RNA & disease (Houston, Tex.)最新文献

{"title":"TALEN-engineered human cell lines with microRNA-21 null mutations","authors":"J. Kurata, R. Lin","doi":"10.14800/RD.727","DOIUrl":"https://doi.org/10.14800/RD.727","url":null,"abstract":"Dysregulation of microRNA-21 (miR-21) is associated with many types of cancer as well as with kidney and cardiovascular diseases. Aberrant expression of miR-21 leads to multiple phenotypic alterations including cellular proliferation, invasiveness, apoptosis, and fibrosis. We recently used transcription activator-like effector nucleases to engineer human cell lines with miR-21 null mutations. As expected, loss of miR-21 resulted in decrease cell proliferation and reduced transforming activity in culture and in xenografts. Besides an increase of apoptotic gene expression, miR-21 knockout cells also had significantly increased expression of genes involved in extracellular matrix interaction. Results from small RNA sequencing suggest that miR-21 deletion changed the microRNA expression profile. These results raise intriguing possibilities that loss of miR-21 expression may influence cellular interactions and that cells with long term miR-21 deficiency may compensate for the loss of this highly expressed microRNA by changing the abundance of alternate microRNAs or the AGO2 protein in order to maintain the microRNA-AGO2 homeostasis. Further characterization and utilization of miR-21 knockout human cells will shed new light on this pathologically important microRNA.","PeriodicalId":90965,"journal":{"name":"RNA & disease (Houston, Tex.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66657667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miRNAs as tools for tailoring personalized therapeutic strategies in ovarian carcinoma","authors":"Bernard Lambert, M. Meryet-Figuiere, P. Gauduchon, Nicolas Vigneron, É. Brotin, L. Poulain, C. Denoyelle","doi":"10.14800/RD.717","DOIUrl":"https://doi.org/10.14800/RD.717","url":null,"abstract":"Ovarian carcinomas are associated with an extremely poor prognosis, resulting in a 5-year survival of 30% for advanced-stage disease. Unlike other malignancies, no significant improvement in disease management and overall survival has been achieved in the past three decades, underlining the urgent need of new therapeutic opportunities. Bcl-xL and Mcl-1 are gateway proteins guarding together against apoptosis in ovarian cancer. Given that miRNAs target the expression of several genes, in a coordinated manner, often at the nodes of important regulatory pathways, we hypothesized that among miRNAs able to kill chemoresistant ovarian cancer cell lines some may target both Bcl-xL and Mcl-1. Recently, we demonstrated that miR-491-5p induces apoptosis in several ovarian cancer cells by inhibiting directly Bcl-xL and indirectly Mcl-1 through the targeting of EGFR leading to BIM activation. Interestingly, the apoptotic effect of miR-491-5p could be mimicked by a combination therapy of an EGFR inhibitor with a BH3‑mimetic molecule (two drugs already used in clinical practice). In addition, the knowledge of the precise molecular effect of miR‑491-5p provided ways to identify downstream genetic alterations impeding the pro‑apoptotic effect of miR-491-5p in another cellular context. The resistance to this combination treatment was finally counteracted by associating pharmacological molecules affecting the involved pathways at pertinent levels. Altogether, our work highlights the potential of phenotype-based miRNA screening approaches to decipher, in the absence of a preconceived idea, new relevant therapeutic targets harboring synthetic lethal interactions to finally propose new rationale drug combinations.","PeriodicalId":90965,"journal":{"name":"RNA & disease (Houston, Tex.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66657632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional analysis of micro RNAs overexpressed in hepatocellular carcinoma","authors":"S. Baek, K. Cho, S. Ro","doi":"10.14800/RD.728","DOIUrl":"https://doi.org/10.14800/RD.728","url":null,"abstract":"Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, ranking third among all cancer-related mortalities. Recent studies have shown that hundreds of microRNAs (miRNAs) were deregulated in human HCC, however their biological functions during hepatocarcinogenesis are incompletely understood. In our recent study, we found miR-221, -181b-1, -155-5p, -25, and -17-5p were upregulated in HCCs from patients and a murine transgenic model. Using human HCC cell lines stably expressing respective miRNAs, we tested pro-tumorigenic roles of the overexpressed miRNAs in HCC. Although their functions in the development of HCC are unknown, some miRNAs can be potentially used as a diagnostic or prognostic serum marker for HCC. In our recent study, we identified several miRNAs that were specifically upregulated in patient sera with an early and/or advanced HCC.","PeriodicalId":90965,"journal":{"name":"RNA & disease (Houston, Tex.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66657677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioimaging of miRNA biogenesis using a color-tunable molecular beacon","authors":"H. Kang, Jonghwa Lee, B. Ali, A. Al-Khedhairy, Soonhag Kim","doi":"10.14800/RD.697","DOIUrl":"https://doi.org/10.14800/RD.697","url":null,"abstract":"Molecular imaging is a novel technology used to study cellular and molecular mechanisms. MicroRNAs (miRNAs or miRs) play important roles in clinical diseases. Bioimaging of miRNA is a powerful tool used to study a variety of biological phenomena. Current bioimaging of miRNA biogenesis uses a reporter gene and a mono-fluorophore-based molecular beacon (MB) to visualize miRNA-regulating cellular developments. However, the miRNA reporter gene is unable to determine the miRNA function-regulating signal-off imaging activity of cellular death. In addition, a miR MB has limited accuracy in detecting miRNA expression when fluorescence intensity in cells is weak. To overcome the disadvantages of both miRNA imaging systems, our group developed dual-fluorophore-based color-tunable miR MBs (ColoR MBs). These MBs consist of a partial double-stranded DNA oligonucleotide containing a target miRNA binding site with a fluorophore (Cy3)/black hole quencher 1 (BHQ1) at one end as a reporter probe and another fluorophore (Cy5.5) without the quencher at the other end as a reference probe. The reference probe of ColoR MB is always turned on regardless of miRNA expression. In the absence of miRNA of interest, the fluorescence activity of the reporter probe from ColoR MB was quenched due to close proximity between the fluorophore and quencher. Therefore, cells expressing little or no miRNA of interest were only visualized by the reference probe, resulting in red color. When the target miRNA was expressed in cells, it bound to the miRNA binding site of the ColoR MB. The quencher then separated from the MB, activating the fluorescence signals of the reporter probe. Cells were visualized as a yellow color due to merging of green from Cy3 and red from Cy5.5. The reference probe of ColoR MB successfully differentiated the low fluorescence activity of the reporter probe resulting from weak expression of target miRNA or low transfection of the ColoR MB in cells. The color-tunable specificity of the ColoR MB for sensing color changes based on miRNA expression and miRNA-regulating cellular development overcame limitations of the miRNA reporter gene, which shows signal-off imaging activity in the presence of target miRNA.","PeriodicalId":90965,"journal":{"name":"RNA & disease (Houston, Tex.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66657614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of intracellular microRNA using a self-assembling magnetic resonance beacon","authors":"Jonghwa Lee, H. Kang, B. Ali, A. Al-Khedhairy, Soonhag Kim","doi":"10.14800/RD.705","DOIUrl":"https://doi.org/10.14800/RD.705","url":null,"abstract":"MicroRNAs (miRNAs or miRs) are implicated in several biological processes such as proliferation, differentiation, apoptosis, development and disease. A number of miRNA imaging tools have been developed due to the scientific and clinical significance of miRNA. Current miRNA imaging techniques are based on reporter gene and molecular beacon systems, and most of these techniques utilize fluorescent probes. These techniques have been successfully used to study the function and interaction of miRNAs in the cellular environment. However, they have limited clinical applicability as imaging systems, mainly due to the inability of fluorescent probes to penetrate tissue. Magnetic resonance imaging (MRI) provides high resolution in three dimensions to analyze the anatomy and structure of tissues. We developed a self-assembling magnetic nanoparticle based molecular beacon (miR124a MR beacon) to detect miR124a in mammalian cells and tissues during neuronal differentiation by T2-weighted magnetic resonance (MR). The self-assembled structure of the miR124a MR beacons was induced by incubating 3’-adaptor, 5’-adaptor and miR linker containing the miR124a binding sequence and adaptor binding sequence. When the miR124a expression level was low in cells and tissues, the MR signal of the miR124a MR beacons was quenched. As the concentration of miR124a increased during neuronal differentiation, selective hybridization occurred between miR124a and the miR124a binding sequence of the miR124a MR beacon. This ultimately induced nanoparticle disassembly and a gradual increase in the MR signal. Our findings suggest that this method can be used to monitor the expression of miRNAs, as well as other intracellular genetic and cellular processes, by MR imaging in vivo .","PeriodicalId":90965,"journal":{"name":"RNA & disease (Houston, Tex.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66657620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced Therapeutic Platforms based on Non-Classical Tripodal Interfering RNA Structural Format","authors":"S. Sajeesh, Dong Ki Lee","doi":"10.14800/RD.708","DOIUrl":"https://doi.org/10.14800/RD.708","url":null,"abstract":"The flexibility of human RNAi (RNA interference) machinery to accommodate unconventional structures has opened the way for the development of novel RNAi triggering formats, suitable for advanced therapeutic applications. Non-classical siRNA structural variants show improved functional features over the conventional siRNA formats including increased potency, reduced non-specific responses, and enhanced cellular delivery. These non-classical RNAi structures with enhanced structural and functional properties, in combination with appropriate delivery vehicles, can be an effective therapeutic module. Here we summarize our recent efforts on expanding the structural repertoire of classical siRNAs, using tripodal interfering RNA formats, to develop novel RNAi based therapeutics for advanced health-care applications.","PeriodicalId":90965,"journal":{"name":"RNA & disease (Houston, Tex.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66657626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proceedings of the discoveries on post-transcriptional Bcl-2 deregulation in human leukemias/lymphomas","authors":"F. Gesualdo, Rosa Loffredo, Irene Granucci, S. Capaccioli, M. Lulli","doi":"10.14800/RD.694","DOIUrl":"https://doi.org/10.14800/RD.694","url":null,"abstract":"The Bcl-2 (B-cell lymphoma 2) antiapoptotic gene has been discovered since over-expressed in B-cell leukemias/lymphomas carrying the 14;18 chromosomal translocation [t(14;18)], which places the Bcl-2 gene next to the immunoglobulin heavy chain ( IgH ) locus. In this condition, the Bcl-2 moiety of the Bcl-2/IgH fusion gene is over-transcribed in virtue of the four enhancers located in 3’ of the IgH moiety leading to excessive amounts of the Bcl-2 protein, which confers a survival advantage associated with neoplastic transformation. Nevertheless, in most malignancies, comprising chronic lymphocytic leukemias, breast, prostate, colorectal and lung cancer, the over-expression of Bcl-2 does not imply chromosomal rearrangements, suggesting it could be caused by alterations at post-transcriptional level. We first disclosed the existence of a Bcl-2 post-transcriptional control, which is based on interplay among an Adenine and uracil-Rich cis-acting Element (ARE) located in the 3’UTR of Bcl-2 mRNA and several trans-acting ARE-Binding Proteins (AUBPs), and demonstrated its deregulation in human leukemias/lymphomas. In particular, we have identified some Bcl-2 AUBPs - such as AUF-1, TINO/hMex-3D, the Bcl-2 protein itself and ζ-Crystallin - and described their qualitative or quantitative alterations in cancer cells. Moreover, in the attempt to correct Bcl-2 deregulation in the human diseases characterized by defects or excesses of apoptosis, we have modulated exogenously Bcl-2 expression by means of different antisense strategies. In this research highlight, we briefly report our proceedings, in which a long non coding Bcl-2/IgH antisense RNA ( Bcl-2/IgH AS) we discovered in a serendipitous manner has played a key role.","PeriodicalId":90965,"journal":{"name":"RNA & disease (Houston, Tex.)","volume":"2 1","pages":"0-0"},"PeriodicalIF":0.0,"publicationDate":"2015-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66657577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-21, a potential therapeutic target of alleviating blood-brain barrier damage after traumatic brain injury","authors":"X. Ge, P. Lei, Jian-ning Zhang","doi":"10.14800/RD.642","DOIUrl":"https://doi.org/10.14800/RD.642","url":null,"abstract":"Traumatic brain injury (TBI) is a disease with high morbidity and leads to high rate of disability and mortality. The blood-brain barrier (BBB) damage is an important pathological change in brain after TBI, which impacts the development and prognosis of the disease. In our previous research, we have reported that miR-21-5p in neurons can exert an anti-apoptosis effect, and promote the restoration of injured BBB after TBI. Up-regulation of miR-21-5p level in brain can amplify the above functions of miR-21-5p, thus alleviate BBB damage and improve the prognosis of TBI. miR-21-3p, which is generated from pre-miR-21 at the same time with miR-21-5p, has been reported to play significant roles in regulating the expression of angiogenic factors, which can impact downstream immuno-inflammatory responses and cellular apoptosis. We made a summary of previous reports on miR-21-3p and inferred that miR-21-3p could influence the development of BBB damage after TBI. Taken together, miR-21 is a vital miRNA that impacts the restoration of traumatic BBB damage, thus it could be a potential therapeutic target for interventions in TBI.","PeriodicalId":90965,"journal":{"name":"RNA & disease (Houston, Tex.)","volume":"128 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66657569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol-conjugated let-7a miRNA mimics: promising tools for HCC systemic","authors":"Y. Liu, Xin Li, Yuanguang Xia, Wei Dai, Hua Ye Han, Jiong Cai, Y. Dong, X. Zeng, F. Luo, Tao Yang, Jie Chen, Jian Guan","doi":"10.14800/RD.630","DOIUrl":"https://doi.org/10.14800/RD.630","url":null,"abstract":"Let-7 microRNA (miRNA) family members have been demonstrated to have potential therapeutic value in vitro and in vivo as tumor suppressors that act by regulating Ras at a posttranscriptional level. Previous studies on these miRNAs have primarily focused on certain cancers in which mutation and abnormal activation of k-ras/ K-Ras occur, such as lung cancer and pancreatic cancers. However, the antitumor potential of let-7 in the case of hepatocellular carcinoma (HCC) has remained untested. Moreover, a major hurdle that limits the clinical use of miRNAs through systemic delivery, including the delivery of let-7 for HCC therapy, is the lack of an effective carrier for targeting tumors. Recently, we confirmed the antitumor efficacy of cholesterol-conjugated let-7a mimics ( Chol-let-7a ) in vitro and in vivo and verified—for the first time—that Chol-let-7a can effectively carry let-7a to orthotopic tumors in the liver and successfully inhibit tumor growth in a preclinical model when delivered systemically. We also evaluated for the first time the potential off-target effects of Chol-let-7a in liver and kidney after long-term systemically delivery, in which Chol-let-7a mainly reached and remained at these organs. Lastly, we showed that Chol-let-7a downregulated all 3 human ras/ Ras at transcriptional and translational levels and primarily functioned in the cytoplasm. Overall, our data suggest that the use of cholesterol-conjugated miRNAs is a promising tool for HCC systemic therapy.","PeriodicalId":90965,"journal":{"name":"RNA & disease (Houston, Tex.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66657526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small but mighty: microRNAs as novel signalling molecules in cancer","authors":"Camille A. Mathey-Andrews, M. Le","doi":"10.14800/RD.627","DOIUrl":"https://doi.org/10.14800/RD.627","url":null,"abstract":"MicroRNAs (miRNAs) are short, noncoding RNAs that silence target messenger RNAs by blocking translation or promoting transcript degradation. While the roles of miRNAs within cells have been extensively characterized, emerging evidence suggests that miRNAs are also transported between cells, providing a novel form of intercellular communication. Circulating miRNAs have been identified, packaged in extracellular vesicles or associated with high-density lipoproteins and Argonaute proteins. Specific extracellular miRNAs have been associated with human cancers. They not only serve as measurable disease biomarkers, but recent findings suggest secreted miRNAs may also mediate crosstalk between cancer cells and other cell types, including those that comprise the prometastatic tumor niche. Previous studies, reviewed here, demonstrate that miRNAs released by cancer cells can be internalized by nearby or distant cells, to modify gene expression and alter the tumor microenvironment. As critical drivers of both oncogenesis and metastasis, miRNAs may be attractive therapeutic targets in a wide range of cancers.","PeriodicalId":90965,"journal":{"name":"RNA & disease (Houston, Tex.)","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66657414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}