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PubMed2005

Reduced expression of Dicer associated with poor prognosis in lung cancer patients.

Emerging evidence suggests that microRNA, which are well-conserved, abundant and small regulatory RNA, may be involved in the pathogenesis of human cancers. We recently reported that expression of let-7 was frequently reduced in lung cancers, and that reduced let-7 expression was significantly associated with shorter patient survival. Two members of the double-stranded RNA-specific endonuclease family, Dicer and Drosha, convert precursor forms of microRNA into their mature forms using a stepwise process. In the present study, we examined expression levels of these genes in 67 non-small cell lung cancer cases, and found for the first time that Dicer expression levels were reduced in a fraction of lung cancers with a significant prognostic impact on the survival of surgically treated cases. It should be noted that multivariate COX regression analysis showed that the prognostic impact of Dicer (P=0.001) appears to be independent of disease stage (P=0.001), while logistic regression analysis demonstrated that the higher incidence of reduced Dicer expression in poorly differentiated tumors remained significant even after correction for other parameters (P=0.02). Given the fundamental and multiple biological roles of Dicer in various cellular processes, our results suggest the involvement of reduced Dicer expression in the development of lung cancers, thus warranting further investigations of the underlying mechanisms, which can be expected to enhance understanding of the molecular pathogenesis of this fatal cancer.

Adult↗

PubMed2006

The small RNA world of plants.

RNA has many functions in addition to being a simple messenger between the genome and the proteome. Over two decades, several classes of small noncoding RNAs c. 21 nucleotides (nt) long have been uncovered in eukaryotic genomes, which appear to play a central role in diverse and fundamental processes. In plants, small RNA-based mechanisms are involved in genome stability, gene expression and defense. Many of the discoveries in this new "small RNA world" were made by plant biologists. Here, we discuss the three major classes of small RNAs that are found in the plant kingdom, namely small interfering RNAs, microRNAs, and the recently discovered trans-acting small interfering RNAs. Recent results shed light on the identification, integration and specialization of the different components (Dicer-like, Argonaute, and others) involved in the biogenesis of the different classes of small RNAs in plants. Owing to the development of better experimental and computational methods, an ever increasing number of small noncoding RNAs are uncovered in different plant genomes. In particular the well-studied microRNAs seem to act as key regulators in several different developmental pathways, with a marked preference for transcription factors as targets. In addition, an increasing amount of data suggest that they also play an important role in other mechanisms, such as response to stress or environmental changes.

Base Sequence↗

PubMed2006

Mir-17-5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA.

MicroRNAs are an extensive family of approximately 22-nucleotide-long noncoding RNAs expressed in a wide range of eukaryotes, including humans, and they are important in development and disease. We found that microRNA Mir-17-5p has extensive complementarity to the mRNA of AIB1 (named for "amplified in breast cancer 1"). Cell culture experiments showed that AIB1 expression was downregulated by Mir-17-5p, primarily through translational inhibition. Expression of Mir-17-5p was low in breast cancer cell lines. We also found that downregulation of AIB1 by Mir-17-5p resulted in decreased estrogen receptor-mediated, as well as estrogen receptor-independent, gene expression and decreased proliferation of breast cancer cells. Mir-17-5p also completely abrogated the insulin-like growth factor 1-mediated, anchorage-independent growth of breast cancer cells. Our results reveal that Mir-17-5p has a role as a tumor suppressor in breast cancer cells.

Breast Neoplasms↗

PubMed2005

Comparative promoter region analysis powered by CORG.

BACKGROUND: Promoters are key players in gene regulation. They receive signals from various sources (e.g. cell surface receptors) and control the level of transcription initiation, which largely determines gene expression. In vertebrates, transcription start sites and surrounding regulatory elements are often poorly defined. To support promoter analysis, we present CORG http://corg.molgen.mpg.de, a framework for studying upstream regions including untranslated exons (5' UTR). DESCRIPTION: The automated annotation of promoter regions integrates information of two kinds. First, statistically significant cross-species conservation within upstream regions of orthologous genes is detected. Pairwise as well as multiple sequence comparisons are computed. Second, binding site descriptions (position-weight matrices) are employed to predict conserved regulatory elements with a novel approach. Assembled EST sequences and verified transcription start sites are incorporated to distinguish exonic from other sequences. As of now, we have included 5 species in our analysis pipeline (man, mouse, rat, fugu and zebrafish). We characterized promoter regions of 16,127 groups of orthologous genes. All data are presented in an intuitive way via our web site. Users are free to export data for single genes or access larger data sets via our DAS server http://tomcat.molgen.mpg.de:8080/das. The benefits of our framework are exemplarily shown in the context of phylogenetic profiling of transcription factor binding sites and detection of microRNAs close to transcription start sites of our gene set. CONCLUSION: The CORG platform is a versatile tool to support analyses of gene regulation in vertebrate promoter regions. Applications for CORG cover a broad range from studying evolution of DNA binding sites and promoter constitution to the discovery of new regulatory sequence elements (e.g. microRNAs and binding sites).

5' Untranslated Regions↗

PubMed2006

Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model.

BACKGROUND: microRNAs (miRNAs) are a group of non-coding single stranded RNAs measuring approximately 22 nt in length that have been found to control cell growth, differentiation and apoptosis. miRNAs negatively regulate their target genes and recently have been implicated in tumourigenesis. Furthermore, miRNA expression profiling correlates with various cancers, with these genes thought to act as both tumour suppressors and oncogenes. ret/PTC 1 is an oncogene with constitutive kinase activity implicated in the development of papillary thyroid carcinoma (PTC). This rearrangement leads to aberrant MAPK activation that is implicated in PTC tumourigenesis. AIM: The aim of this study was to identify the effect that ret/PTC 1 has on transcription and post-transcriptional regulation in PTC by using DNA microarray and microRNA analysis. RESULTS: DNA microarray analysis revealed a group of genes differentially expressed between normal thyroid cell lines and those harbouring a ret/PTC 1 rearrangement.Furthermore, a unique miRNA expression signature differentiated between PTC cell lines with ret/PTC 1 and a normal thyroid cell line. 21 miRNAs showed significant overexpression and 14 miRNAs showed underexpression in these cell lines when compared to normal thyroid. Several of these up/down regulated miRNAs may be involved in PTC pathogenesis.

Biomarkers, Tumor↗

PubMed2003

Dissection of floral induction pathways using global expression analysis.

Flowering of the reference plant Arabidopsis thaliana is controlled by several signaling pathways, which converge on a small set of genes that function as pathway integrators. We have analyzed the genomic response to one type of floral inductive signal, photoperiod, to dissect the function of several genes transducing this stimulus, including CONSTANS, thought to be the major output of the photoperiod pathway. Comparing the effects of CONSTANS with those of FLOWERING LOCUS T, which integrates inputs from CONSTANS and other floral inductive pathways, we find that expression profiles of shoot apices from plants with mutations in either gene are very similar. In contrast, a mutation in LEAFY, which also acts downstream of CONSTANS, has much more limited effects. Another pathway integrator, SUPPRESSOR OF OVEREXPRESSION OF CO 1, is responsive to acute induction by photoperiod even in the presence of the floral repressor encoded by FLOWERING LOCUS C. We have discovered a large group of potential floral repressors that are down-regulated upon photoperiodic induction. These include two AP2 domain-encoding genes that can repress flowering. The two paralogous genes, SCHLAFMUTZE and SCHNARCHZAPFEN, share a signature with partial complementarity to the miR172 microRNA, whose precursor we show to be induced upon flowering. These and related findings on SPL genes suggest that microRNAs play an important role in the regulation of flowering.

Animals↗

PubMed2004

Biochemical dissection of RNA silencing in plants.

Although RNA silencing was first discovered in plants, thus far it has been studied biochemically only in animals, where it is known as RNA interference (RNAi). In animals, two components of the RNAi pathway have been identified: Dicer, a multidomain RNase III that converts long double-stranded RNA (dsRNA) into small interfering RNA (siRNA) and the RNA-induced silencing complex (RISC), as siRNA-containing protein-RNA complex that targets complementary mRNA for destruction. We have developed methods for the biochemical dissection of plant RNA silencing. In this chapter, we describe in detail how to use wheat germ extract to study two distinct Dicer-like activities, RNA-dependent RNA polymerase (RdRP), and endogenous microRNA-programmed RISC activities. These comprehensive protocols should prove useful in the further dissection of the plant RNA silencing pathway, as well as for the validation of the predicted targets of endogenous plant microRNAs.

Animals↗

PubMed2004

[miRNA: a new regulator of gene expression].

Plant and animal genomes contain an abundance of small genes that produce RNAs of about 22 nucleotides in length, which was dubbed as microRNAs. These newly found endogenous RNAs may participate in a wide range of genetic regulatory pathways and play an important role in the development. This paper is focused on the finding of the microRNAs, its mechanism and function, as well as the methods of research.

Animals↗

PubMed2006

RNA interference: natural, experimental, and clinical roles in cancer biology.

The old idea of using antisense RNA to block messenger RNA has recently led to powerful new techniques for knocking down expression of individual protein-coding genes. The simplicity and general applicability of these new methods for RNA interference (RNAi) have turned them into fundamental tools in molecular and cellular biology, with more than 5000 publications using them during the few years since they were developed. These experimental methods are now known to exploit fundamental cellular processes that regulate differentiation via genomically encoded RNAi sequences known as microRNAs (miRNAs); changes in endogenous microRNA regulation have now been implicated in oncogenesis. Clinical trials based on local delivery of interfering RNA have already begun. More general methods for safe and effective delivery of interfering RNA to intact organisms are being developed, which could open the way to widespread clinical applications. Because RNAi can provide selective knockdown of almost any protein, it may soon provide an approach to individualized cancer therapy.

Genetic Techniques↗

PubMed2006

Dicer1 expression in preimplantation mouse embryos: Involvement of Oct3/4 transcription at the blastocyst stage.

Dicer1, an RNAse III enzyme, is a key factor for the production of microRNAs involved in post-transcriptional gene silencing. To elucidate the roles of Dicer1 and the microRNA pathway in early embryo development, we initially evaluated its gene expression in mouse oocytes and embryos in vitro. The transcript levels in GV stage oocytes steadily decreased up to the 2-cell embryo stage, and expression remained stable during morulae and blastocyst formation. DICER1 protein synthesis was additionally observed in mouse oocytes and early embryos. Silencing of mRNA expression by RNA interference (siRNA) did not inhibit development up to the blastocyst stage. Real-time RT-PCR experiments confirmed the decreased expression of selected transcription factors, including POU domain, class 5, transcription factor 1 (Pou5f1), SRY-box containing gene 2 (Sox2), and Nanog homeobox (Nanog). Moreover, POU5F1 protein expression was suppressed by Dicer1 siRNA. The results suggest that Dicer1 gene expression is associated with the levels of transcription factors, Pou5f1, Sox2, and Nanog which possibly regulate differentiation processes at the blastocyst stage.

Animals↗

PubMed2006

RNA interference in cancer.

In the recent years, RNA interference (RNAi) has emerged as a major regulatory mechanism in eukaryotic gene expression. The realization that changes in the levels of microRNAs are directly associated with cancer led to the recognition of a new class of tumor suppressors and oncogenes. Moreover, RNAi has been turned into a potent tool for artificially modulating gene expression through the introduction of short interfering RNAs. A plethora of individual inhibitory RNAs as well as several large collections of these reagents have been generated. The systems for stable and regulated expression of these molecules emerged as well. These tools have helped to delineate the roles of various cellular factors in oncogenesis and tumor suppression and laid the foundation for new approaches in gene discovery. Furthermore, successful inhibition of tumor cell growth by RNAi aimed at oncogenes in vitro and in vivo supports the enthusiasm for potential therapeutic applications of this technique. In this article we review the evidence of microRNA involvement in cancer, the use of short interfering RNAs in forward and reverse genetics of this disease, and as well as both the benefits and limitations of experimental RNAi.

Animals↗

PubMed2004

The cell-type-specificity of inherited predispositions to tumours: review and hypothesis.

Most hereditary predispositions to tumours affect only one particular cell type of the body but the genes bearing the relevant germ-line mutation are not cell-type-specific. Some predisposition syndromes include increased risks of lesions (developmental or tumourous) of unrelated cell types, in any individual predisposed to the main lesion (e.g. osteosarcoma in patients predisposed to retinoblastoma). Other predispositions to additional lesions occur only in members of some families with the predisposition to the basic lesion (e.g. Gardner's syndrome in some families suffering familial adenomatous polyposis). In yet other predisposition syndromes, different mutations of the same gene are associated with markedly differing family-specific clinical syndromes. In particular, identical germline mutations (e.g. in APC, RET and PTEN genes), have been found associated with differing clinical syndromes in different families. This paper reviews previously suggested mechanisms of the cell-type specificity of inherited predispositions to tumour. Models of tumour formation in predisposition syndromes are discussed, especially those involving a germline mutation (the first 'hit') of a tumour suppressor gene (TSG) and a second (somatic) hit on the second allele of the same TSG. A modified model is suggested, such that the second hit is a co-mutation of the second allele of the TSG and a regulator which is specific for growth and/or differentiation of the cell type which is susceptible to the tumour predisposition. In some cases of tumour, the second hit may be large enough to be associated with a cytogenetically-demonstrable abnormality of the part of the chromosome carrying the TSG, but in other cases, the co-mutation may be of 'sub-cytogenetic' size (i.e. 10(2)-10(5) bases). For the latter, mutational mechanisms of frameshift and impaired fidelity of replication of DNA by DNA polyerases may sometimes be involved. Candidate cell-type-specific regulators may include microRNAs and perhaps transcription factors. It is suggested that searching the introns within 10(5)-10(6) bases either side of known of exonic mutations of TSGs associated with inherited tumour predisposition might reveal microRNA cell-type-specific regulators. Additional investigations may involve fluorescent in situ hybridisations on interphase tumour nuclei.

Animals↗

PubMed2026

Exploring the impact of syndecans in prostate cancer: Stage-specific roles and therapeutic implications.

Syndecans (SDCs) 1-4 are a family of transmembrane heparan sulfate proteoglycans (HSPGs) that regulate cell-cell communication, adhesion, extracellular matrix organization, and signaling pathways involved in tumor biology. In prostate cancer (PCa), accumulating evidence suggests that SDCs contribute to tumor progression, therapeutic resistance, and interactions within the tumor microenvironment. However, their specific, stage-dependent roles remain incompletely understood. This review provides an integrated synthesis of current experimental and clinical evidence on SDC1-SDC4 in PCa, complemented by exploratory analyses of publicly available transcriptomic, genomic, and proteomic datasets. In contrast, copy-number alteration (CNA) strata dichotomized by the mean for SDC1, SDC2, and SDC4 showed differences in progression-free interval. Specific CNA subclasses and relationships between CNA values and SDC mRNA or protein abundance could not be determined. Proteomic pseudotime analysis further suggested that SDC4 expression increases during PCa progression, supporting its potential involvement in advanced disease. We discuss the regulation and modulation of SDCs by androgen deprivation therapy (ADT), enzymatic shedding, integrin-mediated signaling, extracellular matrix interactions, lipid signaling pathways, and microRNA networks. In particular, SDC1-microRNA interactions may influence PCa cell proliferation, cellular senescence, epithelial-mesenchymal transition (EMT), and intracellular signaling pathways. Overall, this review highlights SDCs as context-dependent regulators of PCa biology with potential relevance as biomarkers or therapeutic targets. However, clinical translation will require independent validation, standardized assays, compartment-resolved analyses, and mechanistic confirmation.

Prognosis↗

PubMed2004

The plasmodesmatal transport pathway for homeotic proteins, silencing signals and viruses.

Non-cell-autonomous signals in the form of microRNAs and transcription factors could have important developmental functions. Plasmodesmata (PD) form a cytoplasmic network throughout the plant body and provide the means of symplasmic cell-to-cell transport in plants. Homeodomain transcription factors, small RNA molecules and viral genomic information move selectively to adjacent cells via PD microchannels. Tissue-specific expression studies of non-cell-autonomous transcription factors and RNA molecules have confirmed that their intercellular transport is a highly regulated process, which depends on the tissue, developmental stage and nature of the transported macromolecule. We have known for some time that gene-silencing signals spread both locally from cell to cell and across long distances following the source to sink transition. Recent work has provided evidence that small single-stranded silencing-induced RNAs and microRNA molecules are present in the phloem transport system of different plant species. Further, recent evidence has confirmed that the transport of silencing RNA via PD is a regulated and active process, and that an amplification-relay mechanism is in place for the long-distance spread of silencing signals.

Animals↗

PubMed2005

RNA silencing and antiviral defense in plants.

Much progress has been made recently in identifying the molecular components of RNA silencing in plants, and in understanding their roles in the biogenesis of small interfering RNAs and microRNAs, in RNA-directed DNA methylation, and in RNA-mediated antiviral defense. However, many crucial questions remain unanswered. What are the molecular bases of sense and antisense transgene-mediated silencing? Why does silencing only appear to spread through transgenes? Plant viruses encode silencing suppressors to counteract host RNA silencing, and some of these suppressors affect microRNA accumulation and function and hence normal plant development. Is viral pathogenicity determined, partly or entirely, by their silencing suppressor activity?

Animals↗

PubMed2006

Novel genes identified by manual annotation and microarray expression analysis in the pancreas.

The mouse PancChip, a microarray developed for studying endocrine pancreatic development and diabetes, represents over 13,000 cDNAs. After computationally assigning the cDNAs on the array to known genes, manual curation of the remaining sequences identified 211 novel transcripts. In microarray experiments, we found that 196 of these transcripts were expressed in total pancreas and/or pancreatic islets. Of 50 randomly selected clones from these 196 transcripts, 92% were confirmed as expressed by qRT-PCR. We evaluated the coding potential of the novel transcripts and found that 74% of the clones had low coding potential. Since the transcripts may be partial mRNAs, we examined their translated proteins for transmembrane or signal peptide domains and found that about 40 proteins had one of these predicted domains. Interestingly, when we investigated the novel transcripts for their overlap with noncoding microRNAs, we found that 1 of the novel transcripts overlapped a known microRNA gene.

Animals↗

PubMed2004

Recognition of duplex RNA by helix-threading peptides.

Many important biological processes, from the interferon antiviral response to the generation of microRNA regulators of translation, involve duplex RNA. Small molecules capable of binding duplex RNA structures with high affinity and selectivity will be useful in regulating these processes and, as such, are valuable research tools and potentially therapeutic. In this paper, the synthesis and duplex RNA-binding properties of EDTA.Fe-modified peptide-intercalator conjugates (PICs) are described. Peptide appendages at the 4- and 9-positions of the planar acridine ring system render these PICs threading intercalators, directing the substituents into both grooves of double helical RNA simultaneously. Directed hydroxyl radical cleavage experiments conducted with varying RNA stem-loop structures indicate a preferred binding polarity with the N- and C-termini of the PIC in the minor and major grooves, respectively. However, this binding polarity is shown to be dependent on both the structure of the PIC and the RNA secondary structure adjacent to the intercalation site. Definition of the minimal RNA structure required for binding to one of these PICs led to the identification of an intercalation site in a pre-microRNA from Caenorhabditis elegans. Results presented will guide both rational design and combinatorial approaches for the generation of new RNA binding PICs and will continue to facilitate the identification of naturally occurring RNA targets for these small molecules.

Edetic Acid↗

PubMed2005

A database analysis method identifies an endogenous trans-acting short-interfering RNA that targets the Arabidopsis ARF2, ARF3, and ARF4 genes.

Two classes of small RNAs, microRNAs and short-interfering RNA (siRNAs), have been extensively studied in plants and animals. In Arabidopsis, the capacity to uncover previously uncharacterized small RNAs by means of conventional strategies seems to be reaching its limits. To discover new plant small RNAs, we developed a protocol to mine an Arabidopsis nonannotated, noncoding EST database. Using this approach, we identified an endogenous small RNA, trans-acting short-interfering RNA-auxin response factor (tasiR-ARF), that shares a 21- and 22-nt region of sequence similarity with members of the ARF gene family. tasiR-ARF has characteristics of both short-interfering RNA and microRNA, recently defined as tasiRNA. Accumulation of trans-acting siRNA depends on DICER-LIKE1 and RNA-DEPENDENT RNA POLYMERASE6 but not RNA-DEPENDENT RNA POLYMERASE2. We demonstrate that tasiR-ARF targets three ARF genes, ARF2, ARF3/ETT, and ARF4, and that both the tasiR-ARF precursor and its target genes are evolutionarily conserved. The identification of tasiRNA-ARF as a low-abundance, previously uncharacterized small RNA species proves our method to be a useful tool to uncover additional small regulatory RNAs.

Arabidopsis↗