Non-coding RNAs: a promising target for early metastasis intervention / 中华医学杂志(英文版)

Metastases account for the overwhelming majority of cancer-associated deaths. The dissemination of cancer cells from the primary tumor to distant organs involves a complex process known as the invasion-metastasis cascade. The underlying biological mechanisms of metastasis, however, remain largely elusive. Recently, the discovery and characterization of non-coding RNAs (ncRNAs) have revealed the diversity of their regulatory roles, especially as key contributors throughout the metastatic cascade. Here, we review recent progress in how three major types of ncRNAs (microRNAs, long non-coding RNAs, and circular RNAs) are involved in the multistep procedure of metastasis. We further examine interactions among the three ncRNAs as well as current progress in their regulatory mechanisms. We also propose the prevention of metastasis in the early stages of cancer progression and discuss current translational studies using ncRNAs as targets for metastasis diagnosis and treatments. These studies provide insights into developing more effective strategies to target metastatic relapse.

Roles of exosome-derived non-coding RNA in tumor micro-environment and its clinical application / 浙江大学学报·医学版

Tumor-derived exosomes play an important role in the tumor micro-environment. The exosome-derived non-coding RNAs are transmitted in the tumor microenvironment in three ways, communication between tumor cells, normal cells affecting tumor cells, and tumor cells affecting normal cells. Through these three ways, exosomal non-coding RNAs are involved in the regulation of tumor progression, affecting tumor angiogenesis, tumor invasiveness, drug resistance, stemness, tumor metabolic repro-gramming and immune escape, resulting in dual roles in promoting or inhibiting tumor development. Exosomes have a membranous structure and their contents are resistant to degradation by extracellular proteases and remain highly stable in body fluids, thus exosome-derived non-coding RNAs are expected to serve as diagnostic and prognostic indicators for a variety of cancers. In addition, exosomes can be used to deliver non-coding RNAs for targeted therapy, or to knock down or modify tumor-promoting non-coding RNAs for tumor therapy. This article reviews the function and communication mechanism of exosomal non-coding RNAs in the tumor microenvironment, including their pathways of action, effects, potential values for tumor biomarkers and treatment targets. This article also points out the issues that need to be further studied in order to promote the progress of extracellular non-coding RNAs in cancer research and their application in tumor diagnosis and treatment.

Regulation of non-coding RNA in type H vessels angiogenesis of bone / 中国修复重建外科杂志

OBJECTIVE@#To summarize the regulatory effect of non-coding RNA (ncRNA) on type H vessels angiogenesis of bone.@*METHODS@#Recent domestic and foreign related literature about the regulation of ncRNA in type H vessels angiogenesis was widely reviewed and summarized.@*RESULTS@#Type H vessels is a special subtype of bone vessels with the ability to couple bone formation. At present, the research on ncRNA regulating type H vessels angiogenesis in bone diseases mainly focuses on microRNA, long ncRNA, and small interfering RNA, which can affect the expressions of hypoxia inducible factor 1α, platelet derived growth factor BB, slit guidance ligand 3, and other factors through their own unique ways of action, thus regulating type H vessels angiogenesis and participating in the occurrence and development of bone diseases.@*CONCLUSION@#At present, the mechanism of ncRNA regulating bone type H vessels angiogenesis has been preliminarily explored. With the deepening of research, ncRNA is expected to be a new target for the diagnosis and treatment of vascular related bone diseases.

Promising roles of non-exosomal and exosomal non-coding RNAs in the regulatory mechanism and as diagnostic biomarkers in myocardial infarction / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Non-exosomal non-coding RNAs (non-exo-ncRNAs) and exosomal ncRNAs (exo-ncRNAs) have been associated with the pathological development of myocardial infarction (MI). Accordingly, this analytical review provides an overview of current MI studies on the role of plasma non-exo/exo-ncRNAs. We summarize the features and crucial roles of ncRNAs and reveal their novel biological correlations via bioinformatics analysis. The following contributions are made: (1) we comprehensively describe the expression profile, competing endogenous RNA (ceRNA) network, and "pre-necrotic" biomarkers of non-exo/exo-ncRNAs for MI; (2) functional enrichment analysis indicates that the target genes of ncRNAs are enriched in the regulation of apoptotic signaling pathway and cellular response to chemical stress, etc.; (3) we propose an updated and comprehensive view on the mechanisms, pathophysiology, and biomarker roles of non-exo/exo-ncRNAs in MI, thereby providing a theoretical basis for the clinical management of MI.

Regulation of Glial Function by Noncoding RNA in Central Nervous System Disease / 神经科学通报·英文版

Non-coding RNAs (ncRNAs) are a class of functional RNAs that play critical roles in different diseases. NcRNAs include microRNAs, long ncRNAs, and circular RNAs. They are highly expressed in the brain and are involved in the regulation of physiological and pathophysiological processes of central nervous system (CNS) diseases. Mounting evidence indicates that ncRNAs play key roles in CNS diseases. Further elucidating the mechanisms of ncRNA underlying the process of regulating glial function that may lead to the identification of novel therapeutic targets for CNS diseases.

Research advances on the mechanism of non-coding RNA regulated diabetic wound healing / 中华烧伤杂志

Diabetic wounds are a common complication of diabetic patients, and the incidence has been increasing in recent years. In addition, its poor clinical prognosis seriously affects the quality of life of patients, which has become the focus and difficulty of diabetes treatment. As the RNA regulating gene expression, non-coding RNA can regulate the pathophysiological process of diseases, and play an important role in the healing process of diabetic wounds. In this paper, we reviewed the regulatory role, diagnostic value, and therapeutic potential of three common non-coding RNA in diabetic wounds, in order to provide a new solution for the diagnosis and treatment of diabetic wounds at the genetic and molecular level.

Role and mechanism of non-coding RNA in the pathogenesis of acute kidney injury / 生理学报

Acute kidney injury (AKI) is a common clinical syndrome and an independent risk factor of chronic kidney disease and end-stage renal failure. At present, the treatments of AKI are still very limited and the morbidity and mortality of AKI are rising. Non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs and circular RNAs (circRNAs), are RNAs that are transcribed from the genome, but not translated into proteins. It has been widely reported that ncRNA is involved in AKI caused by ischemia reperfusion injury (IRI), drugs and sepsis through different molecular biological mechanisms, such as apoptosis and oxidative stress response. Therefore, ncRNAs are expected to become a new target for clinical prevention and treatment of AKI and a new biomarker for early warning of the occurrence and prognosis of AKI. Here, the role and mechanism of ncRNA in AKI and the research progress of ncRNA as biomarkers are reviewed.

Research Progress of Non-coding RNA in Multiple Myeloma with Heart Disease---Review / 中国实验血液学杂志

Some non-coding RNAs (ncRNA), as functional RNA molecules, lack potential to encode proteins, but can affect gene expression and disease progression through a variety of mechanisms. In multiple myeloma (MM), cardiovascular disease is one of the most common complications, which may be related to a variety of factors, including patient's own factors, disease-related factors, drug factors, etc. Non-coding RNA is considered to be an important regulator of cardiovascular event risk factors and cell function, and an important candidate target for improving the condition and prognostic assessment. This article briefly summarized the role of non-coding RNA in cardiac amyloidosis caused by MM, damage to the heart by inflammatory factors, and heart disease caused by chemotherapy drugs in recent years.

Effect of exosome / 中南大学学报(医学版)

Traumatic brain injury (TBI) is a main cause of death and disability worldwide, posing a serious threat to public health. But currently, the diagnosis and treatments for TBI are still very limited. Exosomes are a group of extracellular vesicles and participate in multiple physiological processes including intercellular communication and substance transport. Non-coding RNAs (ncRNA) are of great abundancy as cargo of exosomes. Previous studies have shown that ncRNAs are involved in several pathophysiological processes of TBI. However, the concrete mechanisms involved in the effects induced by exosome-derived ncRNA remain largely unknown. As an important component of exosomes, ncRNA is of great significance for diagnosis, precise treatment, response evaluation, prognosis prediction, and complication management after TBI.

Research progress of non-coding RNA in regulating the function of T cells in asthma / 生理学报

Bronchial asthma (i.e. asthma) is a chronic inflammatory disease characterized by airway inflammatory response, hyperresponsiveness and airway remodeling, in which T cells play a vital role, especially T helper cells (Th cells). Non-coding RNAs (ncRNAs) are the RNAs that do not encode proteins, mainly including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which are widely found in eukaryotic genomes and participate in the regulation of various biological processes. Previous studies have shown that ncRNAs play an important role in the activation and transformation of T cells and other biological processes in asthma. The specific molecular mechanism and clinical application are worth in-depth discussion. This article reviewed the research progress in regulation of miRNAs, lncRNAs and circRNAs on T cells in asthma in recent years.

Insights on the epigenetic mechanisms underlying pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH), characterized by localized increased arterial blood pressure in the lungs, is a slow developing long-term disease that can be fatal. PAH is characterized by inflammation, vascular tone imbalance, pathological pulmonary vascular remodeling, and right-sided heart failure. Current treatments for PAH are palliative and development of new therapies is necessary. Recent and relevant studies have demonstrated that epigenetic processes may exert key influences on the pathogenesis of PAH and may be promising therapeutic targets in the prevention and/or cure of this condition. The aim of the present mini-review is to summarize the occurrence of epigenetic-based mechanisms in the context of PAH physiopathology, focusing on the roles of DNA methylation, histone post-translational modifications and non-coding RNAs. We also discuss the potential of epigenetic-based therapies for PAH.

Alteraciones epigenéticas en leucemia linfoblástica aguda / Epigenetic alterations in acute lymphoblastic leukemia

Resumen: La leucemia linfoblástica aguda (LLA) es el tipo de cáncer más frecuente en niños. Aunque se sabe que las alteraciones genéticas constituyen la base de la etiología de la LLA, se ha demostrado que no son suficientes para el desarrollo leucémico; son necesarias alteraciones adicionales, como las modificaciones epigenéticas. En la LLA se han identificado alteraciones de este tipo, como la metilación del DNA, la modificación de histonas y la regulación por RNAs no codificantes. La hipermetilación del DNA en regiones promotoras es una de las alteraciones epigenéticas más frecuentes en LLA: y conlleva al silenciamiento de genes que generalmente son supresores de tumor y, en consecuencia, contribuye a la leucemogénesis. También se han detectado alteraciones en proteínas remodeladoras de histonas, como la sobreexpresión de enzimas desacetilasas de histonas, así como alteraciones en enzimas acetil transferasas y metil transferasas. En la LLA también se altera la expresión de miRNAs, lo cual produce desregulación en la expresión de sus genes blanco. Estas modificaciones epigenéticas son eventos clave en la transformación maligna, e involucran la desregulación de oncogenes como BLK, WNT5B y WISP1 y de supresores de tumor como FHIT, CDKN2A, CDKN2B y TP73, lo que afecta diversos procesos celulares fundamentales que conllevan al desarrollo de LLA. Las alteraciones epigenéticas y genéticas contribuyen en conjunto al desarrollo y evolución de la LLA.

Abstract: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. It is well-known that genetic alterations constitute the basis for the etiology of ALL. However, genetic abnormalities are not enough for the complete development of the disease, and additional alterations such as epigenetic modifications are required. Such alterations, like DNA methylation, histone modifications, and noncoding RNA regulation have been identified in ALL. DNA hypermethylation in promoter regions is one of the most frequent epigenetic modifications observed in ALL. This modification frequently leads to gene silencing in tumor suppressor genes, and in consequence, contributes to leukemogenesis. Alterations in histone remodeling proteins have also been detected in ALL, such as the overexpression of histone deacetylases enzymes, and alteration of acetyltransferases and methyltransferases. ALL also shows alteration in the expression of miRNAs, and in consequence, the modification in the expression of their target genes. All of these epigenetic modifications are key events in the malignant transformation since they lead to the deregulation of oncogenes as BLK, WNT5B and WISP1, and tumor suppressors such as FHIT, CDKN2A, CDKN2B, and TP53, which alter fundamental cellular processes and potentially lead to the development of ALL. Both genetic and epigenetic alterations contribute to the development and evolution of ALL.

Simultaneous deletion of floxed genes mediated by CaMKIIalpha-Cre in the brain and in male germ cells: application to conditional and conventional disruption of Goalpha

The Cre/LoxP system is a well-established approach to spatially and temporally control genetic inactivation. The calcium/calmodulin-dependent protein kinase II alpha subunit (CaMKIIalpha) promoter limits expression to specific regions of the forebrain and thus has been utilized for the brain-specific inactivation of the genes. Here, we show that CaMKIIalpha-Cre can be utilized for simultaneous inactivation of genes in the adult brain and in male germ cells. Double transgenic Rosa26(+/stop-lacZ)::CaMKIIalpha-Cre(+/Cre) mice generated by crossing CaMKIIalpha-Cre(+/Cre) mice with floxed ROSA26 lacZ reporter (Rosa26(+/stop-lacZ)) mice exhibited lacZ expression in the brain and testis. When these mice were mated to wild-type females, about 27% of the offspring were whole body blue by X-gal staining without inheriting the Cre transgene. These results indicate that recombination can occur in the germ cells of male Rosa26(+/stop-lacZ)::CaMKIIalpha-Cre(+/Cre) mice. Similarly, when double transgenic Gnao(+/f)::CaMKIIalpha-Cre(+/Cre) mice carrying a floxed Go-alpha gene (Gnao(f/f)) were backcrossed to wild-type females, approximately 22% of the offspring carried the disrupted allele (Gnao(Delta)) without inheriting the Cre transgene. The Gnao(Delta/Delta) mice closely resembled conventional Go-alpha knockout mice (Gnao(-/-)) with respect to impairment of their behavior. Thus, we conclude that CaMKIIalpha-Cre mice afford recombination for both tissue- and time-controlled inactivation of floxed target genes in the brain and for their permanent disruption. This work also emphasizes that extra caution should be exercised in utilizing CaMKIIalpha-Cre mice as breeding pairs.

Automatic prediction of non-coding RNA genes in prokaryotes based on compositional statistics.

Although non-coding RNA (ncRNA) genes do not encode proteins, they play vital roles in cells by producing functionally important RNAs. In this paper, we present a novel method for predicting ncRNA genes based on compositional features extracted directly from gene sequences. Our method consists of two Support Vector Machine (SVM) models — Codon model which uses codon usage features derived from ncRNA genes and protein-coding genes and Kmer model which utilizes features of nucleotide and dinucleotide frequency extracted respectively from ncRNA genes and randomly chosen genome sequences. The 10-fold cross-validation accuracy for the two models is found to be 92% and 91%, respectively. Thus, we could make an automatic prediction of ncRNA genes in one genome without manual filtration of protein-coding genes. After applying our method in Sulfolobus solfataricus genome, 25 prediction results have been generated according to 25 cut-off pairs. We have also applied the approach in E. coli and found our results comparable to those of previous studies. In general, our method enables automatic identification of ncRNA genes in newly sequenced prokaryotic genomes. Datasets and program code used in this work are available at http://cobi.uestc.edu.cn/resource/SS_ncRNA/

Non-coding RNAs in schistosomes: an unexplored world

Non-coding RNAs (ncRNAs) were recently given much higher attention due to technical advances in sequencing which expanded the characterization of transcriptomes in different organisms. ncRNAs have different lengths (22 nt to >1, 000 nt) and mechanisms of action that essentially comprise a sophisticated gene expression regulation network. Recent publication of schistosome genomes and transcriptomes has increased the description and characterization of a large number of parasite genes. Here we review the number of predicted genes and the coverage of genomic bases in face of the public ESTs dataset available, including a critical appraisal of the evidence and characterization of ncRNAs in schistosomes. We show expression data for ncRNAs in Schistosoma mansoni. We analyze three different microarray experiment datasets: (1) adult worms' large-scale expression measurements; (2) differentially expressed S. mansoni genes regulated by a human cytokine (TNF-α) in a parasite culture; and (3) a stage-specific expression of ncRNAs. All these data point to ncRNAs involved in different biological processes and physiological responses that suggest functionality of these new players in the parasite's biology. Exploring this world is a challenge for the scientists under a new molecular perspective of host-parasite interactions and parasite development.

RNAs não codificadores (ncRNAs) têm sido recentemente objeto de atenção muito maior devido aos avanços técnicos no sequenciamento que expandiram a caracterização dos transcritomas em diferentes organismos. ncRNAs possuem diferentes comprimentos (22 nt a >1.000 nt) e mecanismos de ação que essencialmente compreendem uma sofisticada rede de regulação de expressão gênica. A publicação recente dos genomas e transcritomas dos esquistossomos aumentou a descrição e caracterização de um grande número de genes do parasita. Aqui nós revisamos o número de genes preditos e a cobertura das bases do genoma em face dos ESTs públicos disponíveis, incluindo uma avaliação crítica da evidência e caracterização de ncRNAs em esquistossomos. Nós mostramos dados de expressão de ncRNAs em Schistosoma mansoni. Nós analisamos três conjuntos diferentes de dados de experimentos com microarranjos: (1) medidas de expressão em larga escala de vermes adultos; (2) genes diferencialmente expressos de S. mansoni regulados por uma citocina humana (TNF-α) no parasita em cultura; e (3) expressão estágio-especifica de ncRNAs. Todos estes dados apontam para ncRNAs envolvidos em diferentes processos biológicos e respostas fisiológicas que sugerem funcionalidade destes novos personagens na biologia do parasita. Explorar este mundo é um desafio para os cientistas sob uma nova perspectiva molecular da interação parasita-hospedeiro e do desenvolvimento do parasita.

The central role of RNA in the genetic programming of complex organisms

Notwithstanding lineage-specific variations, the number and type of protein-coding genes remain relatively static across the animal kingdom. By contrast there has been a massive expansion in the extent of genomic non-proteincoding sequences with increasing developmental complexity. These non-coding sequences are, in fact, transcribed in a regulated manner to produce large numbers of large and small non-protein-coding RNAs that control gene expression at many levels including chromatin architecture, post-transcriptional processing and translation. Moreover, many RNAs are edited, especially in the nervous system, which may be the basis of epigenome-environment interactions and the function of the brain.

Apesar das variações linhagem-específicas, o número e tipo de genes codificadores de proteínas permanecem relativamente estáticos no reino animal. Em contraste, houve uma expansão maciça da quantidade de sequências genômicas não-codificadoras de proteínas com o aumento da complexidade do desenvolvimento. Essas sequências não codificadoras são, de fato, transcritas de maneira regulada para produzirem numerosos RNAs grandes e pequenos não-codificadores de proteínas que controlam a expressão de genes em vários níveis, incluindo a arquitetura da cromatina, o processamento pós-transcricional e a tradução. Além disso, muitos RNAs são editados, especialmente no sistema nervoso, o que pode ser a base de interações epigenoma-ambiente e a função do cérebro.

hTR RNA component as a marker of cellular proliferation in oral lichen planus.

Previously, we have shown that the telomerase RNA component hTR is highly expressed in the epithelium of non-dysplastic Oral Lichen Planus (OLP) lesions (11). We concluded that it is possible that this high expression might be related to the increased cellular proliferation seen in OLP rather than being an indicator of potential malignant transformation. In the present study, and in order to confirm our finding in the previous study that hTR might be a marker for cellular proliferation in OLP, we analysed OLP biopsies known to be positive for RNA component of Telomerase (hTR) for the expression of Ki-67 as a marker for cellular proliferation. Fourteen OLP tissue biopsies known to be positive for telomerase RNA component hTR, were investigated using an immunohistochemical approach to determine the rate of cellular proliferation in OLP, looking at the expression of Ki-67 protein as a marker for cellular proliferation. A statistically significant increase was found between Ki-67 expression in OLP in comparison to normal control buccal mucosa samples. The expression of hTR component in OLP might thus be a marker for cellular proliferation.

Male sterility associated with overexpression of the noncoding hsromega gene in cyst cells of testis of Drosophila melanogaster.

Of the several noncoding transcripts produced by the hsromega gene of Drosophila melanogaster, the nucleus-limited >10-kb hsromega-n transcript colocalizes with heterogeneous nuclear RNA binding proteins (hnRNPs) to form fine nucleoplasmic omega speckles. Our earlier studies suggested that the noncoding hsromega-n transcripts dynamically regulate the distribution of hnRNPs in active (chromatin bound) and inactive (in omega speckles) compartments. Here we show that a P transposon insertion in this gene's promoter (at -130 bp) in the hsromega05421; enhancer-trap line had no effect on viability or phenotype of males or females, but the insertion-homozygous males were sterile. Testes of hsromega05421; homozygous flies contained nonmotile sperms while their seminal vesicles were empty. RNA:RNA in situ hybridization showed that the somatic cyst cells in testes of the mutant male flies contained significantly higher amounts of hsromega-n transcripts, and unlike the characteristic fine omega speckles in other cell types they displayed large clusters of omega speckles as typically seen after heat shock. Two of the hnRNPs, viz. HRB87F and Hrb57A, which are expressed in cyst cells, also formed large clusters in these cells in parallel with the hsromega-n transcripts. A complete excision of the P transposon insertion restored male fertility as well as the fine-speckled pattern of omega speckles in the cyst cells. The in situ distribution patterns of these two hnRNPs and several other RNA-binding proteins (Hrp40, Hrb57A, S5, Sxl, SRp55 and Rb97D) were not affected by hsromega mutation in any of the meiotic stages in adult testes. The present studies, however, revealed an unexpected presence (in wild-type as well as mutant) of the functional form of Sxl in primary spermatocytes and an unusual distribution of HRB87F along the retracting spindle during anaphase telophase of the first meiotic division. It appears that the P transposon insertion in the promoter region causes a misregulated overexpression of hsromega in cyst cells, which in turn results in excessive sequestration of hnRNPs and formation of large clusters of omega speckles in these cell nuclei. The consequent limiting availability of hnRNPs is likely to trans-dominantly affect processing of other pre-mRNAs in cyst cells. We suggest that a compromise in the activity of cyst cells due to the aberrant hnRNP distribution is responsible for the failure of individualization of sperms in hsromega05421; mutant testes. These results further support a significant role of the noncoding hsromega-n transcripts in basic cellular activities, namely regulation of the availability of hnRNPs in active (chromatin bound) and inactive (in omega speckles) compartments.