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The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding rna and synonymous mutations

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EMBO MOLECULAR MEDICINE 2016年第5期8卷 442-457页

作者： Diederichs, Sven Bartsch, Lorenz Berkmann, Julia C. Froese, Karin Heitmann, Jana Hoppe, Caroline Iggena, Deetje Jazmati, Danny Karschnia, Philipp Linsenmeier, Miriam Maulhardt, Thomas Moehrmann, Lino Morstein, Johannes Paffenholz, Stella V. Roepenack, Paula Rueckert, Timo Sandig, Ludger Schell, Maximilian Steinmann, Anna Voss, Gjendine Wasmuth, Jacqueline Weinberger, Maria E. Wullenkord, Ramona Univ Freiburg Fac Med Med Ctr Div Canc ResDept Thorac Surg Hugstetter Str 55 D-79106 Freiburg Germany German Canc Res Ctr Div RNA Biol & Canc B150 Heidelberg Germany German Canc Consortium DKTK Freiburg Germany German Acad Scholarship Fdn Studienstiftung Deutsch Volkes Bonn Germany

Cancer is a disease of the genome caused by oncogene activation and tumor suppressor gene inhibition. Deep sequencing studies including large consortia such as TCGA and ICGC identified numerous tumor-specific mutations not only in protein-coding sequences but also in non-coding sequences. Although 98% of the genome is not translated into proteins, most studies have neglected the information hidden in this dark matter of the genome. Malignancy-driving mutations can occur in all genetic elements outside the coding region, namely in enhancer, silencer, insulator, and promoter as well as in 5-UTR and 3-UTR. Intron or splice site mutations can alter the splicing pattern. Moreover, cancer genomes contain mutations within non-coding rna, such as microrna, lncrna, and lincrna. A synonymous mutation changes the coding region in the DNA and rna but not the protein sequence. Importantly, oncogenes such as TERT or miR-21 as well as tumor suppressor genes such as TP53/p53, APC, BRCA1, or RB1 can be affected by these alterations. In summary, coding-independent mutations can affect gene regulation from transcription, splicing, mrna stability to translation, and hence, this largely neglected area needs functional studies to elucidate the mechanisms underlying tumorigenesis. This review will focus on the important role and novel mechanisms of these non-coding or allegedly silent mutations in tumorigenesis.

关键词： alternative polyadenylation enhancer mutation non-coding rna synonymous mutation

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The future of genetics in psychology and psychiatry: microarrays, genome-wide association, and non-coding rna

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JOUrnaL OF CHILD PSYCHOLOGY AND PSYCHIATRY 2009年第1-2期50卷 63-71页

作者： Plomin, Robert Davis, Oliver S. P. Kings Coll London Inst Psychiat SGDP Ctr London SE5 8AF England

Much of what we thought we knew about genetics needs to be modified in light of recent discoveries. What are the implications of these advances for identifying genes responsible for the high heritability of many behavioural disorders and dimensions in childhood? Although quantitative genetics such as twin studies will continue to yield important findings, nothing will advance the field as much as identifying the specific genes responsible for heritability. Advances in molecular genetics have been driven by technology, especially DNA microarrays the size of a postage stamp that can genotype a million DNA markers simultaneously. DNA microarrays have led to a dramatic shift in research towards genome-wide association (GWA) studies. The ultimate goal of GWA is to sequence each individual's entire genome, which has begun to happen. GWA studies suggest that for most complex traits and common disorders genetic effects are much smaller than previously considered: The largest effects account for only 1% of the variance of quantitative traits. This finding implies that hundreds of genes are responsible for the heritability of behavioural problems in childhood, and that it will be difficult to identify reliably these genes of small effect. Another discovery with far-reaching implications for future genetic research is the importance of non-coding rna (DNA transcribed into rna but not translated into amino acid sequences), which redefines what the word gene means. non-coding rna underlines the need for a genome-wide approach that is not limited to the 2% of DNA responsible for specifying the amino acid sequences of proteins. The only safe prediction is that the fast pace of genetic discoveries will continue and will increasingly affect research in child psychology and psychiatry. DNA microarrays will make it possible to use hundreds of genes to predict genetic risk and to use these sets of genes in top-down behavioural genomic research that explores developmental change and con

关键词： Microarray genome-wide association quantitative trait loci non-coding rna behavioural genomics

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RiceNCexp: a rice non-coding rna co-expression atlas based on massive rna-seq and small-rna seq data

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JOUrnaL OF EXPERIMENTAL BOTANY 2022年第18期73卷 6068-6077页

作者： Zhang, Baoyi Fei, Yuhan Feng, Jiejie Zhu, Xueai Wang, Rui Xiao, Hanqing Zhang, Hongsheng Huang, Ji Nanjing Agr Univ State Key Lab Crop Genet & Germplasm Enhancement Nanjing 210095 Peoples R China Jiangsu Prov Engn Res Ctr Seed Ind Sci & Technol Nanjing 210095 Peoples R China Tsinghua Univ Beijing Adv Innovat Ctr Struct Biol MOE Key Lab Bioinformat Beijing 100084 Peoples R China Tsinghua Univ Sch Life Sci Ctr Synthet & Syst Biol Frontier Res Ctr Biol Struct Beijing 100084 Peoples R China Jiangsu Key Lab Informat Agr Nanjing 210095 Peoples R China

non-coding rnas (ncrnas) play important roles in regulating expression of protein-coding genes. Although gene expression databases have emerged in a timely manner, a comprehensive expression database for ncrnas is still lacking. Herein, we constructed a rice ncrna co-expression atlas (RiceNCexp), based on 491 rna-seq and 274 small rna (srna)-seq datasets. RiceNCexp hosts four types of ncrnas, namely lncrnas, PHAS genes, mirnas, and phasirnas. RiceNCexp provides comprehensive expression information for rice ncrnas in 22 tissues/organs, an efficient tau-based mining tool for tissue-specific ncrnas, and the robust co-expression analysis among ncrnas or between ncrnas and protein-coding genes, based on 116 pairs of rna-seq and srna-seq libraries from the same experiments. In summary, RiceNCexp is a user-friendly and comprehensive rice ncrna co-expression atlas and can be freely accessed at https://***/RiceNCexp/.

关键词： Co-expression database non-coding rna rice rna-seq srna-seq

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Extracellular vesicles and their non-coding rna cargos: Emerging players in cardiovascular disease

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JOUrnaL OF PHYSIOLOGY-LONDON 2023年第22期601卷 4989-5009页

作者： Collado, Aida Gan, Lu Tengbom, John Kontidou, Eftychia Pernow, John Zhou, Zhichao Karolinska Inst Dept Med Solna Div Cardiol Stockholm Sweden Sichuan Univ West China Hosp Dept Emergency Med Lab Emergency Med Chengdu Peoples R China Karolinska Univ Hosp Dept Cardiol Stockholm Sweden

Extracellular vesicles (EVs), including exosomes, microvesicles and apoptotic bodies, have recently received attention as essential mechanisms for cell-to-cell communication in cardiovascular disease. EVs can be released from different types of cells, including endothelial cells, smooth muscle cells, cardiac cells, fibroblasts, platelets, adipocytes, immune cells and stem cells. non-coding (nc)rnas as EV cargos have recently been investigated in the cardiovascular system. Up- or downregulated ncrnas in EVs have been shown to play a crucial role in various cardiovascular diseases. Communication via EV-derived ncrnas can occur between cells of the same type and between different types of cells involved in the pathophysiology of cardiovascular disease. In the present review, we highlight the important aspects of diverse cell-derived EVs and their ncrna cargos as disease mediators and potential therapeutic targets in atherosclerosis, coronary artery disease, ischaemic heart disease and cardiac fibrosis. In addition, we summarize the potential of EV-derived ncrnas in the treatment of cardiovascular disease. Finally, we discuss the different methods for EV isolation and characterization. A better understanding of the specific role of EVs and their ncrna cargos in the regulation of cardiovascular (dys)function will be of importance for the development of diagnostic and therapeutic tools for cardiovascular disease.

关键词： cardiovascular disease extracellular vesicles non-coding rna therapy

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Deciphering the Role of Exosomal non-coding rna (ncrna) in Drug Resistance of Gastrointestinal Tumors;an Updated Review

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CELL BIOCHEMISTRY AND BIOPHYSICS 2024年第2期82卷 609-621页

作者： Tashakori, Nafiseh Armanfar, Maryam Mashhadi, Anahita Mohammed, Adil Tawfeeq Karim, Manal Morad Hussein, Abbas Hameed Abdul Adil, Mohaned Azimi, Sajad Ataei Abedini, Fatemeh Islamic Azad Univ Fac Internal Med Dept Med Tehran Branch Tehran Iran Univ Shahid Beheshti Med Sci Fac Internal Med Dept Internal Med Tehran Iran Islamic Azad Univ Dept Med Lab Sci Arak branch Arak Iran Al Noor Univ Coll Nineveh Iraq Natl Univ Sci & Technol Coll Pharm Dhi Qar 64001 Iraq Ahl Al Bayt Univ Kerbala Iraq Al Farahidi Univ Pharm Coll Baghdad Iraq Mashhad Univ Med Sci Hematol Oncol Mashhad Iran Sci & Art Univ Dept Biol Yazd Iran

One of the most prevalent types of cancer worldwide today is gastric intestinal (GI) tumors. To guarantee their lives, people with a developed GI require palliative care. This covers the application of targeted medicines in addition to chemotherapy treatments including cisplatin, 5-fluorouracil, oxaliplatin, paclitaxel, and pemetrexed. Because of the evidence of drug resistance emerging in poor patient outcomes and prognoses, determining the exact process of medication resistance is motivated. Besides, it is noteworthy that exosomes and noncoding rnas, like micrornas and long non-coding rnas (lncrnas), produced from tumor cells are implicated in both GI medication resistance and the carcinogenesis and development of GI disease. Biochemical events related to the cell cycle, differentiation of cells, growth, and pluripotency, in addition to gene transcription, splicing, and epigenetics, are all regulated by noncoding rnas (ncrnas). Therefore, it should come as a wonder that several ncrnas have been connected in recent years to drug susceptibility and resistance as well as tumorigenesis. Additionally, through communicating directly with medications, altering the transcriptome of tumor cells, and affecting the immune system, exosomes may govern treatment resistance. Because of this, exosomal lncrnas often act as a competitive endogenous rna (cerna) of mirnas to carry out its role in modifying drug resistance. In light of this, we provide an overview of the roles and processes of ncrna-enriched exosomes in GI medication resistance.

关键词： non-coding rna Cancer GI cancer Drug resistance Exosome

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H19 non-coding rna in urine cells detects urothelial carcinoma: a pilot study

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BIOMARKERS 2017年第7期22卷 661-666页

作者： Gielchinsky, Ilan Gilon, Michal Abu-lail, Rasha Matouk, Imad Hochberg, Avraham Gofrit, Ofer N. Ben-Dov, Iddo Z. Hadassah Hebrew Univ Dept Urol Med Ctr Jerusalem Israel Hebrew Univ Jerusalem Inst Life Sci Dept Biol Chem Jerusalem Israel Hadassah Hebrew Univ Med Ctr Nephrol & Hypertens Serv Jerusalem Israel

Context: Urothelial carcinoma (UC) is common and highly recurrent. Diagnosis and follow-up involve invasive cystoscopies. Objective: To evaluate H19 rna in urine cells as diagnostic tool for UC. Materials and methods: RT-PCR analysis of urine samples from healthy volunteers and UC patients. Results: H19 rna was unequivocally detected in the urine of 90.5% of patients and 25.9% of controls. H19 copies were three orders of magnitude higher in patients. Receiver operating characteristic analysis showed an area under the curve of 0.933. Conclusions: This pilot study shows that urinary cell H19 is a highly sensitive test for UC and pending verification could transform patient management.

关键词： non-coding rna diagnostic biomarkers urine biomarkers bladder cancer

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A systematic review of non-coding rna therapeutics in early clinical trials: a new perspective against cancer

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JOUrnaL OF TRANSLATIONAL MEDICINE 2024年第1期22卷 1-13页

作者： Grillone, Katia Carida, Giulio Luciano, Francesco Cordua, Alessia Di Martino, Maria Teresa Tagliaferri, Pierosandro Tassone, Pierfrancesco Magna Graecia Univ Catanzaro Dept Expt & Clin Med Catanzaro Italy

Targeting non-coding rnas (ncrnas), including micrornas (mirnas) and long non-coding rnas (lncrnas), has recently emerged as a promising strategy for treating malignancies and other diseases. In recent years, the development of ncrna-based therapeutics for targeting protein-coding and non-coding genes has also gained momentum. This review systematically examines ongoing and completed clinical trials to provide a comprehensive overview of the emerging landscape of ncrna-based therapeutics. Significant efforts have been made to advance ncrna therapeutics to early clinical studies. The most advanced trials have been conducted with small interfering rnas (sirnas), mirna replacement using nanovector-entrapped mirna mimics, or mirna silencing by antisense oligonucleotides. While sirna-based therapeutics have already received FDA approval, mirna mimics, inhibitors, and lncrna-based therapeutics are still under evaluation in preclinical and early clinical studies. We critically discuss the rationale and methodologies of ncrna targeting strategies to illustrate this rapidly evolving field.

关键词： rna-therapeutics non-coding rna ncrna therapeutics mirna therapeutics lncrna therapeutics Early clinical trials Cancer therapy Systematic review

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Role of non-coding rna in immune microenvironment and anticancer therapy of gastric cancer

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JOUrnaL OF MOLECULAR MEDICINE-JMM 2022年第12期100卷 1703-1719页

作者： Chen, Liqiao Deng, Jingyu Tianjin Med Univ Canc Inst & Hosp Natl Clin Res Ctr Canc Dept Gastr Surg Tianjin 300060 Peoples R China Key Lab Canc Prevent & Therapy Tianjin 300060 Peoples R China Tianjins Clin Res Ctr Canc Tianjin 300060 Peoples R China

Gastric cancer remains one of the cancers with the highest mortality in the world;therefore, it is very important to investigate its pathogenesis to improve the prognosis of gastric cancer patients. Recently, noncoding rnas have become a research hotspot in the field of oncology. These rna molecules play complex roles in the regulation of tumor cells, immune cells, and the tumor microenvironment. Therefore, studying their ability to regulate the gastric cancer immune microenvironment will provide us with a better perspective to understand their potential role in anticancer therapy. In this review, we discuss the regulatory effects of several common noncoding rnas on the immune microenvironment of gastric cancer and their prospects in anticancer therapy to provide some novel insight into the identification of valuable diagnostic markers and improving the prognosis of gastric cancer patients.

关键词： non-coding rna Gastric cancer Immune microenvironment Anticancer therapy Biomarker

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The double-edged sword of long non-coding rna: The role of human brain-specific BC200 rna in translational control, neurodegenerative diseases, and cancer

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MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2015年 766卷 58-67页

作者： Sosinska, Patrycja Mikula-Pietrasik, Justyna Ksiazek, Krzysztof Poznan Univ Med Sci Dept Pathophysiol PL-60806 Poznan Poland

The complexity of eukaryotic organisms involves the regulation of gene expression through DNA-protein, rna-DNA, rna-rna, and rna-protein interactions. The role of rna molecules in the regulation of genes in higher species has become even more evident with the discovery that about 97% of transcription products are represented by non-protein coding rnas (ncrnas) including short ncrnas and long ncrnas (Incrnas). In addition to the well-characterized role of ncrnas in different physiological cellular processes, numerous studies have also indicated the crucial roles of ncrnas in neurological diseases and cancer. Although involvement of short ncrna in those pathologies has already been well documented, there is only scarce evidence to show the participation of Incrnas. One of the examples of lncrnas is BC200 rna, which plays an important role in the regulation of dendritic protein expression. Mislocalization and overexpression of BC200 rna leads to inadequate rna delivery to the synapses and results in neurodegenerative processes of Alzheimer's disease and neoplastic changes in various groups of tissues. In this review, we summarize the current state of art in the field of the biological significance of Incrnas, with particular attention paid to the physiological and pathophysiological role of BC200 rna. (C) 2015 Elsevier B.V. All rights reserved.

关键词： BC200 rna Neurodegeneration non-coding rna

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Endogenous mirna sponges mediate the generation of oscillatory dynamics for a non-coding rna network

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JOUrnaL OF THEORETICAL BIOLOGY 2019年 481卷 54-60页

作者： Dhawan, Andrew Harris, Adrian L. Buffa, Francesca M. Scott, Jacob G. Univ Oxford Dept Oncol Oxford England Cleveland Clin Dept Translat Hematol Cleveland OH 44106 USA Cleveland Clin Dept Oncol Res Cleveland OH 44106 USA

Oscillations are crucial to the normal function of living organisms, across a wide variety of biological processes. In eukaryotes, oscillatory dynamics are thought to arise from interactions at the protein and rna levels;however, the role of non-coding rna in regulating these dynamics remains understudied. In this work, we show how non-coding rna acting as microrna (mirna) sponges in a conserved mirna transcription factor feedback motif, can give rise to oscillatory behaviour, and how to test for this experimentally. Control of these non-coding rna can dynamically create oscillations or stability, and we show how this behaviour predisposes to oscillations in the stochastic limit. These results, supported by emerging evidence for the role of mirna sponges in development, point towards key roles of different species of mirna sponges, such as circular rna, potentially in the maintenance of yet unexplained oscillatory behaviour. These results help to provide a paradigm for understanding functional differences between the many redundant, but distinct rna species thought to act as mirna sponges in nature, such as long non-coding rna, pseudogenes, competing mrna, circular rna, and3' UTRs. (C) 2018 Elsevier Ltd. All rights reserved.

关键词： mirna mirna sponge circrna non-coding rna rna network

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