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Volume 8, October
 
 

Non-Coding RNA, Volume 8, Issue 6 (December 2022) – 12 articles

Cover Story (view full-size image): Resistance to hormone therapy is the leading cause of death in men with prostate cancer (PCa). In this study, the lncRNA NAALADL2-AS2 (AS2) was found to be upregulated in PCa cells challenged with androgen deprivation therapy. Quantitative PCR analysis of PCa tumor tissue showed AS2 expression to increase along disease severity with peak levels in castration-resistant PCa. AS2 transcripts were found to be confined to nucleus where it is co-expressed with the oncogene NAALADL2. Transcriptome analysis of AS2 knockdown experiments suggests this lncRNA may regulate transcriptional programs involved with glycogen metabolism and cell cycle factors. Following AS2 knockdown, a clear decrease in cell viability coupled with increased apoptosis was observed. Interestingly, AS2 knockdown did not affect NAALADL2 expression. View this paper
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13 pages, 2438 KiB  
Article
The Idiopathic Pulmonary Fibrosis-Associated Single Nucleotide Polymorphism RS35705950 Is Transcribed in a MUC5B Promoter Associated Long Non-Coding RNA (AC061979.1)
by Ruxandra Neatu, Ifeanyi Enekwa, Dean J. Thompson, Edward C. Schwalbe, Giorgio Fois, Gina Abdelaal, Stephany Veuger, Manfred Frick, Peter Braubach and Sterghios A. Moschos
Non-Coding RNA 2022, 8(6), 83; https://doi.org/10.3390/ncrna8060083 - 08 Dec 2022
Cited by 1 | Viewed by 1581
Abstract
LncRNAs are involved in regulatory processes in the human genome, including gene expression. The rs35705950 SNP, previously associated with IPF, overlaps with the recently annotated lncRNA AC061979.1, a 1712 nucleotide transcript located within the MUC5B promoter at chromosome 11p15.5. To document the expression [...] Read more.
LncRNAs are involved in regulatory processes in the human genome, including gene expression. The rs35705950 SNP, previously associated with IPF, overlaps with the recently annotated lncRNA AC061979.1, a 1712 nucleotide transcript located within the MUC5B promoter at chromosome 11p15.5. To document the expression pattern of the transcript, we processed 3.9 TBases of publicly available RNA-SEQ data across 27 independent studies involving lung airway epithelial cells. Epithelial lung cells showed expression of this putative pancRNA. The findings were independently validated in cell lines and primary cells. The rs35705950 is found within a conserved region (from fish to primates) within the expressed sequence indicating functional importance. These results implicate the rs35705950-containing AC061979.1 pancRNA as a novel component of the MUC5B expression control minicircuitry. Full article
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5 pages, 1325 KiB  
Brief Report
Is Evolutionary Conservation a Useful Predictor for Cancer Long Noncoding RNAs? Insights from the Cancer LncRNA Census 3
by Adrienne Vancura, Alejandro H. Gutierrez, Thorben Hennig, Carlos Pulido-Quetglas, Frank J. Slack, Rory Johnson and Simon Haefliger
Non-Coding RNA 2022, 8(6), 82; https://doi.org/10.3390/ncrna8060082 - 07 Dec 2022
Cited by 2 | Viewed by 1999
Abstract
Evolutionary conservation is a measure of gene functionality that is widely used to prioritise long noncoding RNAs (lncRNA) in cancer research. Intriguingly, while updating our Cancer LncRNA Census (CLC), we observed an inverse relationship between year of discovery and evolutionary conservation. This observation [...] Read more.
Evolutionary conservation is a measure of gene functionality that is widely used to prioritise long noncoding RNAs (lncRNA) in cancer research. Intriguingly, while updating our Cancer LncRNA Census (CLC), we observed an inverse relationship between year of discovery and evolutionary conservation. This observation is specific to cancer over other diseases, implying a sampling bias in the selection of lncRNA candidates and casting doubt on the value of evolutionary metrics for the prioritisation of cancer-related lncRNAs. Full article
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17 pages, 3653 KiB  
Article
The Androgen Regulated lncRNA NAALADL2-AS2 Promotes Tumor Cell Survival in Prostate Cancer
by Levi Groen, Viktor Yurevych, Harshitha Ramu, Johnny Chen, Lianne Steenge, Sabrina Boer, Renske Kuiper, Frank P. Smit, Gerald W. Verhaegh, Niven Mehra and Jack A. Schalken
Non-Coding RNA 2022, 8(6), 81; https://doi.org/10.3390/ncrna8060081 - 01 Dec 2022
Cited by 2 | Viewed by 2209
Abstract
Castration resistance is the leading cause of death in men with prostate cancer. Recent studies indicate long noncoding RNAs (lncRNAs) to be important drivers of therapy resistance. The aim of this study was to identify differentially expressed lncRNAs in castration-resistant prostate cancer (CRPC) [...] Read more.
Castration resistance is the leading cause of death in men with prostate cancer. Recent studies indicate long noncoding RNAs (lncRNAs) to be important drivers of therapy resistance. The aim of this study was to identify differentially expressed lncRNAs in castration-resistant prostate cancer (CRPC) and to functionally characterize them in vitro. Tumor-derived RNA-sequencing data were used to quantify and compare the expression of 11,469 lncRNAs in benign, primary prostate cancer, and CRPC samples. CRPC-associated lncRNAs were selected for semi-quantitative PCR validation on 68 surgical tumor specimens. In vitro functional studies were performed by antisense-oligonucleotide-mediated lncRNA knockdown in hormone-sensitive prostate cancer (HSPC) and CRPC cell line models. Subsequently, cell proliferation, apoptosis, cell cycle, transcriptome and pathway analyses were performed using the appropriate assays. Transcriptome analysis of a prostate cancer tumor specimens unveiled NAALADL2-AS2 as a novel CRPC-upregulated lncRNA. The expression of NAALADL2-AS2 was found to be particularly high in HSPC in vitro models and to increase under androgen deprived conditions. NAALADL2-AS2 knockdown decreased cell viability and increased caspase activity and apoptotic cells. Cellular fractionization and RNA fluorescent in situ hybridization identified NAALADL2-AS2 as a nuclear transcript. Transcriptome and pathway analyses revealed that NAALADL2-AS2 modulates the expression of genes involved with cell cycle control and glycogen metabolism. We hypothesize that the nuclear lncRNA, NAALADL2-AS2, functions as a pro-survival signal in prostate cancer cells under pressure of targeted hormone therapy. Full article
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12 pages, 2931 KiB  
Article
SOX2OT lncRNA Inhibition Suppresses the Stemness Characteristics of Esophageal Tumorspheres
by Boshra Haghi, Marie Saghaeian Jazi, Ayyoob Khosravi, Seyyed Mehdi Jafari and Jahanbakhsh Asadi
Non-Coding RNA 2022, 8(6), 80; https://doi.org/10.3390/ncrna8060080 - 28 Nov 2022
Cited by 2 | Viewed by 1591
Abstract
Background: SOX2OT is a novel cancer associated long non-coding RNA (LncRNA) with higher expression in variable tumor tissues, including esophageal squamous cell carcinoma (ESCC). It also plays an important function in embryonic neuronal development. Regarding its function in both stemness and carcinogenesis, here, [...] Read more.
Background: SOX2OT is a novel cancer associated long non-coding RNA (LncRNA) with higher expression in variable tumor tissues, including esophageal squamous cell carcinoma (ESCC). It also plays an important function in embryonic neuronal development. Regarding its function in both stemness and carcinogenesis, here, we aimed to investigate its expression and function in tumorspheres of the esophagus using the RNAi method. Material & Methods: Two esophageal squamous cancer cells (ESCC): KYSE30 and YM1 cells were used for sphere enrichment. Cells were transfected with SOX2OT targeting and control siRNA. The size and the number of spheres were measured using light microscopy. Gene expression of the pluripotency genes was measured by qRT-PCR and docetaxel chemoresistance was assessed by MTS viability assay. Results: Our findings showed that ESCC tumorspheres overexpress SOX2OT gene along with other stemness genes (SOX2, OCT4A, and Nanog) compared to their original cancer cells. RNAi experiments indicated that SOX2OT knockdown can suppress the stemness-related gene expression, sphere formation ability (both size and number), and docetaxel resistance as three of the main cancer stem cell characteristics of tumorspheres. Conclusion: Altogether our results showed the regulatory role of SOX2OT in pluripotency and stemness in ESCC tumorspheres. Our results suggest a potential application of SOX2OT inhibition in combination with docetaxel for ESCC inhibition in vitro. Full article
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2 pages, 168 KiB  
Correction
Correction: Tusup et al. Evaluation of the Interplay between the ADAR Editome and Immunotherapy in Melanoma. Non-Coding RNA 2021, 7, 5
by Marina Tusup, Phil F. Cheng, Ernesto Picardi, Austeja Raziunaite, Reinhard Dummer, Mitchell P. Levesque, Lars E. French, Emmanuella Guenova, Thomas M. Kundig and Steve Pascolo
Non-Coding RNA 2022, 8(6), 79; https://doi.org/10.3390/ncrna8060079 - 21 Nov 2022
Viewed by 962
Abstract
In the original article [...] Full article
6 pages, 423 KiB  
Systematic Review
Polymorphism rs2383207 of CDKN2B-AS and Susceptibility to Atherosclerosis: A Mini Review
by Sofia Vladimorovna Timofeeva, Tatiana Alexandrovna Sherchkova and Tatiana Pavlovna Shkurat
Non-Coding RNA 2022, 8(6), 78; https://doi.org/10.3390/ncrna8060078 - 18 Nov 2022
Cited by 1 | Viewed by 1561
Abstract
We conducted this meta-analysis to estimate associations between CDKN2B antisense (CDKN2B-AS) rs2383207 polymorphism and susceptibility to atherosclerosis. A systematic literature research of Google Scholar and PubMed was performed to identify eligible studies. Overall, eight studies were included for meta-analyses. The association was assessed [...] Read more.
We conducted this meta-analysis to estimate associations between CDKN2B antisense (CDKN2B-AS) rs2383207 polymorphism and susceptibility to atherosclerosis. A systematic literature research of Google Scholar and PubMed was performed to identify eligible studies. Overall, eight studies were included for meta-analyses. The association was assessed by statistical odds’ ratio (OR) with 95% confidence interval (CI). RevMan software (Cochrane Collaboration, 5.3. Copenhagen) was used for the meta-analysis. Pooled overall analyses showed that rs2383207 polymorphism was associated with the risk of atherosclerosis in the whole population. Additional analyses by ethnicity revealed that rs2383207 polymorphism was associated with susceptibility to atherosclerosis in Asians and Caucasians. Our results suggest that rs2383207, might serve as genetic biomarkers of atherosclerosis. Further, studies will be required to confirm the observed association. Full article
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10 pages, 941 KiB  
Review
RNA-Mediated Regulation of Meiosis in Budding Yeast
by Vidya Vardhini Pondugala and Krishnaveni Mishra
Non-Coding RNA 2022, 8(6), 77; https://doi.org/10.3390/ncrna8060077 - 15 Nov 2022
Cited by 1 | Viewed by 2180
Abstract
Cells change their physiological state in response to environmental cues. In the absence of nutrients, unicellular fungi such as budding yeast exit mitotic proliferation and enter the meiotic cycle, leading to the production of haploid cells that are encased within spore walls. These [...] Read more.
Cells change their physiological state in response to environmental cues. In the absence of nutrients, unicellular fungi such as budding yeast exit mitotic proliferation and enter the meiotic cycle, leading to the production of haploid cells that are encased within spore walls. These cell state transitions are orchestrated in a developmentally coordinated manner. Execution of the meiotic cell cycle program in budding yeast, Saccharomyces cerevisiae, is regulated by the key transcription factor, Ime1. Recent developments have uncovered the role of non-coding RNA in the regulation of Ime1 and meiosis. In this review, we summarize the role of ncRNA-mediated and RNA homeostasis-based processes in the regulation of meiosis in Saccharomyces cerevisiae. Full article
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12 pages, 1530 KiB  
Article
The Potential of NORAD–PUMILIO–RALGAPB Regulatory Axis as a Biomarker in Breast Cancer
by Cristiane Sato Mara Muller, Igor Samesima Giner, Érika Pereira Zambalde, Tamyres Mingorance Carvalho, Enilze Maria de Souza Fonseca Ribeiro, Jaqueline Carvalho de Oliveira, Carolina Mathias and Daniela Fiori Gradia
Non-Coding RNA 2022, 8(6), 76; https://doi.org/10.3390/ncrna8060076 - 10 Nov 2022
Cited by 2 | Viewed by 1826
Abstract
Introduction: Long non-coding RNAs (LncRNA) represent a heterogeneous family of RNAs that have emerged as regulators of various biological processes through their association with proteins in ribonucleoproteins complexes. The dynamic of these interactions can affect cell metabolism, including cancer development. Annually, breast [...] Read more.
Introduction: Long non-coding RNAs (LncRNA) represent a heterogeneous family of RNAs that have emerged as regulators of various biological processes through their association with proteins in ribonucleoproteins complexes. The dynamic of these interactions can affect cell metabolism, including cancer development. Annually, breast cancer causes thousands of deaths worldwide, and searching for new biomarkers is pivotal for better diagnosis and treatment. Methods: Based on in silico prediction analysis, we focus on LncRNAs that have binding sites for PUMILIO, an RBP family involved in post-transcriptional regulation and associated with cancer progression. We compared the expression levels of these LncRNAs in breast cancer and non-tumor samples from the TCGA database. We analyzed the impact of overall and disease-free survival associated with the expression of the LncRNAs and co-expressed genes and targets of PUMILIO proteins. Results: Our results found NORAD as the most relevant LncRNA with a PUMILIO binding site in breast cancer, differently expressed between Luminal A and Basal subtypes. Additionally, NORAD was co-expressed in a Basal-like subtype (0.55) with the RALGAPB gene, a target gene of PUMILIO related to chromosome stability during cell division. Conclusion: These data suggest that this molecular axis may provide insights for developing novel therapeutic strategies for breast cancer. Full article
(This article belongs to the Special Issue Feature Papers from Non-coding RNA Reviewers)
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16 pages, 1328 KiB  
Review
Exosome RNA Sequencing as a Tool in the Search for Cancer Biomarkers
by Marina Elkommos-Zakhary, Neeraja Rajesh and Vladimir Beljanski
Non-Coding RNA 2022, 8(6), 75; https://doi.org/10.3390/ncrna8060075 - 09 Nov 2022
Cited by 4 | Viewed by 3187
Abstract
Numerous noninvasive methods are currently being used to determine biomarkers for diseases such as cancer. However, these methods are not always precise and reliable. Thus, there is an unmet need for better diagnostic and prognostic biomarkers that will be used to diagnose cancer [...] Read more.
Numerous noninvasive methods are currently being used to determine biomarkers for diseases such as cancer. However, these methods are not always precise and reliable. Thus, there is an unmet need for better diagnostic and prognostic biomarkers that will be used to diagnose cancer in early, more treatable stages of the disease. Exosomes are extracellular vesicles of endocytic origin released by the majority of cells. Exosomes contain and transport nucleic acids, proteins, growth factors, and cytokines from their parent cells to surrounding or even distant cells via circulation in biofluids. Exosomes have attracted the interest of researchers, as recent data indicate that exosome content may be indicative of disease stages and may contribute to disease progression via exosome-mediated extracellular communication. Therefore, the contents of these vesicles are being investigated as possible biomarkers for disease diagnosis and prognosis. The functions of exosomes and their contents in disease development are becoming clearer as isolation and analytical methods, such as RNA sequencing, advance. In this review, we discuss current advances and challenges in exosomal content analyses with emphasis on information that can be generated using RNA sequencing. We also discuss how the RNA sequencing of exosomes may be used to discover novel biomarkers for the detection of different stages for various cancers using specific microRNAs that were found to be differentially expressed between healthy controls and cancer-diagnosed subjects. Full article
(This article belongs to the Special Issue Non-coding RNA in the USA: Latest Advances and Perspectives)
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16 pages, 6947 KiB  
Review
Navigating the Multiverse of Antisense RNAs: The Transcription- and RNA-Dependent Dimension
by Giulia Pagani, Cecilia Pandini and Paolo Gandellini
Non-Coding RNA 2022, 8(6), 74; https://doi.org/10.3390/ncrna8060074 - 26 Oct 2022
Cited by 6 | Viewed by 2360
Abstract
Evidence accumulated over the past decades shows that the number of identified antisense transcripts is continuously increasing, promoting them from transcriptional noise to real genes with specific functions. Indeed, recent studies have begun to unravel the complexity of the antisense RNA (asRNA) world, [...] Read more.
Evidence accumulated over the past decades shows that the number of identified antisense transcripts is continuously increasing, promoting them from transcriptional noise to real genes with specific functions. Indeed, recent studies have begun to unravel the complexity of the antisense RNA (asRNA) world, starting from the multidimensional mechanisms that they can exert in physiological and pathological conditions. In this review, we discuss the multiverse of the molecular functions of asRNAs, describing their action through transcription-dependent and RNA-dependent mechanisms. Then, we report the workflow and methodologies to study and functionally characterize single asRNA candidates. Full article
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17 pages, 2720 KiB  
Article
Identification of Differentially Expressed Intronic Transcripts in Osteosarcoma
by Emel Rothzerg, Jiake Xu and David Wood
Non-Coding RNA 2022, 8(6), 73; https://doi.org/10.3390/ncrna8060073 - 25 Oct 2022
Cited by 2 | Viewed by 1680
Abstract
Over the past decade; the discovery and characterization of long noncoding RNAs (lncRNAs) have revealed that they play a major role in the development of various diseases; including cancer. Intronic transcripts are one of the most fascinating lncRNAs that are located within intron [...] Read more.
Over the past decade; the discovery and characterization of long noncoding RNAs (lncRNAs) have revealed that they play a major role in the development of various diseases; including cancer. Intronic transcripts are one of the most fascinating lncRNAs that are located within intron regions of protein-coding genes, which have the advantage of encoding micropeptides. There have been several studies looking at intronic transcript expression profiles in cancer; but almost none in osteosarcoma. To overcome this problem; we have investigated differentially expressed intronic transcripts between osteosarcoma and normal bone tissues. The results highlighted that NRG1-IT1; FGF14-IT1; and HAO2-IT1 were downregulated; whereas ER3-IT1; SND1-IT1; ANKRD44-IT1; AGAP1-IT1; DIP2A-IT1; LMO7DN-IT1; SLIT2-IT1; RNF216-IT1; and TCF7L1-IT1 were upregulated in osteosarcoma tissues compared to normal bone tissues. Furthermore, we identified if the transcripts encode micropeptides and the transcripts’ locations in a cell. Full article
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19 pages, 2568 KiB  
Article
Oxidative Stress and Its Modulation by Ladostigil Alter the Expression of Abundant Long Non-Coding RNAs in SH-SY5Y Cells
by Keren Zohar, Eliran Giladi, Tsiona Eliyahu and Michal Linial
Non-Coding RNA 2022, 8(6), 72; https://doi.org/10.3390/ncrna8060072 - 25 Oct 2022
Cited by 1 | Viewed by 1989
Abstract
Neurodegenerative disorders, brain injury, and the decline in cognitive function with aging are accompanied by a reduced capacity of cells in the brain to cope with oxidative stress and inflammation. In this study, we focused on the response to oxidative stress in SH-SY5Y, [...] Read more.
Neurodegenerative disorders, brain injury, and the decline in cognitive function with aging are accompanied by a reduced capacity of cells in the brain to cope with oxidative stress and inflammation. In this study, we focused on the response to oxidative stress in SH-SY5Y, a human neuroblastoma cell line. We monitored the viability of the cells in the presence of oxidative stress. Such stress was induced by hydrogen peroxide or by Sin1 (3-morpholinosydnonimine) that generates reactive oxygen and nitrogen species (ROS and RNS). Both stressors caused significant cell death. Our results from the RNA-seq experiments show that SH-SY5Y cells treated with Sin1 for 24 h resulted in 94 differently expressed long non-coding RNAs (lncRNAs), including many abundant ones. Among the abundant lncRNAs that were upregulated by exposing the cells to Sin1 were those implicated in redox homeostasis, energy metabolism, and neurodegenerative diseases (e.g., MALAT1, MIAT, GABPB1-AS1, NEAT1, MIAT, GABPB1-AS1, and HAND2-AS1). Another group of abundant lncRNAs that were significantly altered under oxidative stress included cancer-related SNHG family members. We tested the impact of ladostigil, a bifunctional reagent with antioxidant and anti-inflammatory properties, on the lncRNA expression levels. Ladostigil was previously shown to enhance learning and memory in the brains of elderly rats. In SH-SY5Y cells, several lncRNAs involved in transcription regulation and the chromatin structure were significantly induced by ladostigil. We anticipate that these poorly studied lncRNAs may act as enhancers (eRNA), regulating transcription and splicing, and in competition for miRNA binding (ceRNA). We found that the induction of abundant lncRNAs, such as MALAT1, NEAT-1, MIAT, and SHNG12, by the Sin1 oxidative stress paradigm specifies only the undifferentiated cell state. We conclude that a global alteration in the lncRNA profiles upon stress in SH-SY5Y may shift cell homeostasis and is an attractive in vitro system to characterize drugs that impact the redox state of the cells and their viability. Full article
(This article belongs to the Collection Feature Papers in Non-Coding RNA)
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