Genome-wide profiling of microRNAs in adipose mesenchymal stem cell differentiation and mouse models of obesity

In recent years, there has been accumulating evidence that microRNAs are key regulator molecules of gene expression. The cellular processes that are regulated by microRNAs include e.g. cell proliferation, programmed cell death and cell differentiation. Adipocyte differentiation is a highly regulated cellular process for which several important regulating factors have been discovered, but still not all are known to fully understand the underlying mechanisms. In the present study, we analyzed the expression of 597 microRNAs during the differentiation of mouse mesenchymal stem cells into terminally differentiated adipocytes by real-time RT-PCR. In total, 66 miRNAs were differentially expressed in mesenchymal stem cell-derived adipocytes compared to the undifferentiated progenitor cells. To further study the regulation of these 66 miRNAs in white adipose tissue in vivo and their dependence on PPARγ activity, mouse models of genetically or diet induced obesity as well as a mouse line expressing a dominant negative PPARγ mutant were employed.     

microRNAs: small molecules with big roles - C. elegans to human cancer.

miRNAs (microRNAs) were first discovered as critical regulators of developmental timing events in Caenorhabditis elegans. Subsequent studies have shown that miRNAs and cellular factors necessary for miRNA biogenesis are conserved in many organisms, suggesting the importance of miRNAs during developmental processes. Indeed, mutations in the miRNA-processing pathway induce pleiotropic defects in development, which accompany perturbation of correct expression of target genes. However, control of gene expression in development is not the only function of miRNAs. Recent work has provided new insights into the role of miRNAs in various biological events, including aging and cancer. C. elegans continues to be helpful in facilitating a further understanding of miRNA function in human diseases.     

病毒编码的miRNA:基因表达新的调控因子

微小RNA(microRNA,miRNA)是一类长约22个核苷酸的RNA,在数量、序列、结构、表达和功能上具有多样性。目前,通过生物信息学手段和分子克隆方法,已发现了3518种miRNA,在控制细胞的生长发育、分化、凋亡等过程中发挥着十分重要的作用。最近研究发现疱疹病毒、多瘤病毒、逆转录病毒的某些病毒基因组也能够编码miRNA,这些miRNA在调控病毒基因自身表达以及病毒与宿主相互作用方面可能起重要的作用。某些病毒甚至能够利用宿主体内的miRNA调控其自身表达。找出病毒可能编码的miRNA,探索其对病毒感染、复制、表达的作用,有助于病毒分子生物学的研究,也会为研发防治病毒的新方法和新途径提供新的思路。     

microRNAs: small molecules with big roles - C. elegans to human cancer

miRNAs (microRNAs) were first discovered as critical regulators of developmental timing events in Caenorhabditis elegans. Subsequent studies have shown that miRNAs and cellular factors necessary for miRNA biogenesis are conserved in many organisms, suggesting the importance of miRNAs during developmental processes. Indeed, mutations in the miRNA-processing pathway induce pleiotropic defects in development, which accompany perturbation of correct expression of target genes. However, control of gene expression in development is not the only function of miRNAs. Recent work has provided new insights into the role of miRNAs in various biological events, including aging and cancer. C. elegans continues to be helpful in facilitating a further understanding of miRNA function in human diseases.     

Regulation of cancer metastasis by microRNAs

MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs that have been found highly conserved among species. MiRNAs are able to negatively regulate gene expression through base pairing of 3’ UTRs of their target genes. Therefore, miRNAs have been shown to play an important role in regulating various cellular activities. Over the past decade, substantial evidences have been obtained to show that miRNAs are aberrantly expressed in human malignancies and could act as “OncomiRs” or “Tumor suppressor miRs”. In recent years, increasing number of studies have demonstrated the involvement of miRNAs in cancer metastasis. Many studies have shown that microRNAs could directly target genes playing a central role in epithelia-mesenchymal-transition (EMT), a cellular transformation process that allows cancer cells to acquire motility and invasiveness. EMT is considered an essential step driving the early phase of cancer metastasis. This review will summarize the recent findings and characterization of miRNAs that are involved in the regulation of EMT, migration, invasion and metastasis of cancer cells. Lastly, we will discuss potential use of miRNAs as diagnostic and prognostic biomarkers as well as therapeutic targets for cancer.     

疱疹病毒编码的miRNAs的研究进展

MicroRNAs (miRNAs)是一类长约22个核苷酸的RNA,在数量、序列、结构、表达和功能上具有多样性。目前,通过生物信息学手段和分子克隆方法,已发现了3518种miRNAs,在控制细胞的生长发育、分化、凋亡等过程中发挥着十分重要的作用。最近研究发现某些病毒基因组也能够编码miRNAs,其中大部分为疱疹病毒,这些miRNAs在调控病毒自身表达以及病毒与宿主相互作用方面可能起到重要的作用。找出病毒可能编码的miRNAs,探索其对病毒感染、复制、表达的作用,有助于病毒分子生物学的研究,也会为研发防治病毒的新方法和新途径提供新的思路。     

Insulin-Like Growth Factor-1 Signaling Regulates miRNA Expression in MCF-7 Breast Cancer Cell Line

In breast carcinomas, increased levels of insulin-like growth factor 1 (IGF-1) can act as a mitogen to augment tumorigenesis through the regulation of MAPK and AKT signaling pathways. Signaling through these two pathways allows IGF-1 to employ mechanisms that favor proliferation and cellular survival. Here we demonstrate a subset of previously described tumor suppressor and oncogenic microRNAs (miRNAs) that are under the direct regulation of IGF-1 signaling. Additionally, we show that the selective inhibition of either the MAPK or AKT pathways prior to IGF-1 stimulation prevents the expression of previously described tumor suppressor miRNAs that are family and cluster specific. Here we have defined, for the first time, specific miRNAs under the direct regulation of IGF-1 signaling in the estrogen receptor positive MCF-7 breast cancer cell line and demonstrate kinase signaling as a modulator of expression for a small subset of microRNAs. Taken together, these data give new insights into mechanisms governing IGF-1 signaling in breast cancer.     

微小RNA对人类免疫缺陷病毒感染的影响: 飞向入侵者的子弹?

微小RNA(miRNA)是一类内源性小RNA,通过结合mRNA的3′非翻译区对基因进行转录后的调节,具有广泛的生物学功能.已有研究表明,宿主miRNA能调节人类免疫缺陷病毒(HIV)的基因表达,影响HIV的复制能力、感染性,并可能与HIV的潜伏有关.与此同时,HIV来源的病毒miRNA同样在病毒的生活史以及病毒与宿主的...     

Identification and pathway analysis of microRNAs with no previous involvement in breast cancer

microRNA expression signatures can differentiate normal and breast cancer tissues and can define specific clinico-pathological phenotypes in breast tumors. In order to further evaluate the microRNA expression profile in breast cancer, we analyzed the expression of 667 microRNAs in 29 tumors and 21 adjacent normal tissues using TaqMan Low-density arrays. 130 miRNAs showed significant differential expression (adjusted P value = 0.05, Fold Change = 2) in breast tumors compared to the normal adjacent tissue. Importantly, the role of 43 of these microRNAs has not been previously reported in breast cancer, including several evolutionary conserved microRNA*, showing similar expression rates to that of their corresponding leading strand. The expression of 14 microRNAs was replicated in an independent set of 55 tumors. Bioinformatic analysis of mRNA targets of the altered miRNAs, identified oncogenes like ERBB2, YY1, several MAP kinases, and known tumor-suppressors like FOXA1 and SMAD4. Pathway analysis identified that some biological process which are important in breast carcinogenesis are affected by the altered microRNA expression, including signaling through MAP kinases and TP53 pathways, as well as biological processes like cell death and communication, focal adhesion and ERBB2-ERBB3 signaling. Our data identified the altered expression of several microRNAs whose aberrant expression might have an important impact on cancer-related cellular pathways and whose role in breast cancer has not been previously described.     

Discovery of novel human breast cancer microRNAs from deep sequencing data by analysis of pri-microRNA secondary structures

MicroRNAs (miRNAs) are key regulators of gene expression and contribute to a variety of biological processes. Abnormal miRNA expression has been reported in various diseases including pathophysiology of breast cancer, where they regulate protumorigenic processes including vascular invasiveness, estrogen receptor status, chemotherapy resistance, invasion and metastasis. The miRBase sequence database, a public repository for newly discovered miRNAs, has grown rapidly with approximately >10,000 entries to date. Despite this rapid growth, many miRNAs have not yet been validated, and several others are yet to be identified. A lack of a full complement of miRNAs has imposed limitations on recognizing their important roles in cancer, including breast cancer. Using deep sequencing technology, we have identified 189 candidate novel microRNAs in human breast cancer cell lines with diverse tumorigenic potential. We further show that analysis of 500-nucleotide pri-microRNA secondary structure constitutes a reliable method to predict bona fide miRNAs as judged by experimental validation. Candidate novel breast cancer miRNAs with stem lengths of greater than 30 bp resulted in the generation of precursor and mature sequences in vivo. On the other hand, candidates with stem length less than 30 bp were less efficient in producing mature miRNA. This approach may be used to predict which candidate novel miRNA would qualify as bona fide miRNAs from deep sequencing data with approximately 90% accuracy.     

Identification of host encoded microRNAs interacting with novel swine-origin influenza A (H1N1) virus and swine influenza virus

The discovery of microRNAs (miRNAs) is a remarkable breakthrough in the field of life science, and they are important actors which regulate gene expression in diverse cellular processes. Recently, several reports indicated that miRNAs can also target viruses and regulate virus replication. Here we discovered 36 pig-encoded miRNAs and 22 human-encoded miRNAs which have putative targets in swine influenza virus (SIV) and Swine-Origin 2009 A/H1N1 influenza virus (S-OIV) genes respectively. Interestingly, the putative interactions of ssc-miR-124a, ssc-miR-136 and ssc-miR-145 with their SIV target genes had been found to be maintained almost throughout all of the virus evolution. Enrichment analysis of previously reported miRNA gene expression profiles revealed that three miRNAs are expressed at higher levels in human lung or trachea tissue. The hsa-miR-145 and hsa-miR-92a putatively target the HA gene and hsa-miR-150 putatively targets the PB2 gene. Analysis results based on the location distribution from which virus was isolated and sequence conservation imply that some putative miRNA-mediated host-virus interactions may characterize the location-specificity.     

Lessons from miR-143/145: the importance of cell-type localization of miRNAs

miR-143 and miR-145 are co-expressed microRNAs (miRNAs) that have been extensively studied as potential tumor suppressors. These miRNAs are highly expressed in the colon and are consistently reported as being downregulated in colorectal and other cancers. Through regulation of multiple targets, they elicit potent effects on cancer cell growth and tumorigenesis. Importantly, a recent discovery demonstrates that miR-143 and miR-145 are not expressed in colonic epithelial cells; rather, these two miRNAs are highly expressed in mesenchymal cells such as fibroblasts and smooth muscle cells. The expression patterns of miR-143 and miR-145 and other miRNAs were initially determined from tissue level data without consideration that multiple different cell types, each with their own unique miRNA expression patterns, make up each tissue. Herein, we discuss the early reports on the identification of dysregulated miR-143 and miR-145 expression in colorectal cancer and how lack of consideration of cellular composition of normal tissue led to the misconception that these miRNAs are downregulated in cancer. We evaluate mechanistic data from miR-143/145 studies in context of their cell type-restricted expression pattern and the potential of these miRNAs to be considered tumor suppressors. Further, we examine other examples of miRNAs being investigated in inappropriate cell types modulating pathways in a non-biological fashion. Our review highlights the importance of determining the cellular expression pattern of each miRNA, so that downstream studies are conducted in the appropriate cell type.     

microRNA——新的髓系白血病致病因子及临床标物

微RNA(MicroRNA,miRNA)是一类长18～25 nt的非编码RNA,主要通过与靶基因mRNA3'UTR上的互补区域结合后在转录后水平(RNA切割或翻译抑制)负性调控靶基因的表达.现已发现,miRNA参与了多种正常细胞过程以及肿瘤发生的调控.miRNA也在造血链系分化和相关白血病中发挥重要作用.急性髓系白血病...