,在多种疾病的发病和治疗中发挥重要作用,可调控细胞增殖、细胞周期、凋亡和迁移等过程中关键基因的表达。miR-20b-5p属于miR-17家族,在多种肿瘤中和非肿瘤性疾病中存在异常表达。在肿瘤中,miR-20b-5p扮演着癌基因或抑癌基因的角色,可通过调控相应靶分子的表达影响肿瘤细胞的增殖、凋亡、侵袭与迁移等生物学行为,进而促进或抑制肿瘤的发生发展。该文对miR-20b-5p在肿瘤和非肿瘤性疾病中的生物学功能和机制进行简要综述。相信随着对miR-20b-5p的功能和机制的深入阐明,miR-20b-5p有望作为多种疾病的诊治靶点。     

microRNA-182的功能研究进展

microRNA是一类含有19~22个核苷酸的非编码RNA,在转录后水平调控基因的表达,参与多种生物学过程,如细胞分化、增殖、凋亡和代谢。microRNA-182(mi R-182)属于miR-183/96/182簇(cluster)的一员,在多种细胞和组织中表达,如成骨细胞、淋巴细胞、视网膜、内耳以及脂肪组织等。研究显示miR-182在这些组织器官的正常分化、发育和功能的维持等方面均发挥了重要作用,而它的异常表达则参与了包括视网膜病变、自身免疫性疾病、肿瘤、肥胖和糖尿病等多种相关疾病的发生发展。本文对miR-182在这些疾病发生发展中的作用及其可能的机制作一综述。     

MicroRNA与变应性鼻炎

在变应性鼻炎(allergic rhinitis,AR)发病的免疫细胞分化及免疫应答过程中,micro RNA(miRNA)发挥着非常重要的调控作用。本文旨在对AR中miRNA研究进行回顾,以期为AR的有效治疗提供新的视角。首先,变应性鼻炎患者鼻粘膜中miR-7和miRPlus-E1194等差异表达。其次,在T辅助细胞发育、分化与活化过程中,miR-181a、miR-155、miR-21、miR-1、miR-31、miR-223、miR-139-3p、miR-126、Let-7家族成员会发生显著上调或下降,而且某些miRNA的相关作用靶点也得到验证。再次,嗜酸粒细胞定向分化祖细胞向成熟嗜酸粒细胞的分化过程中,miR-21和miR-223都有所上调。最后,在肥大细胞激活和脱颗粒过程中,miR-221和miR-222以及其他miRNA显著上调。以上miRNA参与了T辅助细胞分化与活化、嗜酸粒细胞发育、肥大细胞脱颗粒等AR病理进程的各个环节,而且,miRNA还会参与前期的抗原提呈等环节。可见miRNA对AR调控呈现出复杂性和多重性。     

microRNAs与糖尿病肾病

microRNAs(miRNAs)是一类内源性非编码调控单链小RNA,通过与靶mRNA的3'端非翻译区(3'UTRs)序列相互识别而引起靶mRNA降解或蛋白翻译抑制,从而参与机体器官发育分化、细胞增殖凋亡、肿瘤发生等多种生理病理过程。目前研究表明,miRNAs在糖尿病肾病(DN)的发病进展中发挥重要作用,一些miRNAs的表达异常(如miR-192、miR-21、miR-29、miR-377、miR-93、miR-200家族、miR-451和miR-251等的上调或下调)与DN的发生、发展密切相关。近期发现miRNAs在血清、血浆和尿液等多种体液中稳定存在,并且在DN发病状态下,一些miRNAs会发生特异性改变,提示miRNAs可作为DN诊断性标志物。而且,随着对miRNAs调控机制的深入研究,特定的miRNAs有可能成为DN的治疗靶点,为疾病的预防和进展提供新的治疗策略。     

miR-138生物学功能研究进展*

microRNAs(miRNAs)是真核生物体内高度保守的非编码小分子RNA,具有多种生物学功能,参与疾病发生和发展、细胞增殖和分化等多种病理及生理过程的调控。miR-138作为一种肿瘤抑制因子已在肿瘤发生与治疗中被广泛研究和应用,同时在心血管及神经系统疾病、成骨分化、脂肪生成及卵巢功能维持等生命过程中具有调控作用。在总结分析miR-138相关功能最新研究进展的基础上,对miR-138的潜在研究方向进行了分析、讨论和展望,旨在为进一步深入探明miR-138的生物学功能提供参考和理论依据。     

miR-181b promotes hepatic stellate cells proliferation by targeting p27 and is elevated in the serum of cirrhosis patients

MicroRNAs, as a kind of negative gene regulators, were demonstrated to be involved in many types of diseases. In this study, we found that transforming growth factor-beta 1 could induce the expression of miR-181a and miR-181b, and miR-181b increased in the much higher folds than miR-181a. Because of the important role of transforming growth factor-beta 1 in HSC activation and liver cirrhosis, we investigate the effect of miR-181a and miR-181b on HSC proliferation. The results showed that miR-181b could promote HSC-T6 cell proliferation by regulating cell cycle. Further study showed p27, the cell cycle regulator, was the direct target of miR-181b in HSC-T6 cell. But miR-181a had no effects on HSC-T6 cell proliferation and cell cycle, and did not target p27. Interestingly, miR-181b is elevated significantly in serum of liver cirrhosis cases comparing to that of normal persons, whereas miR-181a expression was in the similar level with that of normal persons. These results suggested that miR-181b could be induced by TGF-β1 and promote the growth of HSCs by directly targeting p27. The elevation of miR-181b in serum suggested that it may be potential diagnostic biomarkers for cirrhosis. As for miR-181a, it may work in TGF-β1 pathway by a currently unknown mechanism.     

MiRNA-181b suppresses IGF-1R and functions as a tumor suppressor gene in gliomas

MicroRNAs (miRNAs) are single-stranded, 18- to 23-nt RNA molecules that function as regulators of gene expression. Previous studies have shown that microRNAs play important roles in human cancers, including gliomas. Here, we found that expression levels of miR-181b were decreased in gliomas, and we identified IGF-1R as a novel direct target of miR-181b. MiR-181b overexpression inhibited cell proliferation, migration, invasion, and tumorigenesis by targeting IGF-1R and its downstream signaling pathways, PI3K/AKT and MAPK/ERK1/2. Overexpression of IGF-1R rescued the inhibitory effects of miR-181b. In clinical specimens, IGF-1R was overexpressed, and its protein levels were inversely correlated with miR-181b expression. Taken together, our results indicate that miR-181b functions in gliomas to suppress growth by targeting the IGF-1R oncogene and that miR-181b may serve as a novel therapeutic target for gliomas.     

The lncRNA ZEB1-AS1 sponges miR-181a-5p to promote colorectal cancer cell proliferation by regulating Wnt/β-catenin signaling

Long noncoding RNAs (lncRNAs) are important regulators of the biological functions and underlying molecular mechanisms of colorectal cancer (CRC). However, the role of the lncRNA ZEB1-AS1 in CRC is not thoroughly understood. In this study, we found that ZEB1-AS1 was markedly upregulated in CRC. ZEB1-AS1 knockdown significantly suppressed CRC cell proliferation and induced apoptosis, whereas enhanced expression of ZEB1-AS1 had the opposite effect. Bioinformatics analysis identified miR-181a-5p as a candidate target of ZEB1-AS1. Moreover, we found an inverse correlation between ZEB1-AS1 and miR-181a-5p expression in CRC tissue. Inhibition of miR-181a-5p significantly upregulated ZEB1-AS1, whereas overexpression of miR-181a-5p had the opposite effect, suggesting that ZEB1-AS1 is negatively regulated by miR-181a-5p. Using luciferase reporter and RIP assays, we found that miR-181a-5p directly targets ZEB1-AS1. Importantly, ZEB1-AS1 may act as an endogenous ‘sponge’ to regulate miRNA targets by competing for miR-181a-5p binding. In summary, our findings provide the evidence supporting the role of ZEB1-AS1 as an oncogene in CRC. Our study also demonstrates that miR-181a-5p targets not only protein-coding genes but also the lncRNA ZEB1-AS1.     

MicroRNA-181b promotes ovarian cancer cell growth and invasion by targeting LATS2

MicroRNAs (miRNAs) are strongly implicated in tumorigenesis and metastasis. In this study, we showed significant upregulation of miR-181b in ovarian cancer tissues, compared with the normal ovarian counterparts. Forced expression of miR-181b led to remarkably enhanced proliferation and invasion of ovarian cancer cells while its knockdown induced significant suppression of these cellular events. The tumor suppressor gene, LATS2 (large tumor suppressor 2), was further identified as a novel direct target of miR-181b. Specifically, miR-181b bound directly to the 3′-untranslated region (UTR) of LATS2 and suppressed its expression. Restoration of LATS2 expression partially reversed the oncogenic effects of miR-181b. Our results indicate that miR-181b promotes proliferation and invasion by targeting LATS2 in ovarian cancer cells. These findings support the utility of miR-181b as a potential diagnostic and therapeutic target for ovarian cancer.     

MiR-181b-5p Downregulates NOVA1 to Suppress Proliferation,Migration and Invasion and Promote Apoptosis in Astrocytoma

MicroRNAs (miRNAs) are small, short noncoding RNAs that modulate the expression of numerous genes by targeting their mRNA. Numerous abnormal miRNA expression patterns are observed in various human malignancies, and certain miRNAs can act as oncogenes or tumor suppressors. Astrocytoma, the most common neuroepithelial cancer, represents the majority of malignant brain tumors in humans. In our previous studies, we found that the downregulation of miR-181b-5p in astrocytomas is associated with a poor prognosis. The aim of the present study was to investigate the functional role of miR-181b-5p and its possible target genes. miR-181b-5p was significantly downregulated in astrocytoma specimens, and the reduced expression of miR-181b-5p was inversely correlated with the clinical stage. The ectopic expression of miR-181b-5p inhibited proliferation, migration and invasion and induced apoptosis in astrocytoma cancer cells in vitro. The NOVA1 (neuro-oncological ventral antigen 1) gene was further identified as a novel direct target of miR-181b-5p. Specifically, miR-181b-5p bound directly to the 3''-untranslated region (UTR) of NOVA1 and suppressed its expression. In clinical specimens, NOVA1 was overexpressed, and its protein levels were inversely correlated with miR-181b-5p expression. Furthermore, the changing level of NOVA1 was significantly associated with a poor survival outcome. Similar to restoring miR-181b-5p expression, downregulating NOVA1 inhibited cell growth, migration and invasion. Overexpression of NOVA1 reversed the inhibitory effects of miR-181b-5p. Our results indicate that miR-181b-5p is a tumor suppressor in astrocytoma that inhibits tumor progression by targeting NOVA1. These findings suggest that miR-181b-5p may serve as a novel therapeutic target for astrocytoma.     

微小RNA与细胞凋亡的研究进展

微小RNA(miRNAs)是最近发现的由18~24个核苷酸组成的RNA,通过对目标mRNA的抑制而发挥重要的调节作用。目前所有已研究的多细胞真核生物表明它们是通过miRNAs来调节细胞基本的生理功能,这些功能包括细胞的增殖、分化和死亡。本文讨论了miRNAs在调节细胞增殖和凋亡方面的功能:其中,抗凋亡的miRNAs有miR-17家族、miR-21、bantam和miR-14;促凋亡的miRNAs有let-7、miR-15a和miR-16。     

MiR-181a-5p promotes neural stem cell proliferation and enhances the learning and memory of aged mice

Hippocampal neural stem cell (NSC) proliferation is known to decline with age, which is closely linked to learning and memory impairments. In the current study, we found that the expression level of miR-181a-5p was decreased in the hippocampal NSCs of aged mice and that exogenous overexpression of miR-181a-5p promoted NSC proliferation without affecting NSC differentiation into neurons and astrocytes. The mechanistic study revealed that phosphatase and tensin homolog (PTEN), a negative regulator of the AKT signaling pathway, was the target of miR-181a-5p and knockdown of PTEN could rescue the impairment of NSC proliferation caused by low miR-181a-5p levels. Moreover, overexpression of miR-181a-5p in the dentate gyrus enhanced the proliferation of NSCs and ameliorated learning and memory impairments in aged mice. Taken together, our findings indicated that miR-181a-5p played a functional role in NSC proliferation and aging-related, hippocampus-dependent learning and memory impairments.     

microRNA-181a represses ox-LDL-stimulated inflammatory response in dendritic cell by targeting c-Fos

Oxidized LDL (ox-LDL) activates dendritic cells (DCs), thereby initiating inflammation responses in atherosclerosis, yet the modulatory mechanisms remain unclear. MicroRNAs (miRNAs) are important regulators for DC functions. This study evaluated the regulation by miRNAs of the ox-LDL-induced DC immune response. In CD11c⁺ DCs from ApoE-deficient mice with hyperlipidemia, microRNA miR-181a was significantly up-regulated. In cultured bone marrow-derived DCs (BMDCs), ox-LDL promoted DC maturation and up-regulated miR-181a expression. Abundance of miR-181a attenuated ox-LDL-induced CD83 and CD40 expression, inhibited the secretion of interleukin (IL)-6 and TNF-α, and up-regulated IL-10, an important anti-inflammatory cytokine that was inhibited by ox-LDL. Inhibition of the endogenous miR-181a reversed the effects on CD83 and CD40 as well as the effects on IL-6 and TNF-α. The putative target genes of miR-181a were evaluated by gene ontology assessment, and the c-Fos-mediated inflammation pathway was identified. miR-181a targeted the 3′ untranslated region of c-Fos mRNA by luciferase experiments. Thus, abundance of miR-181a reduced c-Fos protein, whereas inhibition of miR-181a increased c-Fos protein in BMDCs. We therefore suggest that miR-181a attenuates ox-LDL-stimulated immune inflammation responses by targeting c-Fos in DCs.