Publications by authors named "Dorothee Wernicke"

7 Publications

  • Page 1 of 1

microRNA editing in seed region aligns with cellular changes in hypoxic conditions.

Nucleic Acids Res 2016 07 13;44(13):6298-308. Epub 2016 Jun 13.

Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA

RNA editing is a finely tuned, dynamic mechanism for post-transcriptional gene regulation that has been thoroughly investigated in the last decade. Nevertheless, RNA editing in non-coding RNA, such as microRNA (miRNA), have caused great debate and have called for deeper investigation. Until recently, in fact, inadequate methodologies and experimental contexts have been unable to provide detailed insights for further elucidation of RNA editing affecting miRNAs, especially in cancer.In this work, we leverage on recent innovative bioinformatics approaches applied to a more informative experimental context in order to analyze the variations in miRNA seed region editing activity during a time course of a hypoxia-exposed breast cancer cell line. By investigating its behavior in a dynamic context, we found that miRNA editing events in the seed region are not depended on miRNA expression, unprecedentedly providing insights on the targetome shifts derived from these modifications. This reveals that miRNA editing acts under the influence of environmentally induced stimuli.Our results show a miRNA editing activity trend aligning with cellular pathways closely associated to hypoxia, such as the VEGF and PI3K/Akt pathways, providing important novel insights on this poorly elucidated phenomenon.
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http://dx.doi.org/10.1093/nar/gkw532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994866PMC
July 2016

Human anti-nucleolin recombinant immunoagent for cancer therapy.

Proc Natl Acad Sci U S A 2015 Jul 13;112(30):9418-23. Epub 2015 Jul 13.

Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210;

Nucleolin (NCL) is a nucleocytoplasmic protein involved in many biological processes, such as ribosomal assembly, rRNA processing, and mRNA stabilization. NCL also regulates the biogenesis of specific microRNAs (miRNAs) involved in tumor development and aggressiveness. Interestingly, NCL is expressed on the surface of actively proliferating cancer cells, but not on their normal counterparts. Therefore, NCL is an attractive target for antineoplastic treatments. Taking advantage of phage-display technology, we engineered a fully human single-chain fragment variable, named 4LB5. This immunoagent binds NCL on the cell surface, it is translocated into the cytoplasm of target cells, and it abrogates the biogenesis of NCL-dependent miRNAs. Binding of 4LB5 to NCL on the cell surface of a variety of breast cancer and hepatocellular carcinoma cell lines, but not to normal-like MCF-10a breast cells, dramatically reduces cancer cell viability and proliferation. Finally, in orthotopic breast cancer mouse models, 4LB5 administration results in a significant reduction of the tumor volume without evident side effects. In summary, here we describe, to our knowledge, the first anti-NCL single-chain fragment variable displaying antineoplastic activity against established solid tumors, which could represent the prototype of novel immune-based NCL-targeting drugs with clinical potential as diagnostic and therapeutic tools in a wide variety of human cancers.
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http://dx.doi.org/10.1073/pnas.1507087112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522807PMC
July 2015

MicroRNA and cancer--a brief overview.

Adv Biol Regul 2015 Jan 28;57:1-9. Epub 2014 Sep 28.

Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA. Electronic address:

MicroRNAs (miRNAs) are short non-coding RNAs with a length of ∼22 nucleotides, involved in posttranscriptional regulation of gene expression. Until now, over 2588 miRNAs have been identified in humans and the list is growing. MicroRNAs have an important role in all biological processes and aberrant miRNA expression is associated with many diseases including cancer. In the year 2002 the first connection between cancer and miRNA deregulation was discovered. Since then, a lot of information about the key role which miRNAs play in cancer development and drug resistance has been gained. However, there is still a long way to go to fully understand the miRNA world. In this review, we briefly describe miRNA biogenesis and discuss the role of miRNAs in cancer development and drug resistance. Finally we explain how miRNAs can be used as biomarkers and as a novel therapeutic approach in cancer.
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http://dx.doi.org/10.1016/j.jbior.2014.09.013DOI Listing
January 2015

Translocation t(2;11) in CLL cells results in CXCR4/MAML2 fusion oncogene.

Blood 2014 Jul 22;124(2):259-62. Epub 2014 May 22.

Departments of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center and Medicine, The Ohio State University, Columbus, OH; and.

Recent investigations of chromosomal aberrations in chronic lymphocytic leukemia (CLL) led to a better understanding of the molecular causes of CLL. Here we report a rearrangement between MAML2 (mastermind-like protein 2) and CXCR4 (specific receptor for CXC chemokine stromal cell-derived factor-1) in CLL cells of a patient with a t(2;11)(q22.1;q21) chromosomal translocation. The rearrangement between MAML2 and CXCR4, created by a t(2;11)(q22.1;q21) translocation, results in a new fusion gene in which a portion of CXCR4 is linked to the MAML2 gene. This fusion gene encodes for CXCR4/MAML2 protein chimera in which the N-terminal basic domain of MAML2 is replaced by the N-terminal domain of CXCR4.
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http://dx.doi.org/10.1182/blood-2014-02-554675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093682PMC
July 2014

A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis.

Proc Natl Acad Sci U S A 2013 Jun 22;110(24):9845-50. Epub 2013 May 22.

Division of Pathology and Medical Oncology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University Sapienza, Santo Andrea Hospital, 00100 Rome, Italy.

Epithelial ovarian cancer is the most lethal gynecologic malignancy; it is highly aggressive and causes almost 125,000 deaths yearly. Despite advances in detection and cytotoxic therapies, a low percentage of patients with advanced stage disease survive 5 y after the initial diagnosis. The high mortality of this disease is mainly caused by resistance to the available therapies. Here, we profiled microRNA (miR) expression in serous epithelial ovarian carcinomas to assess the possibility of a miR signature associated with chemoresistance. We analyzed tumor samples from 198 patients (86 patients as a training set and 112 patients as a validation set) for human miRs. A signature of 23 miRs associated with chemoresistance was generated by array analysis in the training set. Quantitative RT-PCR in the validation set confirmed that three miRs (miR-484, -642, and -217) were able to predict chemoresistance of these tumors. Additional analysis of miR-484 revealed that the sensitive phenotype is caused by a modulation of tumor vasculature through the regulation of the VEGFB and VEGFR2 pathways. We present compelling evidence that three miRs can classify the response to chemotherapy of ovarian cancer patients in a large multicenter cohort and that one of these three miRs is involved in the control of tumor angiogenesis, indicating an option in the treatment of these patients. Our results suggest, in fact, that blockage of VEGF through the use of an anti-VEGFA antibody may not be sufficient to improve survival in ovarian cancer patients unless VEGFB signaling is also blocked.
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http://dx.doi.org/10.1073/pnas.1305472110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683704PMC
June 2013

MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response.

Proc Natl Acad Sci U S A 2012 Jul 2;109(31):E2110-6. Epub 2012 Jul 2.

Department of Molecular Virology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.

MicroRNAs (miRNAs) are small noncoding RNAs, 19-24 nucleotides in length, that regulate gene expression and are expressed aberrantly in most types of cancer. MiRNAs also have been detected in the blood of cancer patients and can serve as circulating biomarkers. It has been shown that secreted miRNAs within exosomes can be transferred from cell to cell and can regulate gene expression in the receiving cells by canonical binding to their target messenger RNAs. Here we show that tumor-secreted miR-21 and miR-29a also can function by another mechanism, by binding as ligands to receptors of the Toll-like receptor (TLR) family, murine TLR7 and human TLR8, in immune cells, triggering a TLR-mediated prometastatic inflammatory response that ultimately may lead to tumor growth and metastasis. Thus, by acting as paracrine agonists of TLRs, secreted miRNAs are key regulators of the tumor microenvironment. This mechanism of action of miRNAs is implicated in tumor-immune system communication and is important in tumor growth and spread, thus representing a possible target for cancer treatment.
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http://dx.doi.org/10.1073/pnas.1209414109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412003PMC
July 2012

Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer.

Proc Natl Acad Sci U S A 2011 Mar 7;108(12):4908-13. Epub 2011 Mar 7.

Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, Columbus, OH 43210, USA.

Infection-driven inflammation has been implicated in the pathogenesis of ~15-20% of human tumors. Expression of microRNA-155 (miR-155) is elevated during innate immune response and autoimmune disorders as well as in various malignancies. However, the molecular mechanisms providing miR-155 with its oncogenic properties remain unclear. We examined the effects of miR-155 overexpression and proinflammatory environment on the frequency of spontaneous hypoxanthine phosphoribosyltransferase (HPRT) mutations that can be detected based on the resistance to 6-thioguanine. Both miR-155 overexpression and inflammatory environment increased the frequency of HPRT mutations and down-regulated WEE1 (WEE1 homolog-S. pombe), a kinase that blocks cell-cycle progression. The increased frequency of HPRT mutation was only modestly attributable to defects in mismatch repair machinery. This result suggests that miR-155 enhances the mutation rate by simultaneously targeting different genes that suppress mutations and decreasing the efficiency of DNA safeguard mechanisms by targeting of cell-cycle regulators such as WEE1. By simultaneously targeting tumor suppressor genes and inducing a mutator phenotype, miR-155 may allow the selection of gene alterations required for tumor development and progression. Hence, we anticipate that the development of drugs reducing endogenous miR-155 levels might be key in the treatment of inflammation-related cancers.
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http://dx.doi.org/10.1073/pnas.1101795108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064319PMC
March 2011