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Ataei A, Tahsili M, Hayadokht G, Daneshvar M, Mohammadi Nour S, Soofi A, Masoudi A, Kabiri M, Natami M. Targeting long noncoding RNAs in neuroblastoma: Progress and prospects. Chem Biol Drug Des 2023; 102:640-652. [PMID: 37291742 DOI: 10.1111/cbdd.14263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 04/10/2023] [Accepted: 04/18/2023] [Indexed: 06/10/2023]
Abstract
Neuroblastoma (NB) is the third most prevalent tumor that mostly influences infants and young children. Although different treatments have been developed for the treatment of NB, high-risk patients have been reported to have low survival rates. Currently, long noncoding RNAs (lncRNAs) have shown an attractive potential in cancer research and a party of investigations have been performed to understand mechanisms underlying tumor development through lncRNA dysregulation. Researchers have just newly initiated to exhibit the involvement of lncRNAs in NB pathogenesis. In this review article, we tried to clarify the point we stand with respect to the involvement of lncRNAs in NB. Moreover, implications for the pathologic roles of lncRNAs in the development of NB have been discussed. It seems that some of these lncRNAs have promising potential to be applied as biomarkers for NB prognosis and treatment.
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Affiliation(s)
- Ali Ataei
- School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | | | - Golsa Hayadokht
- School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | | | | | - Asma Soofi
- Department of Physical Chemistry, School of Chemistry, College of Sciences, University of Tehran, Tehran, Iran
| | - Alireza Masoudi
- Department of Laboratory Sciences, Faculty of Alied Medical Sciences, Qom University of Medical Sciences, Qom, Iran
| | - Maryam Kabiri
- Faculty of Medicine, Islamic Azad University of Medical Sciences, Tehran, Iran
| | - Mohammad Natami
- Department of Urology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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2
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Anoushirvani AA, Jafarian Yazdi A, Amirabadi S, Asouri SA, Shafabakhsh R, Sheida A, Hosseini Khabr MS, Jafari A, Tamehri Zadeh SS, Hamblin MR, Kalantari L, Talaei Zavareh SA, Mirzaei H. Role of non-coding RNAs in neuroblastoma. Cancer Gene Ther 2023; 30:1190-1208. [PMID: 37217790 DOI: 10.1038/s41417-023-00623-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 03/25/2023] [Accepted: 05/04/2023] [Indexed: 05/24/2023]
Abstract
Neuroblastoma is known as the most prevalent extracranial malignancy in childhood with a neural crest origin. It has been widely accepted that non-coding RNAs (ncRNAs) play important roles in many types of cancer, including glioma and gastrointestinal cancers. They may regulate the cancer gene network. According to recent sequencing and profiling studies, ncRNAs genes are deregulated in human cancers via deletion, amplification, abnormal epigenetic, or transcriptional regulation. Disturbances in the expression of ncRNAs may act either as oncogenes or as anti-tumor suppressor genes, and can lead to the induction of cancer hallmarks. ncRNAs can be secreted from tumor cells inside exosomes, where they can be transferred to other cells to affect their function. However, these topics still need more study to clarify their exact roles, so the present review addresses different roles and functions of ncRNAs in neuroblastoma.
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Affiliation(s)
- Ali Arash Anoushirvani
- Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Sanaz Amirabadi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Sahar Ahmadi Asouri
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University, Kashan, Iran
| | - Rana Shafabakhsh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University, Kashan, Iran
| | - Amirhossein Sheida
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Sadat Hosseini Khabr
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ameneh Jafari
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. BOX: 15179/64311, Tehran, Iran
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
| | - Leila Kalantari
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
| | | | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University, Kashan, Iran.
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3
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Dhakal B, Tomita Y, Drew P, Price T, Maddern G, Smith E, Fenix K. Perhexiline: Old Drug, New Tricks? A Summary of Its Anti-Cancer Effects. Molecules 2023; 28:molecules28083624. [PMID: 37110858 PMCID: PMC10145508 DOI: 10.3390/molecules28083624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/17/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023] Open
Abstract
Cancer metabolic plasticity, including changes in fatty acid metabolism utilisation, is now widely appreciated as a key driver for cancer cell growth, survival and malignancy. Hence, cancer metabolic pathways have been the focus of much recent drug development. Perhexiline is a prophylactic antianginal drug known to act by inhibiting carnitine palmitoyltransferase 1 (CPT1) and 2 (CPT2), mitochondrial enzymes critical for fatty acid metabolism. In this review, we discuss the growing evidence that perhexiline has potent anti-cancer properties when tested as a monotherapy or in combination with traditional chemotherapeutics. We review the CPT1/2 dependent and independent mechanisms of its anti-cancer activities. Finally, we speculate on the clinical feasibility and utility of repurposing perhexiline as an anti-cancer agent, its limitations including known side effects and its potential added benefit of limiting cardiotoxicity induced by other chemotherapeutics.
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Affiliation(s)
- Bimala Dhakal
- Discipline of Surgery, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
- Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, SA 5011, Australia
| | - Yoko Tomita
- Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, SA 5011, Australia
- Medical Oncology, The Queen Elizabeth Hospital, Adelaide, SA 5011, Australia
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
| | - Paul Drew
- Discipline of Surgery, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
- Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, SA 5011, Australia
| | - Timothy Price
- Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, SA 5011, Australia
- Medical Oncology, The Queen Elizabeth Hospital, Adelaide, SA 5011, Australia
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
| | - Guy Maddern
- Discipline of Surgery, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
- Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, SA 5011, Australia
| | - Eric Smith
- Discipline of Surgery, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
- Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, SA 5011, Australia
- Medical Oncology, The Queen Elizabeth Hospital, Adelaide, SA 5011, Australia
| | - Kevin Fenix
- Discipline of Surgery, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
- Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, SA 5011, Australia
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4
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Lan Z, Chen Y, Jin J, Xu Y, Zhu X. Long Non-coding RNA: Insight Into Mechanisms of Alzheimer's Disease. Front Mol Neurosci 2022; 14:821002. [PMID: 35095418 PMCID: PMC8795976 DOI: 10.3389/fnmol.2021.821002] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD), a heterogeneous neurodegenerative disorder, is the most common cause of dementia accounting for an estimated 60–80% of cases. The pathogenesis of AD remains unclear, and no curative treatment is available so far. Increasing evidence has revealed a vital role of non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), in AD. LncRNAs contribute to the pathogenesis of AD via modulating amyloid production, Tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, synaptic impairment and neuroinflammation. This review describes the biological functions and mechanisms of lncRNAs in AD, indicating that lncRNAs may provide potential therapeutic targets for the diagnosis and treatment of AD.
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Affiliation(s)
- Zhen Lan
- Department of Neurology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China
| | - Yanting Chen
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, the Affiliated Hospital of Nanjing University Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
| | - Jiali Jin
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, the Affiliated Hospital of Nanjing University Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
| | - Yun Xu
- Department of Neurology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, the Affiliated Hospital of Nanjing University Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
- Institute of Brain Sciences, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China
- Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, China
| | - Xiaolei Zhu
- Department of Neurology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, the Affiliated Hospital of Nanjing University Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
- Institute of Brain Sciences, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China
- Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, China
- *Correspondence: Xiaolei Zhu
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Abstract
Alu RNA are implicated in the poor prognosis of several human disease states. These RNA are transcription products of primate specific transposable elements called Alu elements. These elements are extremely abundant, comprising over 10% of the human genome, and 100 to 1000 cytoplasmic copies of Alu RNA per cell. Alu RNA do not have a single universal functional role aside from selfish self-propagation. Despite this, Alu RNA have been found to operate in a diverse set of translational and transcriptional mechanisms. This review will focus on the current knowledge of Alu RNA involved in human disease states and known mechanisms of action. Examples of Alu RNA that are transcribed in a variety of contexts such as introns, mature mRNA, and non-coding transcripts will be discussed. Past and present challenges in studying Alu RNA, and the future directions of Alu RNA in basic and clinical research will also be examined.
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Affiliation(s)
| | - Sean A McKenna
- Department of Chemistry, University of Manitoba, Winnipeg, Canada
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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7
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Singh N. Role of mammalian long non-coding RNAs in normal and neuro oncological disorders. Genomics 2021; 113:3250-3273. [PMID: 34302945 DOI: 10.1016/j.ygeno.2021.07.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/10/2021] [Accepted: 07/14/2021] [Indexed: 12/09/2022]
Abstract
Long non-coding RNAs (lncRNAs) are expressed at lower levels than protein-coding genes but have a crucial role in gene regulation. LncRNA is distinct, they are being transcribed using RNA polymerase II, and their functionality depends on subcellular localization. Depending on their niche, they specifically interact with DNA, RNA, and proteins and modify chromatin function, regulate transcription at various stages, forms nuclear condensation bodies and nucleolar organization. lncRNAs may also change the stability and translation of cytoplasmic mRNAs and hamper signaling pathways. Thus, lncRNAs affect the physio-pathological states and lead to the development of various disorders, immune responses, and cancer. To date, ~40% of lncRNAs have been reported in the nervous system (NS) and are involved in the early development/differentiation of the NS to synaptogenesis. LncRNA expression patterns in the most common adult and pediatric tumor suggest them as potential biomarkers and provide a rationale for targeting them pharmaceutically. Here, we discuss the mechanisms of lncRNA synthesis, localization, and functions in transcriptional, post-transcriptional, and other forms of gene regulation, methods of lncRNA identification, and their potential therapeutic applications in neuro oncological disorders as explained by molecular mechanisms in other malignant disorders.
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Affiliation(s)
- Neetu Singh
- Molecular Biology Unit, Department of Centre for Advance Research, King George's Medical University, Lucknow, Uttar Pradesh 226 003, India.
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8
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Li D, Zhang J, Li X, Chen Y, Yu F, Liu Q. Insights into lncRNAs in Alzheimer's disease mechanisms. RNA Biol 2021; 18:1037-1047. [PMID: 32605500 PMCID: PMC8216181 DOI: 10.1080/15476286.2020.1788848] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 06/19/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common dementia among the elderly. The pathophysiology of AD is characterized by two hallmarks: amyloid plaques, produced by amyloid β (Aβ) aggregation, and neurofibrillary tangle (NFT), produced by accumulation of phosphorylated tau. The regulatory roles of non-coding RNAs (ncRNAs), particularly long noncoding RNAs (lncRNAs), have been widely recognized in gene expression at the transcriptional and posttranscriptional levels. Mounting evidence shows that lncRNAs are aberrantly expressed in AD progression. Here, we review the lncRNAs that implicated in the regulation of Aβ peptide, tau, inflammation, cell death, and other aspects which are the main mechanisms of AD pathology. We also discuss the possible clinical or therapeutic utility of lncRNA detection or targeting to help diagnose or possibly combat AD.
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Affiliation(s)
- Dingfeng Li
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
- Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei, China
- National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
| | - Juan Zhang
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
- Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
| | - Xiaohui Li
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
- Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
| | - Yuhua Chen
- Department of Neurology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Feng Yu
- Department of Neurology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Qiang Liu
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
- Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China
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9
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Efficacy of a Three Drug-Based Therapy for Neuroblastoma in Mice. Int J Mol Sci 2021; 22:ijms22136753. [PMID: 34201814 PMCID: PMC8268736 DOI: 10.3390/ijms22136753] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/10/2021] [Accepted: 06/16/2021] [Indexed: 11/21/2022] Open
Abstract
High-risk neuroblastoma (HR-NB) still remains the most dangerous tumor in early childhood. For this reason, the identification of new therapeutic approaches is of fundamental importance. Recently, we combined the conventional pharmacological approach to NB, represented by cisplatin, with fendiline hydrochloride, an inhibitor of several transporters involved in multidrug resistance of cancer cells, which demonstrated an enhancement of the ability of cisplatin to induce apoptosis. In this work, we co-administrated acetazolamide, a carbonic anhydrase isoform IX (CAIX) inhibitor which was reported to increase chemotherapy efficacy in various cancer types, to the cisplatin/fendiline approach in SKNBE2 xenografts in NOD-SCID mice with the aim of identifying a novel and more effective treatment. We observed that the combination of the three drugs increases more than twelvefold the differences in the cytotoxic activity of cisplatin alone, leading to a remarkable decrease of the expression of malignancy markers. Our conclusion is that this approach, based on three FDA-approved drugs, may constitute an appropriate improvement of the pharmacological approach to HR-NB.
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Ferrari R, Grandi N, Tramontano E, Dieci G. Retrotransposons as Drivers of Mammalian Brain Evolution. Life (Basel) 2021; 11:life11050376. [PMID: 33922141 PMCID: PMC8143547 DOI: 10.3390/life11050376] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/20/2021] [Accepted: 04/21/2021] [Indexed: 12/11/2022] Open
Abstract
Retrotransposons, a large and diverse class of transposable elements that are still active in humans, represent a remarkable force of genomic innovation underlying mammalian evolution. Among the features distinguishing mammals from all other vertebrates, the presence of a neocortex with a peculiar neuronal organization, composition and connectivity is perhaps the one that, by affecting the cognitive abilities of mammals, contributed mostly to their evolutionary success. Among mammals, hominids and especially humans display an extraordinarily expanded cortical volume, an enrichment of the repertoire of neural cell types and more elaborate patterns of neuronal connectivity. Retrotransposon-derived sequences have recently been implicated in multiple layers of gene regulation in the brain, from transcriptional and post-transcriptional control to both local and large-scale three-dimensional chromatin organization. Accordingly, an increasing variety of neurodevelopmental and neurodegenerative conditions are being recognized to be associated with retrotransposon dysregulation. We review here a large body of recent studies lending support to the idea that retrotransposon-dependent evolutionary novelties were crucial for the emergence of mammalian, primate and human peculiarities of brain morphology and function.
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Affiliation(s)
- Roberto Ferrari
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy;
| | - Nicole Grandi
- Laboratory of Molecular Virology, Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy; (N.G.); (E.T.)
| | - Enzo Tramontano
- Laboratory of Molecular Virology, Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy; (N.G.); (E.T.)
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042 Monserrato, Italy
| | - Giorgio Dieci
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy;
- Correspondence:
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Baldini F, Calderoni M, Vergani L, Modesto P, Florio T, Pagano A. An Overview of Long Non-Coding (lnc)RNAs in Neuroblastoma. Int J Mol Sci 2021; 22:ijms22084234. [PMID: 33921816 PMCID: PMC8072620 DOI: 10.3390/ijms22084234] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/12/2021] [Accepted: 04/15/2021] [Indexed: 12/14/2022] Open
Abstract
Neuroblastoma (NB) is a heterogeneous developmental tumor occurring in childhood, which arises from the embryonic sympathoadrenal cells of the neural crest. Although the recent progress that has been done on this tumor, the mechanisms involved in NB are still partially unknown. Despite some genetic aberrations having been identified, the sporadic cases represent the majority. Due to its wide heterogeneity in clinical behavior and etiology, NB represents a challenge in terms of prevention and treatment. Since a definitive therapy is lacking so far, there is an urgent necessity to unveil the molecular mechanisms behind NB onset and progression to develop new therapeutic approaches. Long non-coding RNAs (lncRNAs) are a group of RNAs longer than 200 nucleotides. Whether lncRNAs are destined to become a protein or not, they exert multiple biological functions such as regulating gene expression and functions. In recent decades, different research has highlighted the possible role of lncRNAs in the pathogenesis of many diseases, including cancer. Moreover, lncRNAs may represent potential markers or targets for diagnosis and treatment of diseases. This mini-review aimed to briefly summarize the most recent findings on the involvement of some lncRNAs in NB disease by focusing on their mechanisms of action and possible role in unveiling NB onset and progression.
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Affiliation(s)
- Francesca Baldini
- Department of Experimental Medicine, University of Genova, 16132 Genova, Italy; (F.B.); (M.C.)
| | - Matilde Calderoni
- Department of Experimental Medicine, University of Genova, 16132 Genova, Italy; (F.B.); (M.C.)
| | - Laura Vergani
- Department of Earth, Environment and Life Sciences DISTAV, University of Genova, 16132 Genova, Italy;
| | - Paola Modesto
- National Reference Center for Veterinary and Comparative Oncology-Veterinary Medical Research Institute for Piemonte, Liguria and Valle d’Aosta, 10154 Torino, Italy;
| | - Tullio Florio
- IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy;
- Department of Internal Medicine (DIMI), University of Genova, 16132 Genova, Italy
| | - Aldo Pagano
- Department of Experimental Medicine, University of Genova, 16132 Genova, Italy; (F.B.); (M.C.)
- IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy;
- Correspondence: ; Tel.: +39-010-5558213
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12
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Yang S, Lim KH, Kim SH, Joo JY. Molecular landscape of long noncoding RNAs in brain disorders. Mol Psychiatry 2021; 26:1060-1074. [PMID: 33173194 DOI: 10.1038/s41380-020-00947-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/28/2020] [Accepted: 10/27/2020] [Indexed: 02/08/2023]
Abstract
According to current paradigms, various risk factors, such as genetic mutations, oxidative stress, neural network dysfunction, and abnormal protein degradation, contribute to the progression of brain disorders. Through the cooperation of gene transcripts in biological processes, the study of noncoding RNAs can lead to insights into the cause and treatment of brain disorders. Recently, long noncoding RNAs (lncRNAs) which are longer than 200 nucleotides in length have been suggested as key factors in various brain disorders. Accumulating evidence suggests the potential of lncRNAs as diagnostic or prognostic biomarkers and therapeutic targets. High-throughput screening-based sequencing has been instrumental in identification of lncRNAs that demand new approaches to understanding the progression of brain disorders. In this review, we discuss the recent progress in the study of lncRNAs, and addresses the pathogenesis of brain disorders that involve lncRNAs and describes the associations of lncRNAs with neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and neurodevelopmental disorders. We also discuss potential targets of lncRNAs and their promise as novel therapeutics and biomarkers in brain disorders.
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Affiliation(s)
- Sumin Yang
- Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea
| | - Key-Hwan Lim
- Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea
| | - Sung-Hyun Kim
- Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea
| | - Jae-Yeol Joo
- Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea.
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13
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Brizzolara A, Garbati P, Vella S, Calderoni M, Quattrone A, Tonini GP, Capasso M, Longo L, Barbieri R, Florio T, Pagano A. Co-Administration of Fendiline Hydrochloride Enhances Chemotherapeutic Efficacy of Cisplatin in Neuroblastoma Treatment. Molecules 2020; 25:molecules25225234. [PMID: 33182713 PMCID: PMC7698186 DOI: 10.3390/molecules25225234] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/20/2020] [Accepted: 11/03/2020] [Indexed: 12/11/2022] Open
Abstract
Despite significant improvement of neuroblastoma (NB) patients’ survival due to recent treatment advancements in recent years, NB is still associated with high mortality rate. In search of novel strategies to increase NB’s susceptibility to pharmacological treatments, we investigated the in vitro and in vivo effects of fendiline hydrochloride as an enhancer of cisplatin antitumor activity. To assess the modulation of fendiline treatment on cisplatin responses, we used in vitro (evaluating NB cell proliferation by XCELLigence technology and colony formation, and gene expression by RT-PCR) and in vivo (NB cell grafts in NOD-SCID mice) models of NB. NB cell treatment with fendiline induced the expression of the ncRNA NDM29, leading to cell differentiation and to the reduction of the expression of MDRs/ABC transporters linked to multidrug resistance. These events were correlated to higher NB cell susceptibility to cisplatin and, consequently, increased its cytotoxic potency. In vivo, this drug interaction causes an enhanced ability of cisplatin to induce apoptosis in NB masses, resulting in tumor growth reduction and prolonged animal survival rate. Thus, the administration of fendiline might be a possible novel therapeutic approach to increase cisplatin efficacy in aggressive and poorly responsive NB cases.
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Affiliation(s)
| | - Patrizia Garbati
- Department of Experimental Medicine (DIMES), University of Genova, 16126 Genova, Italy; (P.G.); (M.C.); (R.B.)
| | - Serena Vella
- Department of Laboratory Medicine and Advanced Biotechnologies, Institute of Hospitalization and Care of a Scientific Nature—Mediterranean Institute for Transplantation and Highly Specialized Therapies (IRCCS- ISMETT), 90127 Palermo, Italy;
- Anemocyte S.r.l., 21040 Gerenzano, Italy
| | - Matilde Calderoni
- Department of Experimental Medicine (DIMES), University of Genova, 16126 Genova, Italy; (P.G.); (M.C.); (R.B.)
| | - Alessandro Quattrone
- Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy;
| | - Gian Paolo Tonini
- Neuroblastoma Laboratory, Pediatric Research Institute, The “Città della Speranza” Foundation, 35128 Padua, Italy;
| | - Mario Capasso
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80145 Naples, Italy;
- CEINGE Biotecnologie Avanzate, 80131 Naples, Italy
- SDN Research Institute Diagnostics and Nuclear, 80133 Naples, Italy
| | - Luca Longo
- Lung Cancer Unit, Division of Medical Oncology II, IRCCS San Martino Polyclinic Hospital, 16132 Genova, Italy;
| | - Raffaella Barbieri
- Department of Experimental Medicine (DIMES), University of Genova, 16126 Genova, Italy; (P.G.); (M.C.); (R.B.)
| | - Tullio Florio
- IRCCS AOU San Martino Polyclinic Hospital, 16132 Genova, Italy; (A.B.); (T.F.)
- Department of Internal Medicine (DIMI), University of Genova, 16126 Genova, Italy
| | - Aldo Pagano
- IRCCS AOU San Martino Polyclinic Hospital, 16132 Genova, Italy; (A.B.); (T.F.)
- Department of Experimental Medicine (DIMES), University of Genova, 16126 Genova, Italy; (P.G.); (M.C.); (R.B.)
- Correspondence: ; Tel.: +39-010-5558213
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14
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MCM2 and Carbonic Anhydrase 9 Are Novel Potential Targets for Neuroblastoma Pharmacological Treatment. Biomedicines 2020; 8:biomedicines8110471. [PMID: 33153038 PMCID: PMC7692293 DOI: 10.3390/biomedicines8110471] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 10/29/2020] [Accepted: 10/31/2020] [Indexed: 02/07/2023] Open
Abstract
To overcome the lack of effective pharmacological treatments for high-risk neuroblastoma (HR-NB), the development of novel in vitro and in vivo models that better recapitulate the disease is required. Here, we used an in vitro multiclonal cell model encompassing NB cell differentiation stages, to identify potential novel pharmacological targets. This model allowed us to identify, by low-density RT-PCR arrays, two gene sets, one over-expressed during NB cell differentiation, and the other up-regulated in more malignant cells. Challenging two HR-NB gene expression datasets, we found that these two gene sets are related to high and low survival, respectively. Using mouse NB cisplatin-treated xenografts, we identified two genes within the list associated to the malignant stage (MCM2 and carbonic anhydrase 9), whose expression is positively correlated with tumor growth. Thus, we tested their pharmacological targeting as potential therapeutic strategy. We measured mice survival and tumor growth rate after xenografts of human NB treated with cisplatin in the presence of MCM2/carbonic anhydrase 9 inhibitors (ciprofloxacin and acetazolamide). MCM2 or carbonic anhydrase 9 inhibition significantly increased cisplatin activity, supporting their possible testing for NB therapy.
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15
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Medoro A, Bartollino S, Mignogna D, Marziliano N, Porcile C, Nizzari M, Florio T, Pagano A, Raimo G, Intrieri M, Russo C. Proteases Upregulation in Sporadic Alzheimer's Disease Brain. J Alzheimers Dis 2020; 68:931-938. [PMID: 30814362 DOI: 10.3233/jad-181284] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Certain proteases are involved in Alzheimer's disease (AD) and their erroneous control may contribute to the pathology onset and progression. In this study we evaluated the cerebral expression of eight proteases, involved in both AβPP processing and extracellular matrix remodeling. Among these proteases, ADAM10, ADAMTS1, Cathepsin D, and Meprin β show a significantly higher mRNAs expression in sporadic AD subjects versus controls, while ADAMTS1, Cathepsin D, and Meprin β show an increment also at the protein level. These data indicate that transcriptional events affecting brain proteases are activated in AD patients, suggesting a link between proteolysis and AD.
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Affiliation(s)
- Alessandro Medoro
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Silvia Bartollino
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Donatella Mignogna
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Nicola Marziliano
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy.,Clinical Pathology Laboratory, ASL Taranto, Italy
| | - Carola Porcile
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Mario Nizzari
- Department of Internal Medicine and Centre of Excellence for Biomedical Research, University of Genova, Genova, Italy
| | - Tullio Florio
- Department of Internal Medicine and Centre of Excellence for Biomedical Research, University of Genova, Genova, Italy.,IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Aldo Pagano
- Department of Experimental Medicine, University of Genova, Genova, Italy.,IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Gennaro Raimo
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Mariano Intrieri
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Claudio Russo
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
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16
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Ahmadi S, Zobeiri M, Bradburn S. Molecular mechanisms underlying actions of certain long noncoding RNAs in Alzheimer's disease. Metab Brain Dis 2020; 35:681-693. [PMID: 32185592 DOI: 10.1007/s11011-020-00564-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 03/05/2020] [Indexed: 01/08/2023]
Abstract
Long non-coding RNAs (lncRNAs) are a group of non-protein coding RNAs that have more than 200 nucleotides. LncRNAs play an important role in the regulation of protein-coding genes at the transcriptional and post-transcriptional levels. They are found in most organs, with a high prevalence in the central nervous system. Accumulating data suggests that lncRNAs are involved in various neurodegenerative disorders, including the onset and progression of Alzheimer's disease (AD). Recent insights suggest lncRNAs, such as BACE1-AS, 51A, 17A, NDM29 and AS-UCHL1, are dysregulated in AD tissues. Furthermore, there are ongoing efforts to explore the clinical usability of lncRNAs as biomarkers in the disease. In this review, we explore the mechanisms by which aberrant expressions of the most studied lncRNAs contribute to the neuropathologies associated with AD, including amyloid β plaques and neurofibrillary tangles. Understanding the molecular mechanisms of lncRNAs in patients with AD will reveal novel diagnosis strategies and more effective therapeutic targets.
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Affiliation(s)
- Shamseddin Ahmadi
- Department of Biological Science, Faculty of Science, University of Kurdistan, P.O. Box 416, Sanandaj, Iran.
| | - Mohammad Zobeiri
- Department of Biological Science, Faculty of Science, University of Kurdistan, P.O. Box 416, Sanandaj, Iran
| | - Steven Bradburn
- Bioscience Research Centre, Manchester Metropolitan University, Manchester, UK
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17
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Petrie JL, Swan C, Ingram RM, Frame FM, Collins AT, Dumay-Odelot H, Teichmann M, Maitland NJ, White RJ. Effects on prostate cancer cells of targeting RNA polymerase III. Nucleic Acids Res 2019; 47:3937-3956. [PMID: 30820548 PMCID: PMC6486637 DOI: 10.1093/nar/gkz128] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/13/2019] [Accepted: 02/19/2019] [Indexed: 12/12/2022] Open
Abstract
RNA polymerase (pol) III occurs in two forms, containing either the POLR3G subunit or the related paralogue POLR3GL. Whereas POLR3GL is ubiquitous, POLR3G is enriched in undifferentiated cells. Depletion of POLR3G selectively triggers proliferative arrest and differentiation of prostate cancer cells, responses not elicited when POLR3GL is depleted. A small molecule pol III inhibitor can cause POLR3G depletion, induce similar differentiation and suppress proliferation and viability of cancer cells. This response involves control of the fate-determining factor NANOG by small RNAs derived from Alu short interspersed nuclear elements. Tumour initiating activity in vivo can be reduced by transient exposure to the pol III inhibitor. Untransformed prostate cells appear less sensitive than cancer cells to pol III depletion or inhibition, raising the possibility of a therapeutic window.
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Affiliation(s)
- John L Petrie
- Department of Biology, University of York, Heslington, York YO10 5DD, UK
| | - Caroline Swan
- Department of Biology, University of York, Heslington, York YO10 5DD, UK
| | - Richard M Ingram
- Department of Biology, University of York, Heslington, York YO10 5DD, UK
| | - Fiona M Frame
- Department of Biology, University of York, Heslington, York YO10 5DD, UK
| | - Anne T Collins
- Department of Biology, University of York, Heslington, York YO10 5DD, UK
| | - Hélène Dumay-Odelot
- Université de Bordeaux, ARNA Laboratory, F-33076 Bordeaux, France INSERM, U1212 - CNRS UMR 5320, ARNA Laboratory, F-33000 Bordeaux, France
| | - Martin Teichmann
- Université de Bordeaux, ARNA Laboratory, F-33076 Bordeaux, France INSERM, U1212 - CNRS UMR 5320, ARNA Laboratory, F-33000 Bordeaux, France
| | - Norman J Maitland
- Department of Biology, University of York, Heslington, York YO10 5DD, UK
| | - Robert J White
- Department of Biology, University of York, Heslington, York YO10 5DD, UK
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18
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Alu RNA Modulates the Expression of Cell Cycle Genes in Human Fibroblasts. Int J Mol Sci 2019; 20:ijms20133315. [PMID: 31284509 PMCID: PMC6651528 DOI: 10.3390/ijms20133315] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 06/27/2019] [Accepted: 07/02/2019] [Indexed: 12/18/2022] Open
Abstract
Alu retroelements, whose retrotransposition requires prior transcription by RNA polymerase III to generate Alu RNAs, represent the most numerous non-coding RNA (ncRNA) gene family in the human genome. Alu transcription is generally kept to extremely low levels by tight epigenetic silencing, but it has been reported to increase under different types of cell perturbation, such as viral infection and cancer. Alu RNAs, being able to act as gene expression modulators, may be directly involved in the mechanisms determining cellular behavior in such perturbed states. To directly address the regulatory potential of Alu RNAs, we generated IMR90 fibroblasts and HeLa cell lines stably overexpressing two slightly different Alu RNAs, and analyzed genome-wide the expression changes of protein-coding genes through RNA-sequencing. Among the genes that were upregulated or downregulated in response to Alu overexpression in IMR90, but not in HeLa cells, we found a highly significant enrichment of pathways involved in cell cycle progression and mitotic entry. Accordingly, Alu overexpression was found to promote transition from G1 to S phase, as revealed by flow cytometry. Therefore, increased Alu RNA may contribute to sustained cell proliferation, which is an important factor of cancer development and progression.
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19
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Yerukala Sathipati S, Sahu D, Huang HC, Lin Y, Ho SY. Identification and characterization of the lncRNA signature associated with overall survival in patients with neuroblastoma. Sci Rep 2019; 9:5125. [PMID: 30914706 PMCID: PMC6435792 DOI: 10.1038/s41598-019-41553-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 03/05/2019] [Indexed: 01/16/2023] Open
Abstract
Neuroblastoma (NB) is a commonly occurring cancer among infants and young children. Recently, long non-coding RNAs (lncRNAs) have been using as prognostic biomarkers for therapeutics and interventions in various cancers. Considering the poor survival of NB, the lncRNA-based therapeutic strategies must be improved. This work proposes an overall survival time estimator called SVR-NB to identify the lncRNA signature that is associated with the overall survival of patients with NB. SVR-NB is an optimized support vector regression (SVR)-based method that uses an inheritable bi-objective combinatorial genetic algorithm for feature selection. The dataset of 231 NB patients that contains overall survival information and expression profiles of 783 lncRNAs was used to design and evaluate SVR-NB from the database of gene expression omnibus accession GSE62564. SVR-NB identified a signature of 35 lncRNAs and achieved a mean squared correlation coefficient of 0.85 and a mean absolute error of 0.56 year between the actual and estimated overall survival time using 10-fold cross-validation. Further, we ranked and characterized the 35 lncRNAs according to their contribution towards the estimation accuracy. Functional annotations and co-expression gene analysis of LOC440896, LINC00632, and IGF2-AS revealed the association of co-expressed genes in Kyoto Encyclopedia of Genes and Genomes pathways.
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Grants
- This work was funded by Ministry of Science and Technology ROC under the contract numbers MOST 106-2634-F-075-001-, 106-2218-E-009-031-, 107-2221-E-009-154-, 107-2218-E-029-001-, and 107-2314-B-039-025-. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- This work was funded by Ministry of Science and Technology ROC under the contract numbers MOST 107-2221-E-009 -154 –, 107-2634-F-075 -001 –, 107-2218-E-009 -005 –, 107-2218-E-029 -001 –, and 107-2319-B-400 -001 –, and was financially supported by the “Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B)” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Affiliation(s)
| | - Divya Sahu
- Institute of Biomedical Informatics, Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan
| | - Hsuan-Cheng Huang
- Institute of Biomedical Informatics, Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan
- Bioinformatics Program, Taiwan International Graduate Program, Institute of Information Science, Academia Sinica, Taipei, Taiwan
| | - Yenching Lin
- Interdisciplinary Neuroscience Ph.D. Program, National Chiao Tung University, Hsinchu, Taiwan
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.
- Bioinformatics Program, Taiwan International Graduate Program, Institute of Information Science, Academia Sinica, Taipei, Taiwan.
- Interdisciplinary Neuroscience Ph.D. Program, National Chiao Tung University, Hsinchu, Taiwan.
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
- Center For Intelligent Drug Systems and Smart Bio-devices (IDSB), National Chiao Tung University, Hsinchu, Taiwan.
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20
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Decoding epigenetic cell signaling in neuronal differentiation. Semin Cell Dev Biol 2019; 95:12-24. [PMID: 30578863 DOI: 10.1016/j.semcdb.2018.12.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 12/18/2018] [Indexed: 12/18/2022]
Abstract
Neurogenesis is the process by which new neurons are generated in the brain. Neural stem cells (NSCs) are differentiated into neurons, which are integrated into the neural network. Nowadays, pluripotent stem cells, multipotent stem cells, and induced pluripotent stem cells can be artificially differentiated into neurons utilizing several techniques. Specific transcriptional profiles from NSCs during differentiation are frequently used to approach and observe phenotype alteration and functional determination of neurons. In this context, the role of non-coding RNA, transcription factors and epigenetic changes in neuronal development and differentiation has gained importance. Epigenetic elucidation has become a field of intense research due to distinct patterns of normal conditions and different neurodegenerative disorders, which can be explored to develop new diagnostic methods or gene therapies. In this review, we discuss the complexity of transcription factors, non-coding RNAs, and extracellular vesicles that are responsible for guiding and coordinating neural development.
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21
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Laneve P, Rea J, Caffarelli E. Long Noncoding RNAs: Emerging Players in Medulloblastoma. Front Pediatr 2019; 7:67. [PMID: 30923703 PMCID: PMC6426782 DOI: 10.3389/fped.2019.00067] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 02/18/2019] [Indexed: 01/02/2023] Open
Abstract
Central Nervous System tumors are the leading cause of cancer-related death in children, and medulloblastoma has the highest incidence rate. The current therapies achieve a 5-year survival rate of 50-80%, but often inflict severe secondary effects demanding the urgent development of novel, effective, and less toxic therapeutic strategies. Historically identified on a histopathological basis, medulloblastoma was later classified into four major subgroups-namely WNT, SHH, Group 3, and Group 4-each characterized by distinct transcriptional profiles, copy-number aberrations, somatic mutations, and clinical outcomes. Additional complexity was recently provided by integrating gene- and non-gene-based data, which indicates that each subclass can be further subdivided into specific subtypes. These deeper classifications, while getting over the typical tumor heterogeneity, indicate that different forms of medulloblastoma hold different molecular drivers that can be successfully exploited for a greater diagnostic accuracy and for the development of novel, targeted treatments. Long noncoding RNAs are transcripts that lack coding potential and play relevant roles as regulators of gene expression in mammalian differentiation and developmental processes. Their cell type- and tissue-specificity, higher than mRNAs, make them more informative about cell- type identity than protein-coding genes. Remarkably, about 40% of long noncoding RNAs are expressed in the brain and their aberrant expression has been linked to neuro-oncological disorders. However, while their involvement in gliomas and neuroblastomas has been extensively studied, their role in medulloblastoma is still poorly explored. Here, we present an overview of current knowledge regarding the function played by long noncoding RNAs in medulloblastoma biology.
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Affiliation(s)
- Pietro Laneve
- Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
| | - Jessica Rea
- Department of Biology and Biotechnology, Sapienza University of Rome, Rome, Italy
| | - Elisa Caffarelli
- Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
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22
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Nakagawara A, Li Y, Izumi H, Muramori K, Inada H, Nishi M. Neuroblastoma. Jpn J Clin Oncol 2018; 48:214-241. [PMID: 29378002 DOI: 10.1093/jjco/hyx176] [Citation(s) in RCA: 135] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Indexed: 02/07/2023] Open
Abstract
Neuroblastoma is one of the most common solid tumors in children and has a diverse clinical behavior that largely depends on the tumor biology. Neuroblastoma exhibits unique features, such as early age of onset, high frequency of metastatic disease at diagnosis in patients over 1 year of age and the tendency for spontaneous regression of tumors in infants. The high-risk tumors frequently have amplification of the MYCN oncogene as well as segmental chromosome alterations with poor survival. Recent advanced genomic sequencing technology has revealed that mutation of ALK, which is present in ~10% of primary tumors, often causes familial neuroblastoma with germline mutation. However, the frequency of gene mutations is relatively small and other aberrations, such as epigenetic abnormalities, have also been proposed. The risk-stratified therapy was introduced by the Japan Neuroblastoma Study Group (JNBSG), which is now moving to the Neuroblastoma Committee of Japan Children's Cancer Group (JCCG). Several clinical studies have facilitated the reduction of therapy for children with low-risk neuroblastoma disease and the significant improvement of cure rates for patients with intermediate-risk as well as high-risk disease. Therapy for patients with high-risk disease includes intensive induction chemotherapy and myeloablative chemotherapy, followed by the treatment of minimal residual disease using differentiation therapy and immunotherapy. The JCCG aims for better cures and long-term quality of life for children with cancer by facilitating new approaches targeting novel driver proteins, genetic pathways and the tumor microenvironment.
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Affiliation(s)
| | - Yuanyuan Li
- Laboratory of Molecular Biology, Life Science Research Institute, Saga Medical Center Koseikan
| | - Hideki Izumi
- Laboratory of Molecular Biology, Life Science Research Institute, Saga Medical Center Koseikan
| | | | - Hiroko Inada
- Department of Pediatrics, Saga Medical Center Koseikan
| | - Masanori Nishi
- Department of Pediatrics, Saga University, Saga 849-8501, Japan
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23
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Rota F, Conti A, Campo L, Favero C, Cantone L, Motta V, Polledri E, Mercadante R, Dieci G, Bollati V, Fustinoni S. Epigenetic and Transcriptional Modifications in Repetitive Elements in Petrol Station Workers Exposed to Benzene and MTBE. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2018; 15:E735. [PMID: 29649143 PMCID: PMC5923777 DOI: 10.3390/ijerph15040735] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 03/30/2018] [Accepted: 04/08/2018] [Indexed: 12/19/2022]
Abstract
Benzene, a known human carcinogen, and methyl tert-butyl ether (MTBE), not classifiable as to its carcinogenicity, are fuel-related pollutants. This study investigated the effect of these chemicals on epigenetic and transcriptional alterations in DNA repetitive elements. In 89 petrol station workers and 90 non-occupationally exposed subjects the transcriptional activity of retrotransposons (LINE-1, Alu), the methylation on repeated-element DNA, and of H3K9 histone, were investigated in peripheral blood lymphocytes. Median work shift exposure to benzene and MTBE was 59 and 408 µg/m³ in petrol station workers, and 4 and 3.5 µg/m³, in controls. Urinary benzene (BEN-U), S-phenylmercapturic acid, and MTBE were significantly higher in workers than in controls, while trans,trans-muconic acid (tt-MA) was comparable between the two groups. Increased BEN-U was associated with increased Alu-Y and Alu-J expression; moreover, increased tt-MA was associated with increased Alu-Y and Alu-J and LINE-1 (L1)-5'UTR expression. Among repetitive element methylation, only L1-Pa5 was hypomethylated in petrol station workers compared to controls. While L1-Ta and Alu-YD6 methylation was not associated with benzene exposure, a negative association with urinary MTBE was observed. The methylation status of histone H3K9 was not associated with either benzene or MTBE exposure. Overall, these findings only partially support previous observations linking benzene exposure with global DNA hypomethylation.
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Affiliation(s)
- Federica Rota
- EPIGET, Epidemiology, Epigenetics and Toxicology Lab, Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, via San Barnaba 8, 20122 Milan, Italy.
| | - Anastasia Conti
- Department of Life Sciences, University of Parma, 43124 Parma, Italy.
- Present address: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), 20132 Milan, Italy.
| | - Laura Campo
- Occupational Medicine Unit, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, 20122 Milan, Italy.
| | - Chiara Favero
- EPIGET, Epidemiology, Epigenetics and Toxicology Lab, Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, via San Barnaba 8, 20122 Milan, Italy.
| | - Laura Cantone
- EPIGET, Epidemiology, Epigenetics and Toxicology Lab, Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, via San Barnaba 8, 20122 Milan, Italy.
| | - Valeria Motta
- EPIGET, Epidemiology, Epigenetics and Toxicology Lab, Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, via San Barnaba 8, 20122 Milan, Italy.
| | - Elisa Polledri
- Occupational Medicine Unit, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, 20122 Milan, Italy.
| | - Rosa Mercadante
- EPIGET, Epidemiology, Epigenetics and Toxicology Lab, Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, via San Barnaba 8, 20122 Milan, Italy.
| | - Giorgio Dieci
- Department of Life Sciences, University of Parma, 43124 Parma, Italy.
| | - Valentina Bollati
- EPIGET, Epidemiology, Epigenetics and Toxicology Lab, Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, via San Barnaba 8, 20122 Milan, Italy.
- Occupational Medicine Unit, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, 20122 Milan, Italy.
| | - Silvia Fustinoni
- EPIGET, Epidemiology, Epigenetics and Toxicology Lab, Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, via San Barnaba 8, 20122 Milan, Italy.
- Occupational Medicine Unit, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, 20122 Milan, Italy.
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24
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Zhao X, Li D, Huang D, Song H, Mei H, Fang E, Wang X, Yang F, Zheng L, Huang K, Tong Q. Retracted: Risk-Associated Long Noncoding RNA FOXD3-AS1 Inhibits Neuroblastoma Progression by Repressing PARP1-Mediated Activation of CTCF. Mol Ther 2018; 26:755-773. [PMID: 29398485 PMCID: PMC5910666 DOI: 10.1016/j.ymthe.2017.12.017] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 12/13/2017] [Accepted: 12/18/2017] [Indexed: 01/22/2023] Open
Abstract
Neuroblastoma (NB) is the most common extracranial tumor in childhood. Recent studies have implicated the emerging roles of long noncoding RNAs (lncRNAs) in tumorigenesis and aggressiveness. However, the functions and targets of risk-associated lncRNAs in NB progression still remain to be determined. Herein, through mining of public microarray datasets, we identify lncRNA forkhead box D3 antisense RNA 1 (FOXD3-AS1) as an independent prognostic marker for favorable outcome of NB patients. FOXD3-AS1 is downregulated in NB tissues and cell lines, and ectopic expression of FOXD3-AS1 induces neuronal differentiation and decreases the aggressiveness of NB cells in vitro and in vivo. Mechanistically, as a nuclear lncRNA, FOXD3-AS1 interacts with poly(ADP-ribose) polymerase 1 (PARP1) to inhibit the poly(ADP-ribosyl)ation and activation of CCCTC-binding factor (CTCF), resulting in derepressed expression of downstream tumor-suppressive genes. Rescue experiments indicate that FOXD3-AS1 harbors tumor-suppressive properties by inhibiting the oncogenic roles of PARP1 or CTCF and plays crucial roles in all-trans-retinoic-acid-mediated therapeutic effects on NB. Administration of FOXD3-AS1 construct or siRNAs against PARP1 or CTCF reduces the tumor growth and prolongs the survival of nude mice. These findings suggest that as a risk-associated lncRNA, FOXD3-AS1 inhibits the progression of NB through repressing PARP1-mediated CTCF activation.
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Affiliation(s)
- Xiang Zhao
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China
| | - Dan Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China
| | - Dandan Huang
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China
| | - Huajie Song
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China
| | - Hong Mei
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China
| | - Erhu Fang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China
| | - Xiaojing Wang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China
| | - Feng Yang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China
| | - Liduan Zheng
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China; Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China.
| | - Kai Huang
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China.
| | - Qiangsong Tong
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China; Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China.
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25
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Larsen PA, Hunnicutt KE, Larsen RJ, Yoder AD, Saunders AM. Warning SINEs: Alu elements, evolution of the human brain, and the spectrum of neurological disease. Chromosome Res 2018; 26:93-111. [PMID: 29460123 PMCID: PMC5857278 DOI: 10.1007/s10577-018-9573-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 01/14/2018] [Accepted: 01/15/2018] [Indexed: 12/28/2022]
Abstract
Alu elements are a highly successful family of primate-specific retrotransposons that have fundamentally shaped primate evolution, including the evolution of our own species. Alus play critical roles in the formation of neurological networks and the epigenetic regulation of biochemical processes throughout the central nervous system (CNS), and thus are hypothesized to have contributed to the origin of human cognition. Despite the benefits that Alus provide, deleterious Alu activity is associated with a number of neurological and neurodegenerative disorders. In particular, neurological networks are potentially vulnerable to the epigenetic dysregulation of Alu elements operating across the suite of nuclear-encoded mitochondrial genes that are critical for both mitochondrial and CNS function. Here, we highlight the beneficial neurological aspects of Alu elements as well as their potential to cause disease by disrupting key cellular processes across the CNS. We identify at least 37 neurological and neurodegenerative disorders wherein deleterious Alu activity has been implicated as a contributing factor for the manifestation of disease, and for many of these disorders, this activity is operating on genes that are essential for proper mitochondrial function. We conclude that the epigenetic dysregulation of Alu elements can ultimately disrupt mitochondrial homeostasis within the CNS. This mechanism is a plausible source for the incipient neuronal stress that is consistently observed across a spectrum of sporadic neurological and neurodegenerative disorders.
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Affiliation(s)
- Peter A Larsen
- Department of Biology, Duke University, Durham, NC, 27708, USA.
- Duke Lemur Center, Duke University, Durham, NC, 27708, USA.
- Department of Biology, Duke University, 130 Science Drive, Box 90338, Durham, NC, 27708, USA.
| | | | - Roxanne J Larsen
- Duke University School of Medicine, Duke University, Durham, NC, 27710, USA
| | - Anne D Yoder
- Department of Biology, Duke University, Durham, NC, 27708, USA
- Duke Lemur Center, Duke University, Durham, NC, 27708, USA
| | - Ann M Saunders
- Zinfandel Pharmaceuticals Inc, Chapel Hill, NC, 27709, USA
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26
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Choquet K, Yang S, Moir RD, Forget D, Larivière R, Bouchard A, Poitras C, Sgarioto N, Dicaire MJ, Noohi F, Kennedy TE, Rochford J, Bernard G, Teichmann M, Coulombe B, Willis IM, Kleinman CL, Brais B. Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation. Mol Brain 2017; 10:13. [PMID: 28407788 PMCID: PMC5391615 DOI: 10.1186/s13041-017-0294-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 04/04/2017] [Indexed: 01/08/2023] Open
Abstract
Recessive mutations in the ubiquitously expressed POLR3A gene cause one of the most frequent forms of childhood-onset hypomyelinating leukodystrophy (HLD): POLR3-HLD. POLR3A encodes the largest subunit of RNA Polymerase III (Pol III), which is responsible for the transcription of transfer RNAs (tRNAs) and a large array of other small non-coding RNAs. In order to study the central nervous system pathophysiology of the disease, we introduced the French Canadian founder Polr3a mutation c.2015G > A (p.G672E) in mice, generating homozygous knock-in (KI/KI) as well as compound heterozygous mice for one Polr3a KI and one null allele (KI/KO). Both KI/KI and KI/KO mice are viable and are able to reproduce. To establish if they manifest a motor phenotype, WT, KI/KI and KI/KO mice were submitted to a battery of behavioral tests over one year. The KI/KI and KI/KO mice have overall normal balance, muscle strength and general locomotion. Cerebral and cerebellar Luxol Fast Blue staining and measurement of levels of myelin proteins showed no significant differences between the three groups, suggesting that myelination is not overtly impaired in Polr3a KI/KI and KI/KO mice. Finally, expression levels of several Pol III transcripts in the brain showed no statistically significant differences. We conclude that the first transgenic mice with a leukodystrophy-causing Polr3a mutation do not recapitulate the childhood-onset HLD observed in the majority of human patients with POLR3A mutations, and provide essential information to guide selection of Polr3a mutations for developing future mouse models of the disease.
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Affiliation(s)
- Karine Choquet
- Montreal Neurological Institute, McGill University, 3801 University Street, room 622, Montréal, Québec, H3A 2B4, Canada.,Department of Human Genetics, McGill University, Montréal, Québec, Canada.,Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada
| | - Sharon Yang
- Montreal Neurological Institute, McGill University, 3801 University Street, room 622, Montréal, Québec, H3A 2B4, Canada
| | - Robyn D Moir
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Diane Forget
- Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec, Canada
| | - Roxanne Larivière
- Montreal Neurological Institute, McGill University, 3801 University Street, room 622, Montréal, Québec, H3A 2B4, Canada
| | - Annie Bouchard
- Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec, Canada
| | - Christian Poitras
- Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec, Canada
| | - Nicolas Sgarioto
- Montreal Neurological Institute, McGill University, 3801 University Street, room 622, Montréal, Québec, H3A 2B4, Canada
| | - Marie-Josée Dicaire
- Montreal Neurological Institute, McGill University, 3801 University Street, room 622, Montréal, Québec, H3A 2B4, Canada
| | - Forough Noohi
- Montreal Neurological Institute, McGill University, 3801 University Street, room 622, Montréal, Québec, H3A 2B4, Canada.,Department of Human Genetics, McGill University, Montréal, Québec, Canada
| | - Timothy E Kennedy
- Montreal Neurological Institute, McGill University, 3801 University Street, room 622, Montréal, Québec, H3A 2B4, Canada
| | | | - Geneviève Bernard
- Departments of Neurology and Neurosurgery, and Pediatrics, McGill University, Montreal, Canada.,Department of Medical Genetics, Montreal Children's Hospital, McGill University Health Center, Montreal, Canada.,Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, Canada
| | - Martin Teichmann
- INSERM U1212 - CNRS UMR5320, Université de Bordeaux, Bordeaux, France
| | - Benoit Coulombe
- Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec, Canada.,Département de biochimie et médecine moléculaire, Université de Montréal, Montréal, Québec, Canada
| | - Ian M Willis
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Claudia L Kleinman
- Department of Human Genetics, McGill University, Montréal, Québec, Canada.,Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada
| | - Bernard Brais
- Montreal Neurological Institute, McGill University, 3801 University Street, room 622, Montréal, Québec, H3A 2B4, Canada. .,Department of Human Genetics, McGill University, Montréal, Québec, Canada.
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27
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Penna I, Gigoni A, Costa D, Vella S, Russo D, Poggi A, Villa F, Brizzolara A, Canale C, Mescola A, Daga A, Russo C, Nizzari M, Florio T, Menichini P, Pagano A. The inhibition of 45A ncRNA expression reduces tumor formation, affecting tumor nodules compactness and metastatic potential in neuroblastoma cells. Oncotarget 2017; 8:8189-8205. [PMID: 28029658 PMCID: PMC5352393 DOI: 10.18632/oncotarget.14138] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Accepted: 11/23/2016] [Indexed: 11/25/2022] Open
Abstract
We recently reported the in vitro over-expression of 45A, a RNA polymerase III-transcribed non-coding (nc)RNA, that perturbs the intracellular content of FE65L1 affecting cell proliferation rate, short-term response to genotoxic stress, substrate adhesion capacity and, ultimately, increasing the tumorigenic potential of human neuroblastoma cells. In this work, to deeply explore the mechanism by which 45A ncRNA contributes to cancer development, we targeted in vitro and in vivo 45A levels by the stable overexpression of antisense 45A RNA.45A downregulation leads to deep modifications of cytoskeleton organization, adhesion and migration of neuroblastoma cells. These effects are correlated with alterations in the expression of several genes including GTSE1 (G2 and S phase-expressed-1), a crucial regulator of tumor cell migration and metastatic potential. Interestingly, the downregulation of 45A ncRNA strongly affects the in vivo tumorigenic potential of SKNBE2 neuroblastoma cells, increasing tumor nodule compactness and reducing GTSE1 protein expression in a subcutaneous neuroblastoma mouse model. Moreover, intracardiac injection of neuroblastoma cells showed that downregulation of 45A ncRNA also influences tumor metastatic ability. In conclusion, our data highlight a key role of 45A ncRNA in cancer development and suggest that its modulation might represent a possible novel anticancer therapeutic approach.
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Affiliation(s)
- Ilaria Penna
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy
- IRCCS-AOU San Martino-IST, Genova, Italy
| | - Arianna Gigoni
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy
- IRCCS-AOU San Martino-IST, Genova, Italy
| | - Delfina Costa
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy
- IRCCS-AOU San Martino-IST, Genova, Italy
| | - Serena Vella
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Palermo, Italy
| | | | | | - Federico Villa
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy
- IRCCS-AOU San Martino-IST, Genova, Italy
| | - Antonella Brizzolara
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy
- IRCCS-AOU San Martino-IST, Genova, Italy
| | - Claudio Canale
- Nanophysics Unit, Italian Institute of Technology, Morego, Genova, Italy
| | - Andrea Mescola
- Nanophysics Unit, Italian Institute of Technology, Morego, Genova, Italy
| | | | - Claudio Russo
- Department of Health Sciences, University of Molise, Campobasso, Italy
| | - Mario Nizzari
- Department of Internal Medicine (DIMI), University of Genova, Genova, Italy
| | - Tullio Florio
- Department of Internal Medicine (DIMI), University of Genova, Genova, Italy
- Center of Excellence for Biomedical Research (CEBR), University of Genova, Genova, Italy
| | | | - Aldo Pagano
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy
- IRCCS-AOU San Martino-IST, Genova, Italy
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28
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PPAR Gamma in Neuroblastoma: The Translational Perspectives of Hypoglycemic Drugs. PPAR Res 2016; 2016:3038164. [PMID: 27799938 PMCID: PMC5069360 DOI: 10.1155/2016/3038164] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 09/14/2016] [Indexed: 12/15/2022] Open
Abstract
Neuroblastoma (NB) is the most common and aggressive pediatric cancer, characterized by a remarkable phenotypic diversity and high malignancy. The heterogeneous clinical behavior, ranging from spontaneous remission to fatal metastatic disease, is attributable to NB biology and genetics. Despite major advances in therapies, NB is still associated with a high morbidity and mortality. Thus, novel diagnostic, prognostic, and therapeutic approaches are required, mainly to improve treatment outcomes of high-risk NB patients. Among neuroepithelial cancers, NB is the most studied tumor as far as PPAR ligands are concerned. PPAR ligands are endowed with antitumoral effects, mainly acting on cancer stem cells, and constitute a possible add-on therapy to antiblastic drugs, in particular for NB with unfavourable prognosis. While discussing clinical background, this review will provide a synopsis of the major studies about PPAR expression in NB, focusing on the potential beneficial effects of hypoglycemic drugs, thiazolidinediones and metformin, to reduce the occurrence of relapses as well as tumor regrowth in NB patients.
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29
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Alloisio S, Garbati P, Viti F, Dante S, Barbieri R, Arnaldi G, Petrelli A, Gigoni A, Giannoni P, Quarto R, Nobile M, Vassalli M, Pagano A. Generation of a Functional Human Neural Network by NDM29 Overexpression in Neuroblastoma Cancer Cells. Mol Neurobiol 2016; 54:6097-6106. [PMID: 27699601 DOI: 10.1007/s12035-016-0161-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 09/23/2016] [Indexed: 11/28/2022]
Abstract
Recent advances in life sciences suggest that human and rodent cell responses to stimuli might differ significantly. In this context, the results achieved in neurotoxicology and biomedical research practices using neural networks obtained from mouse or rat primary culture of neurons would benefit of the parallel evaluation of the same parameters using fully differentiated neurons with a human genetic background, thus emphasizing the current need of neuronal cells with human origin. In this work, we developed a human functionally active neural network derived by human neuroblastoma cancer cells genetically engineered to overexpress NDM29, a non-coding RNA whose increased synthesis causes the differentiation toward a neuronal phenotype. These cells are here analyzed accurately showing functional and morphological traits of neurons such as the expression of neuron-specific proteins and the possibility to generate the expected neuronal current traces and action potentials. Their morphometrical analysis is carried out by quantitative phase microscopy showing soma and axon sizes compatible with those of functional neurons. The ability of these cells to connect autonomously forming physical junctions recapitulates that of hippocampal neurons, as resulting by connect-ability test. Lastly, these cells self-organize in neural networks able to produce spontaneous firing, in which spikes can be clustered in bursts. Altogether, these results show that the neural network obtained by NDM29-dependent differentiation of neuroblastoma cells is a suitable tool for biomedical research practices.
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Affiliation(s)
- Susanna Alloisio
- ETT Spa, via Sestri 37, 16154, Genoa, Italy.,National Research Council, Institute of Biophysics, via De Marini 6, 16149, Genoa, Italy
| | | | - Federica Viti
- National Research Council, Institute of Biophysics, via De Marini 6, 16149, Genoa, Italy
| | - Silvia Dante
- Istituto Italiano di Tecnologia, Via Morego 30, I-16163, Genova, Italy
| | | | - Giovanni Arnaldi
- IRCCS-AOU San Martino-IST, Genova, Italy.,Department of Experimental Medicine (DIMES), University of Genova, Largo Rosanna Benzi 10, 16132, Genova, Italy
| | - Alessia Petrelli
- Istituto Italiano di Tecnologia, Via Morego 30, I-16163, Genova, Italy
| | - Arianna Gigoni
- IRCCS-AOU San Martino-IST, Genova, Italy.,Department of Experimental Medicine (DIMES), University of Genova, Largo Rosanna Benzi 10, 16132, Genova, Italy
| | - Paolo Giannoni
- Department of Experimental Medicine (DIMES), University of Genova, Largo Rosanna Benzi 10, 16132, Genova, Italy
| | - Rodolfo Quarto
- IRCCS-AOU San Martino-IST, Genova, Italy.,Department of Experimental Medicine (DIMES), University of Genova, Largo Rosanna Benzi 10, 16132, Genova, Italy
| | - Mario Nobile
- National Research Council, Institute of Biophysics, via De Marini 6, 16149, Genoa, Italy
| | - Massimo Vassalli
- National Research Council, Institute of Biophysics, via De Marini 6, 16149, Genoa, Italy
| | - Aldo Pagano
- IRCCS-AOU San Martino-IST, Genova, Italy. .,Department of Experimental Medicine (DIMES), University of Genova, Largo Rosanna Benzi 10, 16132, Genova, Italy.
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30
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Gigoni A, Costa D, Gaetani M, Tasso R, Villa F, Florio T, Pagano A. Down-regulation of 21A Alu RNA as a tool to boost proliferation maintaining the tissue regeneration potential of progenitor cells. Cell Cycle 2016; 15:2420-30. [PMID: 27494068 DOI: 10.1080/15384101.2016.1181242] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
21A is an Alu non-coding (nc) RNA transcribed by RNA polymerase (pol) III. While investigating the biological role of 21A ncRNA we documented an inverse correlation between its expression level and the rate of cell proliferation. The downregulation of this ncRNA not only caused a boost in cell proliferation, but was also associated to a transient cell dedifferentiation, suggesting a possible involvement of this RNA in cell dedifferentiation/reprogramming. In this study, we explored the possibility to enhance proliferation and dedifferentiation of cells of interest, by 21A down-regulation, using a mixture of chemically modified Anti-21A RNAs. Our results confirmed the validity of this approach that allows the amplification of specific cell populations, in a controlled manner and without inducing permanent effects. In addition to induce cell proliferation, the procedure did not decrease the tissue regeneration potential of progenitor cells in two different cell systems.
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Affiliation(s)
- Arianna Gigoni
- a Dept. of Experimental Medicine (DIMES) , University of Genova , Genova , Italy
| | | | - Massimiliano Gaetani
- c ISMETT, Mediterranean Institute for Transplantation and Advanced Specialized Therapies , Palermo , Italy.,d Ri.MED Foundation , Palermo , Italy
| | - Roberta Tasso
- a Dept. of Experimental Medicine (DIMES) , University of Genova , Genova , Italy.,b IRCCS-AOU San Martino-IST , Genova , Italy
| | - Federico Villa
- a Dept. of Experimental Medicine (DIMES) , University of Genova , Genova , Italy
| | - Tullio Florio
- e Sect. of Pharmacology, Dept. of Internal Medicine (DiMI) and Center of Excellence for Biomedical Research (CEBR), University of Genova , Genova , Italy
| | - Aldo Pagano
- a Dept. of Experimental Medicine (DIMES) , University of Genova , Genova , Italy.,b IRCCS-AOU San Martino-IST , Genova , Italy
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31
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Conti A, Rota F, Ragni E, Favero C, Motta V, Lazzari L, Bollati V, Fustinoni S, Dieci G. Hydroquinone induces DNA hypomethylation-independent overexpression of retroelements in human leukemia and hematopoietic stem cells. Biochem Biophys Res Commun 2016; 474:691-695. [DOI: 10.1016/j.bbrc.2016.05.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 05/02/2016] [Indexed: 10/21/2022]
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32
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Abstract
Neuroblastoma is a disease that affects infants and despite intense multimodal therapy, high-risk patients have low survival rates (<50%). In recent years long noncoding RNAs (lncRNAs) have become the cutting edge of cancer research with inroads made in understanding their roles in multiple cancer types, including prostate and breast cancers. The roles of lncRNAs in neuroblastoma have just begun to be elucidated. This review summarises where we are with regards to lncRNAs in neuroblastoma. The known mechanistic roles of lncRNAs during neuroblastoma pathogenesis are discussed, as well as the relationship between lncRNA expression and the differentiation capacity of neuroblastoma cells. We speculate about the use of some of these lncRNAs, such as those mapping to the 6p22 hotspot, as biomarkers for neuroblastoma prognosis and treatment. This novel way of thinking about both neuroblastoma and lncRNAs brings a new perspective to the prognosis and treatment of high-risk patients.
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33
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Perhexiline maleate enhances antitumor efficacy of cisplatin in neuroblastoma by inducing over-expression of NDM29 ncRNA. Sci Rep 2015; 5:18144. [PMID: 26674674 PMCID: PMC4682181 DOI: 10.1038/srep18144] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 11/11/2015] [Indexed: 01/02/2023] Open
Abstract
High Risk Neuroblastoma (HR-NB) is a pediatric cancer characterized by high malignancy and remarkable cell heterogeneity within the tumour nodules. In a recent study, we demonstrated that in vitro and in vivo over-expression of the non-coding RNA NDM29 (neuroblastoma differentiation marker 29) induces NB cell differentiation, dramatically reducing their malignancy. Among gene expression changes, differentiated phenotype induced by NDM29 is characterized by decrease of the expression of ABC transporters responsible for anticancer drug resistance. Thus, the pharmacological induction of NDM29, in principle, might represent a possible novel strategy to increase cytotoxic drug responses. In this work, we identify a small molecule able to induce the expression of NDM29 in NB cells, conferring to malignant cells increased susceptibility to cisplatin cytotoxic effects. We demonstrate that the pharmacological induction of NDM29 expression in vivo enhances the antitumoral effects of chemotherapy specifically on tumour initiating/cancer stem cells sub-population, usually refractory to therapies and responsible for tumour relapse. In summary, we suggest a novel therapeutical approach possibly useful to treat very aggressive NB cases with poor prognosis. This novel pharmacological strategy aims to promote differentiation of “stem-like” cells to render them more susceptible to the killing action of cytotoxic anticancer drugs.
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34
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Smalheiser NR. The RNA-centred view of the synapse: non-coding RNAs and synaptic plasticity. Philos Trans R Soc Lond B Biol Sci 2015; 369:rstb.2013.0504. [PMID: 25135965 PMCID: PMC4142025 DOI: 10.1098/rstb.2013.0504] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
If mRNAs were the only RNAs made by a neuron, there would be a simple mapping of mRNAs to proteins. However, microRNAs and other non-coding RNAs (ncRNAs; endo-siRNAs, piRNAs, BC1, BC200, antisense and long ncRNAs, repeat-related transcripts, etc.) regulate mRNAs via effects on protein translation as well as transcriptional and epigenetic mechanisms. Not only are genes ON or OFF, but their ability to be translated can be turned ON or OFF at the level of synapses, supporting an enormous increase in information capacity. Here, I review evidence that ncRNAs are expressed pervasively within dendrites in mammalian brain; that some are activity-dependent and highly enriched near synapses; and that synaptic ncRNAs participate in plasticity responses including learning and memory. Ultimately, ncRNAs can be viewed as the post-it notes of the neuron. They have no literal meaning of their own, but derive their functions from where (and to what) they are stuck. This may explain, in part, why ncRNAs differ so dramatically from protein-coding genes, both in terms of the usual indicators of functionality and in terms of evolutionary constraints. ncRNAs do not appear to be direct mediators of synaptic transmission in the manner of neurotransmitters or receptors, yet they orchestrate synaptic plasticity—and may drive species-specific changes in cognition.
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Affiliation(s)
- Neil R Smalheiser
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA
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35
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Conti A, Carnevali D, Bollati V, Fustinoni S, Pellegrini M, Dieci G. Identification of RNA polymerase III-transcribed Alu loci by computational screening of RNA-Seq data. Nucleic Acids Res 2014; 43:817-35. [PMID: 25550429 PMCID: PMC4333407 DOI: 10.1093/nar/gku1361] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Of the ∼1.3 million Alu elements in the human genome, only a tiny number are estimated to be active in transcription by RNA polymerase (Pol) III. Tracing the individual loci from which Alu transcripts originate is complicated by their highly repetitive nature. By exploiting RNA-Seq data sets and unique Alu DNA sequences, we devised a bioinformatic pipeline allowing us to identify Pol III-dependent transcripts of individual Alu elements. When applied to ENCODE transcriptomes of seven human cell lines, this search strategy identified ∼1300 Alu loci corresponding to detectable transcripts, with ∼120 of them expressed in at least three cell lines. In vitro transcription of selected Alus did not reflect their in vivo expression properties, and required the native 5′-flanking region in addition to internal promoter. We also identified a cluster of expressed AluYa5-derived transcription units, juxtaposed to snaR genes on chromosome 19, formed by a promoter-containing left monomer fused to an Alu-unrelated downstream moiety. Autonomous Pol III transcription was also revealed for Alus nested within Pol II-transcribed genes. The ability to investigate Alu transcriptomes at single-locus resolution will facilitate both the identification of novel biologically relevant Alu RNAs and the assessment of Alu expression alteration under pathological conditions.
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Affiliation(s)
- Anastasia Conti
- Department of Life Sciences, University of Parma, 43124 Parma, Italy Department of Clinical and Experimental Medicine, University of Parma, 43126 Parma, Italy
| | - Davide Carnevali
- Department of Life Sciences, University of Parma, 43124 Parma, Italy
| | - Valentina Bollati
- Department of Clinical Sciences and Community Health, University of Milano and Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via S. Barnaba, 8-20122 Milano, Italy
| | - Silvia Fustinoni
- Department of Clinical Sciences and Community Health, University of Milano and Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via S. Barnaba, 8-20122 Milano, Italy
| | - Matteo Pellegrini
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90095-7239, USA
| | - Giorgio Dieci
- Department of Life Sciences, University of Parma, 43124 Parma, Italy
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Barnhill LM, Williams RT, Cohen O, Kim Y, Batova A, Mielke JA, Messer K, Pu M, Bao L, Yu AL, Diccianni MB. High expression of CAI2, a 9p21-embedded long noncoding RNA, contributes to advanced-stage neuroblastoma. Cancer Res 2014; 74:3753-63. [PMID: 25028366 DOI: 10.1158/0008-5472.can-13-3447] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Neuroblastoma is a pediatric cancer with significant genomic and biologic heterogeneity. p16 and ARF, two important tumor-suppressor genes on chromosome 9p21, are inactivated commonly in most cancers, but paradoxically overexpressed in neuroblastoma. Here, we report that exon γ in p16 is also part of an undescribed long noncoding RNA (lncRNA) that we have termed CAI2 (CDKN2A/ARF Intron 2 lncRNA). CAI2 is a single-exon gene with a poly A signal located in but independent of the p16/ARF exon 3. CAI2 is expressed at very low levels in normal tissue, but is highly expressed in most tumor cell lines with an intact 9p21 locus. Concordant expression of CAI2 with p16 and ARF in normal tissue along with the ability of CAI2 to induce p16 expression suggested that CAI2 may regulate p16 and/or ARF. In neuroblastoma cells transformed by serial passage in vitro, leading to more rapid proliferation, CAI2, p16, and ARF expression all increased dramatically. A similar relationship was also observed in primary neuroblastomas where CAI2 expression was significantly higher in advanced-stage neuroblastoma, independently of MYCN amplification. Consistent with its association with high-risk disease, CAI2 expression was also significantly associated with poor clinical outcomes, although this effect was reduced when adjusted for MYCN amplification. Taken together, our findings suggested that CAI2 contributes to the paradoxical overexpression of p16 in neuroblastoma, where CAI2 may offer a useful biomarker of high-risk disease.
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Affiliation(s)
- Lisa M Barnhill
- Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego
| | - Richard T Williams
- Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego
| | - Olga Cohen
- Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego
| | - Youngjin Kim
- Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego
| | - Ayse Batova
- Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego
| | - Jenna A Mielke
- Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego
| | - Karen Messer
- Division of Biostatistics and Bioinformatics, Moores UCSD Cancer Center, La Jolla, California
| | - Minya Pu
- Division of Biostatistics and Bioinformatics, Moores UCSD Cancer Center, La Jolla, California
| | - Lei Bao
- Division of Biostatistics and Bioinformatics, Moores UCSD Cancer Center, La Jolla, California
| | - Alice L Yu
- Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego; Academia Sinica, Genomics Research Center, Taipei; and Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Mitchell B Diccianni
- Authors' Affiliations: Department of Pediatrics Hematology/Oncology, University of California, San Diego, San Diego;
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Dynamic Alu methylation during normal development, aging, and tumorigenesis. BIOMED RESEARCH INTERNATIONAL 2014; 2014:784706. [PMID: 25243180 PMCID: PMC4163490 DOI: 10.1155/2014/784706] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 08/16/2014] [Indexed: 12/15/2022]
Abstract
DNA methylation primarily occurs on CpG dinucleotides and plays an important role in transcriptional regulations during tissue development and cell differentiation. Over 25% of CpG dinucleotides in the human genome reside within Alu elements, the most abundant human repeats. The methylation of Alu elements is an important mechanism to suppress Alu transcription and subsequent retrotransposition. Decades of studies revealed that Alu methylation is highly dynamic during early development and aging. Recently, many environmental factors were shown to have a great impact on Alu methylation. In addition, aberrant Alu methylation has been documented to be an early event in many tumors and Alu methylation levels have been associated with tumor aggressiveness. The assessment of the Alu methylation has become an important approach for early diagnosis and/or prognosis of cancer. This review focuses on the dynamic Alu methylation during development, aging, and tumor genesis. The cause and consequence of Alu methylation changes will be discussed.
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Costa D, Gigoni A, Würth R, Cancedda R, Florio T, Pagano A. Metformin inhibition of neuroblastoma cell proliferation is differently modulated by cell differentiation induced by retinoic acid or overexpression of NDM29 non-coding RNA. Cancer Cell Int 2014; 14:59. [PMID: 25120382 PMCID: PMC4128937 DOI: 10.1186/1475-2867-14-59] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Accepted: 06/04/2014] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Metformin is a widely used oral hypoglycemizing agent recently proposed as potential anti-cancer drug. In this study we report the antiproliferative effect of metformin treatment in a high risk neuroblastoma cell model, focusing on possible effects associated to different levels of differentiation and/or tumor initiating potential. METHODS Antiproliferative and cytotoxic effects of metformin were tested in human SKNBE2 and SH-SY5Y neuroblastoma cell lines and in SKNBE2 cells in which differentiation is induced by retinoic acid treatment or stable overexpression of NDM29 non-coding RNA, both conditions characterized by a neuron-like differentiated phenotype. RESULTS We found that metformin significantly inhibits the proliferation of NB cells, an effect that correlates with the inhibition of Akt, while AMPK activity resulted unchanged. Notably, metformin effects were modulated in a different ways by differentiating stimuli, being abolished after retinoic acid treatment but potentiated by overexpression of NDM29. CONCLUSION These data suggest the efficacy of metformin as neuroblastoma anticancer agent, and support the requirement of further studies on the possible role of the differentiation status on the antiproliferative effects of this drug.
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Affiliation(s)
- Delfina Costa
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy ; IRCCS-AOU San Martino-IST, Genova, Italy
| | - Arianna Gigoni
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy ; IRCCS-AOU San Martino-IST, Genova, Italy
| | - Roberto Würth
- Internal Medicine (DIMI), University of Genova, Genova, Italy
| | - Ranieri Cancedda
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy ; IRCCS-AOU San Martino-IST, Genova, Italy
| | - Tullio Florio
- Internal Medicine (DIMI), University of Genova, Genova, Italy ; Center of Excellence for Biomedical Research (CEBR), University of Genova, Genova, Italy
| | - Aldo Pagano
- Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy ; IRCCS-AOU San Martino-IST, Genova, Italy
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Gavazzo P, Vassalli M, Costa D, Pagano A. Novel ncRNAs transcribed by Pol III and elucidation of their functional relevance by biophysical approaches. Front Cell Neurosci 2013; 7:203. [PMID: 24223537 PMCID: PMC3819595 DOI: 10.3389/fncel.2013.00203] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 11/17/2013] [Indexed: 11/25/2022] Open
Abstract
In the last decade the role of non coding (nc) RNAs in neurogenesis and in the onset of neurological diseases has been assessed by a multitude of studies. In this scenario, approximately 30 small RNA polymerase (pol) III-dependent ncRNAs were recently identified by computational tools and proposed as regulatory elements. The function of several of these transcripts was elucidated in vitro and in vivo confirming their involvement in cancer and in metabolic and neurodegenerative disorders. Emerging biophysical technologies together with the introduction of a physical perspective have been advantageous in regulatory RNA investigation providing original results on: (a) the differentiation of neuroblastoma (NB) cells towards a neuron-like phenotype triggered by Neuroblastoma Differentiation Marker 29 (NDM29) ncRNA; (b) the modulation of A-type K(+) current in neurons induced by the small ncRNA 38A and (c) the synthesis driven by 17A ncRNA of a GABAB2 receptor isoform unable to trigger intracellular signaling. Moreover, the application of Single Cell Force Spectroscopy (SCFS) to these studies suggests a correlation between the malignancy stage of NB and the micro-adhesive properties of the cells, allowing to investigate the molecular basis of such a correlation.
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Affiliation(s)
- Paola Gavazzo
- Institute of Biophysics, National Research Council (CNR)Genoa, Italy
| | - Massimo Vassalli
- Institute of Biophysics, National Research Council (CNR)Genoa, Italy
| | - Delfina Costa
- Department of Experimental Medicine, University of GenoaGenoa, Italy
| | - Aldo Pagano
- Department of Experimental Medicine, University of GenoaGenoa, Italy
- IRCCS Azienda Ospedaliera Universitaria San Martino-ISTGenoa, Italy
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Li J, Xuan Z, Liu C. Long non-coding RNAs and complex human diseases. Int J Mol Sci 2013; 14:18790-808. [PMID: 24036441 PMCID: PMC3794807 DOI: 10.3390/ijms140918790] [Citation(s) in RCA: 153] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Revised: 08/28/2013] [Accepted: 09/03/2013] [Indexed: 02/07/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are a heterogeneous class of RNAs that are generally defined as non-protein-coding transcripts longer than 200 nucleotides. Recently, an increasing number of studies have shown that lncRNAs can be involved in various critical biological processes, such as chromatin remodeling, gene transcription, and protein transport and trafficking. Moreover, lncRNAs are dysregulated in a number of complex human diseases, including coronary artery diseases, autoimmune diseases, neurological disorders, and various cancers, which indicates their important roles in these diseases. Here, we reviewed the current understanding of lncRNAs, including their definition and subclassification, regulatory functions, and potential roles in different types of complex human diseases.
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Affiliation(s)
- Jing Li
- Bioinformatics Research Group, Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China; E-Mail:
| | - Zhenyu Xuan
- Department of Molecular and Cell Biology, Center for Systems Biology, University of Texas at Dallas, 800 W Campbell Road, Richardson, TX 75080, USA
| | - Changning Liu
- Bioinformatics Research Group, Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China; E-Mail:
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Penna I, Vassallo I, Nizzari M, Russo D, Costa D, Menichini P, Poggi A, Russo C, Dieci G, Florio T, Cancedda R, Pagano A. A novel snRNA-like transcript affects amyloidogenesis and cell cycle progression through perturbation of Fe65L1 (APBB2) alternative splicing. BIOCHIMICA ET BIOPHYSICA ACTA 2013; 1833:1511-1526. [PMID: 23485396 DOI: 10.1016/j.bbamcr.2013.02.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Revised: 01/17/2013] [Accepted: 02/18/2013] [Indexed: 11/24/2022]
Abstract
FE65 proteins constitute a family of adaptors which modulates the processing of amyloid precursor protein and the consequent amyloid β production. Thus, they have been involved in the complex and partially unknown cascade of reactions at the base of Alzheimer's disease etiology. However, FE65 and FE65-like proteins may be linked to neurodegeneration through the regulation of cell cycle in post-mitotic neurons. In this work we disclose novel molecular mechanisms by which APBB2 can modulate APP processing. We show that APBB2 mRNA splicing, driven by the over-expression of a novel non-coding RNA named 45A, allow the generation of alternative protein forms endowed with differential effects on Aβ production, cell cycle control, and DNA damage response. 45A overexpression also favors cell transformation and tumorigenesis leading to a marked increase of malignancy of neuroblastoma cells. Therefore, our results highlight a novel regulatory pathway of considerable interest linking APP processing with cell cycle regulation and DNA-surveillance systems, that may represent a molecular mechanism to induce neurodegeneration in post-mitotic neurons.
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Affiliation(s)
- Ilaria Penna
- Dept. of Experimental Medicine, University of Genova, Genova, Italy
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The Murine PSE/TATA-dependent transcriptome: evidence of functional homologies with its human counterpart. Int J Mol Sci 2012. [PMID: 23203095 PMCID: PMC3509611 DOI: 10.3390/ijms131114813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
A series of recent studies demonstrated an unexpectedly high frequency of intronic RNA polymerase (pol) III transcription units spread throughout the human genome. The investigation of a subset of these transcripts revealed their tissue/cell-specific transcription together with the involvement in relevant physiopathological pathways. Despite this evidence, these transcripts did not seem to have murine orthologs, based on their nucleotide sequence, resulting in a limitation of the experimental approaches aimed to study their function. In this work, we have extended our investigation to the murine genome identifying 121 pairs of mouse/human transcripts displaying syntenic subchromosomal localization. The analysis in silico of this set of putative noncoding (nc)RNAs suggest their association with alternative splicing as suggested by recent experimental evidence. The investigation of one of these pairs taken as experimental model in mouse hippocampal neurons provided evidence of a human/mouse functional homology that does not depend on underlying sequence conservation. In this light, the collection of transcriptional units here reported can be considered as a novel source for the identification and the study of novel regulatory elements involved in relevant biological processes.
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Dieci G, Conti A, Pagano A, Carnevali D. Identification of RNA polymerase III-transcribed genes in eukaryotic genomes. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2012; 1829:296-305. [PMID: 23041497 DOI: 10.1016/j.bbagrm.2012.09.010] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Revised: 09/20/2012] [Accepted: 09/21/2012] [Indexed: 12/16/2022]
Abstract
The RNA polymerase (Pol) III transcription system is devoted to the production of short, generally abundant noncoding (nc) RNAs in all eukaryotic cells. Previously thought to be restricted to a few housekeeping genes easily detectable in genome sequences, the set of known Pol III-transcribed genes (class III genes) has been expanding in the last ten years, and the issue of their detection, annotation and actual expression has been stimulated and revived by the results of recent high-resolution genome-wide location analyses of the mammalian Pol III machinery, together with those of Pol III-centered computational studies and of ncRNA-focused transcriptomic approaches. In this article, we provide an outline of distinctive features of Pol III-transcribed genes that have allowed and currently allow for their detection in genome sequences, we critically review the currently practiced strategies for the identification of novel class III genes and transcripts, and we discuss emerging themes in Pol III transcription regulation which might orient future transcriptomic studies. This article is part of a Special Issue entitled: Transcription by Odd Pols.
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Affiliation(s)
- Giorgio Dieci
- Dipartimento di Bioscienze, Università degli Studi di Parma, Parco Area delle Scienze 23/A, 43124 Parma, Italy.
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Ciarlo E, Massone S, Penna I, Nizzari M, Gigoni A, Dieci G, Russo C, Florio T, Cancedda R, Pagano A. An intronic ncRNA-dependent regulation of SORL1 expression affecting Aβ formation is upregulated in post-mortem Alzheimer's disease brain samples. Dis Model Mech 2012; 6:424-33. [PMID: 22996644 PMCID: PMC3597024 DOI: 10.1242/dmm.009761] [Citation(s) in RCA: 131] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Recent studies indicated that sortilin-related receptor 1 (SORL1) is a risk gene for late-onset Alzheimer's disease (AD), although its role in the aetiology and/or progression of this disorder is not fully understood. Here, we report the finding of a non-coding (nc) RNA (hereafter referred to as 51A) that maps in antisense configuration to intron 1 of the SORL1 gene. 51A expression drives a splicing shift of SORL1 from the synthesis of the canonical long protein variant A to an alternatively spliced protein form. This process, resulting in a decreased synthesis of SORL1 variant A, is associated with impaired processing of amyloid precursor protein (APP), leading to increased Aβ formation. Interestingly, we found that 51A is expressed in human brains, being frequently upregulated in cerebral cortices from individuals with Alzheimer's disease. Altogether, these findings document a novel ncRNA-dependent regulatory pathway that might have relevant implications in neurodegeneration.
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Affiliation(s)
- Eleonora Ciarlo
- Department of Experimental Medicine, University of Genoa, Genoa 16132, Italy
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45
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Garritano S, Gigoni A, Costa D, Malatesta P, Florio T, Cancedda R, Pagano A. A novel collection of snRNA-like promoters with tissue-specific transcription properties. Int J Mol Sci 2012; 13:11323-11332. [PMID: 23109855 PMCID: PMC3472747 DOI: 10.3390/ijms130911323] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Revised: 08/28/2012] [Accepted: 08/30/2012] [Indexed: 12/28/2022] Open
Abstract
We recently identified a novel dataset of snRNA-like trascriptional units in the human genome. The investigation of a subset of these elements showed that they play relevant roles in physiology and/or pathology. In this work we expand our collection of small RNAs taking advantage of a newly developed algorithm able to identify genome sequence stretches with RNA polymerase (pol) III type 3 promoter features thus constituting putative pol III binding sites. The bioinformatic analysis of a subset of these elements that map in introns of protein-coding genes in antisense configuration suggest their association with alternative splicing, similarly to other recently characterized small RNAs. Interestingly, the analysis of the transcriptional activity of these novel promoters shows that they are active in a cell-type specific manner, in accordance with the emerging body of evidence of a tissue/cell-specific activity of pol III.
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Affiliation(s)
- Sonia Garritano
- Department of Experimental Medicine (DiMES), University of Genoa, 16132 Genoa, Italy; E-Mails: (S.G.); (A.G.); (D.C.); (P.M.); (R.C.)
| | - Arianna Gigoni
- Department of Experimental Medicine (DiMES), University of Genoa, 16132 Genoa, Italy; E-Mails: (S.G.); (A.G.); (D.C.); (P.M.); (R.C.)
| | - Delfina Costa
- Department of Experimental Medicine (DiMES), University of Genoa, 16132 Genoa, Italy; E-Mails: (S.G.); (A.G.); (D.C.); (P.M.); (R.C.)
| | - Paolo Malatesta
- Department of Experimental Medicine (DiMES), University of Genoa, 16132 Genoa, Italy; E-Mails: (S.G.); (A.G.); (D.C.); (P.M.); (R.C.)
- IRCCS-AOU San Martino-IST, Largo Rosanna Benzi 10, 16132 Genoa, Italy
| | - Tullio Florio
- Department of Internal Medicine (DIMI), University of Genoa, 16132 Genoa, Italy; E-Mail:
- Centre of Excellence for Biomedical research (CEBR), University of Genoa, 16132 Genoa, Italy
| | - Ranieri Cancedda
- Department of Experimental Medicine (DiMES), University of Genoa, 16132 Genoa, Italy; E-Mails: (S.G.); (A.G.); (D.C.); (P.M.); (R.C.)
- IRCCS-AOU San Martino-IST, Largo Rosanna Benzi 10, 16132 Genoa, Italy
| | - Aldo Pagano
- Department of Experimental Medicine (DiMES), University of Genoa, 16132 Genoa, Italy; E-Mails: (S.G.); (A.G.); (D.C.); (P.M.); (R.C.)
- IRCCS-AOU San Martino-IST, Largo Rosanna Benzi 10, 16132 Genoa, Italy
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +39-010-5737241; Fax: +39-010-5737257
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Abstract
Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Amplification and overexpression of the MYCN proto-oncogene occurs in approximately 20% of neuroblastomas and is associated with advanced stage disease, rapid tumor progression, and poor prognosis. MYCN encodes the transcriptional regulator N-myc, which has been shown to both up- and downregulate many target genes involved in cell cycle, DNA damage, differentiation, and apoptosis in neuroblastoma. During the last years, it has become clear that N-myc also modulates the expression of several classes of noncoding RNAs, in particular microRNAs. MicroRNAs are the most widely studied noncoding RNA molecules in neuroblastoma. They function as negative regulators of gene expression at the posttranscriptional level in diverse cellular processes. Aberrant regulation of miRNA expression has been implicated in the pathogenesis of neuroblastoma. While the N-myc protein is established as an important regulator of several miRNAs involved in neuroblastoma tumorigenesis, tumor suppressor miRNAs have also been documented to repress MYCN expression and inhibit cell proliferation of MYCN-amplified neuroblastoma cells. It is now becoming increasingly evident that N-myc also regulates the expression of long noncoding RNAs such as T-UCRs and ncRAN. This review summarizes the current knowledge about the interplay between N-myc and noncoding RNAs in neuroblastoma and how this contributes to neuroblastoma tumorigenesis.
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Affiliation(s)
- Jochen Buechner
- Department of Pediatrics, University Hospital of North Norway, Tromsø, Norway
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Massone S, Ciarlo E, Vella S, Nizzari M, Florio T, Russo C, Cancedda R, Pagano A. NDM29, a RNA polymerase III-dependent non coding RNA, promotes amyloidogenic processing of APP and amyloid β secretion. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2012; 1823:1170-7. [DOI: 10.1016/j.bbamcr.2012.05.001] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Revised: 03/29/2012] [Accepted: 05/02/2012] [Indexed: 10/28/2022]
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Bhartiya D, Kapoor S, Jalali S, Sati S, Kaushik K, Sachidanandan C, Sivasubbu S, Scaria V. Conceptual approaches for lncRNA drug discovery and future strategies. Expert Opin Drug Discov 2012; 7:503-13. [DOI: 10.1517/17460441.2012.682055] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Mescola A, Vella S, Scotto M, Gavazzo P, Canale C, Diaspro A, Pagano A, Vassalli M. Probing cytoskeleton organisation of neuroblastoma cells with single-cell force spectroscopy. J Mol Recognit 2012; 25:270-7. [DOI: 10.1002/jmr.2173] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Andrea Mescola
- Nanophysics Unit; Italian Institute of Technology; Morego; Genova; Italy
| | - Serena Vella
- Department of Oncology, Biology and Genetics; University of Genova; Genova; Italy
| | - Marco Scotto
- Nanophysics Unit; Italian Institute of Technology; Morego; Genova; Italy
| | - Paola Gavazzo
- Institute of Biophysics; National Research Council; Genova; Italy
| | - Claudio Canale
- Nanophysics Unit; Italian Institute of Technology; Morego; Genova; Italy
| | | | | | - Massimo Vassalli
- Institute of Biophysics; National Research Council; Genova; Italy
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