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Anti-cancer Drugs Jul 2022Long noncoding RNA (lncRNA) plays an important role in multiple cancers. So far, the exact function of lncRNAs in papillary thyroid carcinoma (PTC) is unclear. The...
Long noncoding RNA (lncRNA) plays an important role in multiple cancers. So far, the exact function of lncRNAs in papillary thyroid carcinoma (PTC) is unclear. The purposes of this work were to investigate the function and underlying mechanisms of RNF185 antisense RNA 1 (RNF185-AS1) in PTC. The expression of RNF185-AS1 was analyzed by quantitative real-time PCR (qRT-PCR). Colony formation, 5-ethynyl-2'-deoxyuridine, and Cell Counting Kit-8 assays were utilized to determine cell proliferation. Cell migration and invasion were tested using wound healing and transwell assays. A mouse transplantation tumor model was used for tumor growth analyses in vivo. The regulation of RNF185-AS1 on the downstream miR-429/lipoprotein receptor-related protein (LRP4) axis was predicted and identified through bioinformatic analysis, dual-luciferase reporter assay, and RNA immunoprecipitation (RIP) assay. RNF185-AS1 was dramatically overexpressed in PTC tumors and cells. High RNF185-AS1 expression was associated with bigger tumor size, lymph node metastasis, and advanced tumor-node-metastasis stage in PTC patients. Silencing of RNF185-AS1 impeded the proliferation, migration, and invasion in vitro and constrained tumorigenesis in vivo. Mechanistically, RNF185-AS1 could act as a sponge of miR-429 to regulate the expression of LRP4. In addition, downregulation of miR-429 or upregulation of LRP4 could relieve the proliferation, migration, and invasion of IHH-4 and TPC-1 cells that inhibited by RNF185-AS1 knockdown. Downregulation of RNF185-AS1 may suppress PTC progression through functioning as a sponge of miR-429 to hinder the expression of LRP4. The RNF185-AS1/miR-429/LRP4 axis will lay the groundwork for future therapeutic strategies in PTC.
Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Mice; MicroRNAs; Mitochondrial Proteins; RNA, Antisense; RNA, Long Noncoding; Thyroid Cancer, Papillary; Thyroid Neoplasms; Ubiquitin-Protein Ligases
PubMed: 35324519
DOI: 10.1097/CAD.0000000000001295 -
International Journal of Molecular... Apr 2022The development of computational logic that carries programmable and predictable features is one of the key requirements for next-generation synthetic biological...
The development of computational logic that carries programmable and predictable features is one of the key requirements for next-generation synthetic biological devices. Despite considerable progress, the construction of synthetic biological arithmetic logic units presents numerous challenges. In this paper, utilizing the unique advantages of RNA molecules in building complex logic circuits in the cellular environment, we demonstrate the RNA-only bitwise logical operation of XOR gates and basic arithmetic operations, including a half adder, a half subtractor, and a Feynman gate, in . Specifically, de-novo-designed riboregulators, known as toehold switches, were concatenated to enhance the functionality of an OR gate, and a previously utilized antisense RNA strategy was further optimized to construct orthogonal NIMPLY gates. These optimized synthetic logic gates were able to be seamlessly integrated to achieve final arithmetic operations on small molecule inputs in cells. Toehold-switch-based ribocomputing devices may provide a fundamental basis for synthetic RNA-based arithmetic logic units or higher-order systems in cells.
Topics: Computers, Molecular; Escherichia coli; Logic; RNA, Antisense
PubMed: 35457085
DOI: 10.3390/ijms23084265 -
Biomedicine & Pharmacotherapy =... May 2020RNA therapy is a treatment that regulates cell proteins and cures diseases by affecting the metabolism of mRNAs in cells, which has cut a figure in the studies on... (Review)
Review
RNA therapy is a treatment that regulates cell proteins and cures diseases by affecting the metabolism of mRNAs in cells, which has cut a figure in the studies on various incurable illnesses like hereditary diseases, tumors, etc. In this review, we introduced the discovery and development of RNA therapy and discussed its classification, mechanisms, advantages, and challenges. Moreover, we highlighted how RNA therapy works in killing tumor cells as well as what progresses it has made in related researches. And the development of RNA anti-tumor drugs and the clinical trial process were also included.
Topics: Animals; Biomarkers, Tumor; Cellular Reprogramming; Genetic Therapy; Humans; Immunotherapy; Molecular Targeted Therapy; Neoplasm Grading; Neoplasm Staging; Neoplasms; RNA; RNA Interference; RNA, Antisense; RNA, Messenger; Translational Research, Biomedical
PubMed: 32062550
DOI: 10.1016/j.biopha.2020.109997 -
Human Molecular Genetics Aug 2018Duchenne muscular dystrophy (DMD) is a fatal genetic disorder characterized by progressive muscle wasting that has currently no cure. Exon-skipping strategy represents... (Review)
Review
Duchenne muscular dystrophy (DMD) is a fatal genetic disorder characterized by progressive muscle wasting that has currently no cure. Exon-skipping strategy represents one of the most promising therapeutic approaches that aim to restore expression of a shorter but functional dystrophin protein. The antisense field has remarkably progress over the last years with recent accelerated approval of the first antisense oligonucleotide-based therapy for DMD, Exondys 51, though the therapeutic benefit remains to be proved in patients. Despite clinical advances, the poor effective delivery to target all muscle remains the main hurdle for antisense drug therapy. This review describes the antisense-based exon-skipping approach for DMD, from proof-of-concept to first marketed drug. We discuss the main obstacles to achieve a successful exon-skipping therapy and the latest advances of the international community to develop more powerful chemistries and more sophisticated delivery systems in order to increase potency, bioavailability and safety. Finally, we highlight the importance of collaborative efforts and early dialogue between drug developers and regulatory agencies in order to overcome difficulties, find appropriate outcome markers and collect useful data.
Topics: Alternative Splicing; Animals; Dystrophin; Exons; Genetic Therapy; Humans; Morpholinos; Muscular Dystrophy, Duchenne; Oligonucleotides, Antisense; RNA Splicing; RNA, Antisense
PubMed: 29771317
DOI: 10.1093/hmg/ddy171 -
Current Opinion in Genetics &... Jun 2017More than 30 incurable neurological and neuromuscular diseases are caused by simple microsatellite expansions consisted of 3-6 nucleotides. These repeats can occur in... (Review)
Review
More than 30 incurable neurological and neuromuscular diseases are caused by simple microsatellite expansions consisted of 3-6 nucleotides. These repeats can occur in non-coding regions and often result in a dominantly inherited disease phenotype that is characteristic of a toxic RNA gain-of-function. The expanded RNA adopts unusual secondary structures, sequesters various RNA binding proteins to form insoluble nuclear foci, and causes cellular defects at a multisystem level. Nuclear foci are dynamic in size, shape and colocalization of RNA binding proteins in different expansion diseases and tissue types. This review sets to provide new insights into the disease mechanisms of RNA toxicity and foci modulation, in light of recent advancement on bi-directional transcription, antisense RNA, repeat-associated non-ATG translation and beyond.
Topics: Humans; Microsatellite Repeats; Nervous System Diseases; Neuromuscular Diseases; Nucleic Acid Conformation; RNA; RNA, Antisense; RNA-Binding Proteins; Trinucleotide Repeat Expansion
PubMed: 28208060
DOI: 10.1016/j.gde.2017.01.005 -
Current Opinion in Genetics &... Jun 2017Myotonic dystrophy (DM) is a dominantly-inherited genetic disorder affecting skeletal muscle, heart, brain, and other organs. DM type 1 is caused by expansion of a CTG... (Review)
Review
Myotonic dystrophy (DM) is a dominantly-inherited genetic disorder affecting skeletal muscle, heart, brain, and other organs. DM type 1 is caused by expansion of a CTG triplet repeat in DMPK, whereas DM type 2 is caused by expansion of a CCTG tetramer repeat in CNBP. In both cases the DM mutations lead to expression of dominant-acting RNAs. Studies of RNA toxicity have now revealed novel mechanisms and new therapeutic targets. Preclinical data have suggested that RNA dominance is responsive to therapeutic intervention and that DM therapy can be approached at several different levels. Here we review recent efforts to alleviate RNA toxicity in DM.
Topics: Gene Expression Regulation; Genetic Therapy; Humans; Mutation; Myotonic Dystrophy; Myotonin-Protein Kinase; RNA, Antisense; RNA-Binding Proteins; Trinucleotide Repeat Expansion
PubMed: 28376341
DOI: 10.1016/j.gde.2017.03.007 -
Biomedicine & Pharmacotherapy =... Jan 2022Advances in high-throughput sequencing over the past decades have led to the identification of thousands of non-coding RNAs (ncRNAs), which play a major role in... (Review)
Review
Advances in high-throughput sequencing over the past decades have led to the identification of thousands of non-coding RNAs (ncRNAs), which play a major role in regulating gene expression. One emerging class of ncRNAs is the natural antisense transcripts (NATs), the RNA molecules transcribed from the opposite strand of a protein-coding gene locus. NATs are known to concordantly and discordantly regulate gene expression in both cis and trans manners at the transcriptional, post-transcriptional, translational, and epigenetic levels. Aberrant expression of NATs can therefore cause dysregulation in many biological pathways and has been observed in many genetic diseases. This review outlines the involvements and mechanisms of NATs in the pathogenesis of various diseases, with a special emphasis on neurodegenerative diseases and cancer. We also summarize recent findings on NAT knockdown and/or overexpression experiments and discuss the potential of NATs as promising targets for future gene therapies.
Topics: Animals; Gene Expression Regulation; Gene Knockdown Techniques; High-Throughput Nucleotide Sequencing; Humans; Neoplasms; Neurodegenerative Diseases; RNA, Antisense; RNA, Untranslated; Transcription, Genetic
PubMed: 34749054
DOI: 10.1016/j.biopha.2021.112265 -
Proceedings of the National Academy of... Dec 2022R-loops, or RNA:DNA hybrids, can induce DNA damage, which requires DNA repair factors including breast cancer type 1 susceptibility protein (BRCA1) to restore genomic...
R-loops, or RNA:DNA hybrids, can induce DNA damage, which requires DNA repair factors including breast cancer type 1 susceptibility protein (BRCA1) to restore genomic integrity. To date, several pathogenic mutations have been found within the tandem BRCA1 carboxyl-terminal (BRCT) domains that mediate BRCA1 interactions with proteins and DNA in response to DNA damage. Here, we describe a nonrepair role of BRCA1 BRCT in suppressing ribosomal R-loops via two mechanisms. Through its RNA binding and annealing activities, BRCA1 BRCT facilitates the formation of double-stranded RNA between ribosomal RNA (rRNA) and antisense-rRNA (as-rRNA), hereby minimizing rRNA hybridization to ribosomal DNA to form R-loops. BRCA1 BRCT also promotes RNA polymerase I-dependent transcription of as-rRNA to enhance double-stranded rRNA (ds-rRNA) formation. In addition, BRCA1 BRCT-mediated as-rRNA production restricts rRNA maturation in unperturbed cells. Hence, impairing as-rRNA transcription and ds-rRNA formation due to BRCA1 BRCT deficiency deregulates rRNA processing and increases ribosomal R-loops and DNA breaks. Our results link ribosomal biogenesis dysfunction to BRCA1-associated genomic instability.
Topics: BRCA1 Protein; RNA, Double-Stranded; RNA, Antisense; DNA Repair; DNA Damage; DNA
PubMed: 36490315
DOI: 10.1073/pnas.2217542119 -
Pathology, Research and Practice Oct 2021Growth arrest specific 6 (GAS6) encodes a protein that serves as a ligand for AXL receptor tyrosine kinase and stimulates cell proliferation. Notably, an antisense RNA,... (Review)
Review
Growth arrest specific 6 (GAS6) encodes a protein that serves as a ligand for AXL receptor tyrosine kinase and stimulates cell proliferation. Notably, an antisense RNA, namely GAS6-AS1 is transcribed from chromosome 13q34, near GAS6 gene. In vitro functional experiments have demonstrated that GAS6-AS1 can promote proliferation, migration and invasive properties of transformed cells through enhancing entry into S-phase. Notably, mechanistic investigations have shown that GAS6-AS1 can regulate expression of GAS6 at the transcriptional or translational stages through constructing a RNA-RNA duplex, thus enhancing expression of AXL and inducing AXL signaling. Both GAS6 and its antisense transcript contribute in the pathogenesis of human malignancies. In the current review, we provide a summary of studies that appraised the role of these genes in the carcinogenesis.
Topics: Animals; Carcinogenesis; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Intercellular Signaling Peptides and Proteins; Proto-Oncogene Proteins; RNA, Antisense; Receptor Protein-Tyrosine Kinases; Axl Receptor Tyrosine Kinase
PubMed: 34481213
DOI: 10.1016/j.prp.2021.153596 -
DNA and Cell Biology Apr 2022Lung cancer is a common life-threatening tumor with high malignancy and high invasiveness. Long non-coding RNAs (lncRNAs) are involved in almost every stage of tumor...
Lung cancer is a common life-threatening tumor with high malignancy and high invasiveness. Long non-coding RNAs (lncRNAs) are involved in almost every stage of tumor initiation and progression. Here, we identified an antisense lncRNA, MetaLnc9 antisense (Metalnc9-AS), which arises from the antisense strand of Metalnc9, located on chr9q34.11, while its biological function and mechanism are not clear in lung cancer. In this study, we demonstrated that the expression of Metalnc9-AS was upregulated in non-small cell lung cancer (NSCLC) tissues compared with corresponding non-tumorous tissues. The gain of MetaLnc9-AS was highly associated with the malignant features of NSCLC. Overexpression of MetaLnc9-AS enhanced tumor metastasis and . Mechanically, MetaLnc9-AS could form an RNA-RNA hybrid with its cognate sense counterpart, MetaLnc9, to regulate its expression in NSCLC cells, and that such complexes were protected from ribonuclease degradation. Thus, Metalnc9-AS might be a potential and effective treatment for NSCLC.
Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Neoplasm Metastasis; RNA, Antisense; RNA, Long Noncoding
PubMed: 35333617
DOI: 10.1089/dna.2021.1088