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Patange V, Ahirwar K, Tripathi T, Tripathi P, Shukla R. Scientific investigation of non-coding RNAs in mitochondrial epigenetic and aging disorders: Current nanoengineered approaches for their therapeutic improvement. Mitochondrion 2025; 80:101979. [PMID: 39505245 DOI: 10.1016/j.mito.2024.101979] [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: 06/25/2024] [Revised: 10/29/2024] [Accepted: 11/02/2024] [Indexed: 11/08/2024]
Abstract
Genetic control is vital for the growth of cells and tissues, and it also helps living things, from single-celled organisms to complex creatures, maintain a stable internal environment. Within cells, structures called mitochondria act like tiny power plants, producing energy and keeping the cell balanced. The two primary categories of RNA are messenger RNA (mRNA) and non-coding RNA (ncRNA). mRNA carries the instructions for building proteins, while ncRNA does various jobs at the RNA level. There are different kinds of ncRNA, each with a specific role. Some help put RNA molecules together correctly, while others modify other RNAs or cut them into smaller pieces. Still others control how much protein is made from a gene. Scientists have recently discovered many more ncRNAs than previously known, and their functions are still being explored. This article analyzes the RNA molecules present within mitochondria, which have a crucial purpose in the operation of mitochondria. We'll also discuss how genes can be turned on and off without changing their DNA code, and how this process might be linked to mitochondrial RNA. Finally, we'll explore how scientists are using engineered particles to silence genes and develop new treatments based on manipulating ncRNA.
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Affiliation(s)
- Vaibhav Patange
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP 226002, India
| | - Kailash Ahirwar
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP 226002, India
| | - Tripti Tripathi
- Department of Physiology, Integral University, Kursi Road, Dashauli, UP 226026, India
| | - Pratima Tripathi
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP 226002, India.
| | - Rahul Shukla
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP 226002, India.
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2
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Gibert MK, Zhang Y, Saha S, Marcinkiewicz P, Dube C, Hudson K, Sun Y, Bednarek S, Chagari B, Sarkar A, Roig-Laboy C, Neace N, Saoud K, Setiady I, Hanif F, Schiff D, Kumar P, Kefas B, Hafner M, Abounader R. A comprehensive analysis of Transcribed Ultra Conserved Regions uncovers important regulatory functions of novel non-coding transcripts in gliomas. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.09.12.557444. [PMID: 38562826 PMCID: PMC10983853 DOI: 10.1101/2023.09.12.557444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Transcribed Ultra-Conserved Regions (TUCRs) represent a severely understudied class of putative non-coding RNAs (ncRNAs) that are 100% conserved across multiple species. We performed the first-ever analysis of TUCRs in glioblastoma (GBM) and low-grade gliomas (LGG). We leveraged large human datasets to identify the genomic locations, chromatin accessibility, transcription, differential expression, correlation with survival, and predicted functions of all 481 TUCRs, and identified TUCRs that are relevant to glioma biology. Of these, we investigated the expression, function, and mechanism of action of the most highly upregulated intergenic TUCR, uc.110, identifying it as a new tumor enhancer. Uc.110 was highly overexpressed in GBM and LGG, where it promoted malignancy and tumor growth. Uc.110 activated the WNT pathway by upregulating the expression of membrane frizzled-related protein (MFRP), by sponging the tumor suppressor microRNA miR-544. This pioneering study shows important roles for TUCRs in gliomas and provides an extensive database and novel methods for future TUCR research.
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3
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Esteller M, Dawson MA, Kadoch C, Rassool FV, Jones PA, Baylin SB. The Epigenetic Hallmarks of Cancer. Cancer Discov 2024; 14:1783-1809. [PMID: 39363741 DOI: 10.1158/2159-8290.cd-24-0296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/08/2024] [Accepted: 06/24/2024] [Indexed: 10/05/2024]
Abstract
Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, in the latest iteration of the cancer hallmarks, "nonmutational epigenetic reprogramming" was newly added. However, epigenetics, much like genetics, is a broad scientific area that deserves further attention due to its multiple roles in cancer initiation, progression, and adaptive nature. Herein, we present a detailed examination of the epigenetic hallmarks affected in human cancer, elucidating the pathways and genes involved, and dissecting the disrupted landscapes for DNA methylation, histone modifications, and chromatin architecture that define the disease. Significance: Cancer is a disease characterized by constant evolution, spanning from its initial premalignant stages to the advanced invasive and disseminated stages. It is a pathology that is able to adapt and survive amidst hostile cellular microenvironments and diverse treatments implemented by medical professionals. The more fixed setup of the genetic structure cannot fully provide transformed cells with the tools to survive but the rapid and plastic nature of epigenetic changes is ready for the task. This review summarizes the epigenetic hallmarks that define the ecological success of cancer cells in our bodies.
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Affiliation(s)
- Manel Esteller
- Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
- Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
- Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
| | - Mark A Dawson
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Centre for Cancer Research, University of Melbourne, Melbourne, Australia
| | - Cigall Kadoch
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Howard Hughes Medical Institute, Chevy Chase, Maryland
| | - Feyruz V Rassool
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Peter A Jones
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
| | - Stephen B Baylin
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
- Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
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4
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Lv H, Qian D, Xu S, Fan G, Qian Q, Cha D, Qian X, Zhou G, Lu B. Modulation of long noncoding RNAs by polyphenols as a novel potential therapeutic approach in lung cancer: A comprehensive review. Phytother Res 2024; 38:3240-3267. [PMID: 38739454 DOI: 10.1002/ptr.8202] [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: 11/13/2023] [Revised: 03/10/2024] [Accepted: 03/19/2024] [Indexed: 05/16/2024]
Abstract
Lung cancer stands as a formidable global health challenge, necessitating innovative therapeutic strategies. Polyphenols, bioactive compounds synthesized by plants, have garnered attention for their diverse health benefits, particularly in combating various cancers, including lung cancer. The advent of whole-genome and transcriptome sequencing technologies has illuminated the pivotal roles of long noncoding RNAs (lncRNAs), operating at epigenetic, transcriptional, and posttranscriptional levels, in cancer progression. This review comprehensively explores the impact of polyphenols on both oncogenic and tumor-suppressive lncRNAs in lung cancer, elucidating on their intricate regulatory mechanisms. The comprehensive examination extends to the potential synergies when combining polyphenols with conventional treatments like chemotherapy, radiation, and immunotherapy. Recognizing the heterogeneity of lung cancer subtypes, the review emphasizes the need for the integration of nanotechnology for optimized polyphenol delivery and personalized therapeutic approaches. In conclusion, we collect the latest research, offering a holistic overview of the evolving landscape of polyphenol-mediated modulation of lncRNAs in lung cancer therapy. The integration of polyphenols and lncRNAs into multidimensional treatment strategies holds promise for enhancing therapeutic efficacy and navigating the challenges associated with lung cancer treatment.
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Affiliation(s)
- Hong Lv
- Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Taicang, China
| | - Dawei Qian
- Department of Thoracic Surgery, Tongling Yi'an District People's Hospital, Tongling, China
| | - Shuhua Xu
- Department of Cardiothoracic Surgery, Dongtai Hospital of Traditional Chinese Medicine, Dongtai, China
| | - Guiqin Fan
- Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Taicang, China
| | - Qiuhong Qian
- Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Taicang, China
| | - Dongsheng Cha
- Department of Thoracic Surgery, Tongling Yi'an District People's Hospital, Tongling, China
| | - Xingjia Qian
- Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Taicang, China
| | - Guoping Zhou
- Department of Cardiothoracic Surgery, Dongtai Hospital of Traditional Chinese Medicine, Dongtai, China
| | - Bing Lu
- Department of Pulmonary and Critical Care Medicine, Taicang TCM Hospital, Taicang, China
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5
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Gibert MK, Zhang Y, Saha S, Marcinkiewicz P, Dube C, Hudson K, Sun Y, Bednarek S, Chagari B, Sarkar A, Roig-Laboy C, Neace N, Saoud K, Setiady I, Hanif F, Schiff D, Kumar P, Kefas B, Hafner M, Abounader R. A first comprehensive analysis of Transcribed Ultra Conserved Regions uncovers important regulatory functions of novel non-coding transcripts in gliomas. RESEARCH SQUARE 2024:rs.3.rs-4164642. [PMID: 38699302 PMCID: PMC11065071 DOI: 10.21203/rs.3.rs-4164642/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
Transcribed Ultra-Conserved Regions (TUCRs) represent a severely understudied class of putative non-coding RNAs (ncRNAs) that are 100% conserved across multiple species. We performed the first-ever analysis of TUCRs in glioblastoma (GBM) and low-grade gliomas (LGG). We leveraged large human datasets to identify the genomic locations, chromatin accessibility, transcription, differential expression, correlation with survival, and predicted functions of all 481 TUCRs, and identified TUCRs that are relevant to glioma biology. Of these, we investigated the expression, function, and mechanism of action of the most highly upregulated intergenic TUCR, uc.110, identifying it as a new oncogene. Uc.110 was highly overexpressed in GBM and LGG, where it promoted malignancy and tumor growth. Uc.110 activated the WNT pathway by upregulating the expression of membrane frizzled-related protein (MFRP), by sponging the tumor suppressor microRNA miR-544. This pioneering study shows important roles for TUCRs in gliomas and provides an extensive database and novel methods for future TUCR research.
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Affiliation(s)
- Myron K Gibert
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Ying Zhang
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Shekhar Saha
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Pawel Marcinkiewicz
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Collin Dube
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Kadie Hudson
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Yunan Sun
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Sylwia Bednarek
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Bilhan Chagari
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Aditya Sarkar
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Christian Roig-Laboy
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Natalie Neace
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Karim Saoud
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Initha Setiady
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - Farina Hanif
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
| | - David Schiff
- University of Virginia Department of Neurology, Charlottesville, VA, 22908, USA
| | - Pankaj Kumar
- University of Virginia Department of Public Health Sciences and Bioinformatics Core, Charlottesville, VA, 22908, USA
| | | | | | - Roger Abounader
- University of Virginia Department of Microbiology, Immunology & Cancer Biology, Charlottesville, VA, 22908, USA
- University of Virginia Department of Neurology, Charlottesville, VA, 22908, USA
- University of Virginia Department of Cancer Center, Charlottesville, VA, 22908, USA
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Hussain MS, Afzal O, Gupta G, Altamimi ASA, Almalki WH, Alzarea SI, Kazmi I, Fuloria NK, Sekar M, Meenakshi DU, Thangavelu L, Sharma A. Long non-coding RNAs in lung cancer: Unraveling the molecular modulators of MAPK signaling. Pathol Res Pract 2023; 249:154738. [PMID: 37595448 DOI: 10.1016/j.prp.2023.154738] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/02/2023] [Accepted: 08/03/2023] [Indexed: 08/20/2023]
Abstract
Lung cancer (LC) continues to pose a significant global medical burden, necessitating a comprehensive understanding of its molecular foundations to establish effective treatment strategies. The mitogen-activated protein kinase (MAPK) signaling system has been scientifically associated with LC growth; however, the intricate regulatory mechanisms governing this system remain unknown. Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of diverse cellular activities, including cancer growth. LncRNAs have been implicated in LC, which can function as oncogenes or tumor suppressors, and their dysregulation has been linked to cancer cell death, metastasis, spread, and proliferation. Due to their involvement in critical pathophysiological processes, lncRNAs are gaining attention as potential candidates for anti-cancer treatments. This article aims to elucidate the regulatory role of lncRNAs in MAPK signaling in LC. We provide a comprehensive review of the key components of the MAPK pathway and their relevance in LC, focusing on aberrant signaling processes associated with disease progression. By examining recent research and experimental findings, this article examines the molecular mechanisms through which lncRNAs influence MAPK signaling in lung cancer, ultimately contributing to tumor development.
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Affiliation(s)
- Md Sadique Hussain
- School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, 302017 Jaipur, Rajasthan, India
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur, India; Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India; School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | | | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | | | - Mahendran Sekar
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Subang Jaya 47500, Selangor, Malaysia
| | | | - Lakshmi Thangavelu
- Center for Global Health Research , Saveetha Medical College , Saveetha Institute of Medical and Technical Sciences, Saveetha University, India
| | - Ajay Sharma
- Delhi Pharmaceutical Science and Research University, Pushp Vihar Sector-3, MB Road, New Delhi 110017, India.
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Khalafiyan A, Emadi-Baygi M, Wolfien M, Salehzadeh-Yazdi A, Nikpour P. Construction of a three-component regulatory network of transcribed ultraconserved regions for the identification of prognostic biomarkers in gastric cancer. J Cell Biochem 2023; 124:396-408. [PMID: 36748954 DOI: 10.1002/jcb.30373] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 01/04/2023] [Accepted: 01/09/2023] [Indexed: 02/08/2023]
Abstract
Altered expression and functional roles of the transcribed ultraconserved regions (T-UCRs), as genomic sequences with 100% conservation between the genomes of human, mouse, and rat, in the pathophysiology of neoplasms has already been investigated. Nevertheless, the relevance of the functions for T-UCRs in gastric cancer (GC) is still the subject of inquiry. In the current study, we first used a genome-wide profiling approach to analyze the expression of T-UCRs in GC patients. Then, we constructed a three-component regulatory network and investigated potential diagnostic and prognostic values of the T-UCRs. The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) dataset was used as a resource for the RNA-sequencing data. FeatureCounts was utilized to quantify the number of reads mapped to each T-UCR. Differential expression analysis was then conducted using DESeq2. In the following, interactions between T-UCRs, microRNAs (miRNAs), and messenger RNAs (mRNAs) were combined into a three-component network. Enrichment analyses were performed and a protein-protein interaction (PPI) network was constructed. The R Survival package was utilized to identify survival-related significantly differentially expressed T-UCRs (DET-UCRs). Using an in-house cohort of GC tissues, expression of two DET-UCRs was furthermore experimentally verified. Our results showed that several T-UCRs were dysregulated in TCGA-STAD tumoral samples compared to nontumoral counterparts. The three-component network was constructed which composed of DET-UCRs, miRNAs, and mRNAs nodes. Functional enrichment and PPI network analyses revealed important enriched signaling pathways and gene ontologies such as "pathway in cancer" and regulation of cell proliferation and apoptosis. Five T-UCRs were significantly correlated with the overall survival of GC patients. While no expression of uc.232 was observed in our in-house cohort of GC tissues, uc.343 showed an increased expression, although not statistically significant, in gastric tumoral tissues. The constructed three-component regulatory network of T-UCRs in GC presents a comprehensive understanding of the underlying gene expression regulation processes involved in tumor development and can serve as a basis to investigate potential prognostic biomarkers and therapeutic targets.
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Affiliation(s)
- Anis Khalafiyan
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Modjtaba Emadi-Baygi
- Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran
| | - Markus Wolfien
- Department of System Biology and Bioinformatics, University of Rostock, Rostock, Germany
- Center for Medical Informatics, Dresden, Germany
| | - Ali Salehzadeh-Yazdi
- Department of Life Sciences and Chemistry, Jacobs University Bremen, Bremen, Germany
| | - Parvaneh Nikpour
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Aprile M, Costa V, Cimmino A, Calin GA. Emerging role of oncogenic long noncoding RNA as cancer biomarkers. Int J Cancer 2023; 152:822-834. [PMID: 36082440 DOI: 10.1002/ijc.34282] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 02/05/2023]
Abstract
The view of long noncoding RNAs as nonfunctional "garbage" has been definitely outdated by the large body of evidence indicating this class of ncRNAs as "golden junk", especially in precision oncology. Indeed, in light of their oncogenic role and the higher expression in multiple cancer types compared with paired adjacent tissues, the clinical interest for lncRNAs as diagnostic and/or prognostic biomarkers has been rapidly increasing. The emergence of large-scale sequencing technologies, their subsequent diffusion even in small research and clinical centers, the technological advances for the detection of low-copy lncRNAs in body fluids, coupled to the huge reduction of operating costs, have nowadays made possible to rapidly and comprehensively profile them in multiple tumors and large cohorts. In this review, we first summarize some relevant data about the oncogenic role of well-studied lncRNAs having a clinical relevance. Then, we focus on the description of their potential use as diagnostic/prognostic biomarkers, including an updated overview about licensed patents or clinical trials on lncRNAs in oncology.
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Affiliation(s)
- Marianna Aprile
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | - Valerio Costa
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | - Amelia Cimmino
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council (CNR), Naples, Italy
| | - George Adrian Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Zheng J, Dou R, Zhang X, Zhong B, Fang C, Xu Q, Di Z, Huang S, Lin Z, Song J, Wang S, Xiong B. LINC00543 promotes colorectal cancer metastasis by driving EMT and inducing the M2 polarization of tumor associated macrophages. J Transl Med 2023; 21:153. [PMID: 36841801 PMCID: PMC9960415 DOI: 10.1186/s12967-023-04009-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 02/16/2023] [Indexed: 02/27/2023] Open
Abstract
BACKGROUND The interaction between the tumor-microenvironment (TME) and the cancer cells has emerged as a key player in colorectal cancer (CRC) metastasis. A small proportion of CRC cells which undergo epithelial-mesenchymal transition (EMT) facilitate the reshaping of the TME by regulating various cellular ingredients. METHODS Immunohistochemical analysis, RNA immunoprecipitation (RIP), RNA Antisense Purification (RAP), dual luciferase assays were conducted to investigate the biological function and regulation of LINC00543 in CRC. A series in vitro and in vivo experiments were used to clarify the role of LINC00543 in CRC metastasis. RESULTS Here we found that the long non-coding RNA LINC00543, was overexpressed in colorectal cancer tissues, which correlated with advanced TNM stage and poorer prognosis of CRC patients. The overexpression of LINC00543 promoted tumorigenesis and metastasis of CRC cells by enhancing EMT and remodeling the TME. Mechanistically, LINC00543 blocked the transport of pre-miR-506-3p across the nuclear-cytoplasmic transporter XPO5, thereby reducing the production of mature miR-506-3p, resulting in the increase in the expression of FOXQ1 and induction of EMT. In addition, upregulation of FOXQ1 induced the expression of CCL2 that accelerated the recruitment of macrophages and their M2 polarization. CONCLUSIONS Our study showed that LINC00543 enhanced EMT of CRC cells through the pre-miR-506-3p/FOXQ1 axis. This resulted in the upregulation of CCL2, leading to macrophages recruitment and M2 polarization, and ultimately stimulating the progression of CRC.
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Affiliation(s)
- Jinsen Zheng
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Rongzhang Dou
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Xinyao Zhang
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Bo Zhong
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.49470.3e0000 0001 2331 6153Medical Research Institute of Wuhan University, Wuhan University, Wuhan, China
| | - Chenggang Fang
- grid.49470.3e0000 0001 2331 6153Medical Research Institute of Wuhan University, Wuhan University, Wuhan, China
| | - Qian Xu
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Ziyang Di
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Sihao Huang
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Zaihuan Lin
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Jialin Song
- grid.413247.70000 0004 1808 0969Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413247.70000 0004 1808 0969Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071 Hubei China ,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071 Hubei China ,grid.413606.60000 0004 1758 2326Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071 Hubei China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, Hubei, China. .,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, Hubei, China. .,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071, Hubei, China. .,Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071, Hubei, China.
| | - Bin Xiong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, Hubei, China. .,Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, Hubei, China. .,Hubei Key Laboratory of Tumor Biological Behaviors, Donghu Road 169, Wuhan, 430071, Hubei, China. .,Hubei Cancer Clinical Study Center, Donghu Road 169, Wuhan, 430071, Hubei, China.
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10
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de Oliveira JC. Transcribed Ultraconserved Regions: New regulators in cancer signaling and potential biomarkers. Genet Mol Biol 2023; 46:e20220125. [PMID: 36622962 PMCID: PMC9829027 DOI: 10.1590/1678-4685-gmb-2022-0125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 11/06/2022] [Indexed: 01/11/2023] Open
Abstract
The ultraconserved regions (UCRs) are 481 genomic elements, longer than 200 bp, 100% conserved in human, mouse, and rat genomes. Usually, coding regions are more conserved, but more than 80% of UCRs are either intergenic or intronic, and many of them produce long non-coding RNAs (lncRNAs). Recently, the deregulated expression of transcribed UCRs (T-UCRs) has been associated with pathological conditions. But, differently from many lncRNAs with recognized crucial effects on malignant cell processes, the role of T-UCRs in the control of cancer cell networks is understudied. Furthermore, the potential utility of these molecules as molecular markers is not clear. Based on this information, the present review aims to organize information about T-UCRs with either oncogenic or tumor suppressor role associated with cancer cell signaling, and better describe T-UCRs with potential utility as prognosis markers. Out of 481 T-UCRs, 297 present differential expression in cancer samples, 23 molecules are associated with tumorigenesis processes, and 12 have more clear potential utility as prognosis markers. In conclusion, T-UCRs are deregulated in several tumor types, highlighted as important molecules in cancer networks, and with potential utility as prognosis markers, although further investigation for translational medicine is still needed.
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11
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Yang Z, Xu F, Teschendorff AE, Zhao Y, Yao L, Li J, He Y. Insights into the role of long non-coding RNAs in DNA methylation mediated transcriptional regulation. Front Mol Biosci 2022; 9:1067406. [PMID: 36533073 PMCID: PMC9755597 DOI: 10.3389/fmolb.2022.1067406] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 11/17/2022] [Indexed: 09/12/2023] Open
Abstract
DNA methylation is one of the most important epigenetic mechanisms that governing regulation of gene expression, aberrant DNA methylation patterns are strongly associated with human malignancies. Long non-coding RNAs (lncRNAs) have being discovered as a significant regulator on gene expression at the epigenetic level. Emerging evidences have indicated the intricate regulatory effects between lncRNAs and DNA methylation. On one hand, transcription of lncRNAs are controlled by the promoter methylation, which is similar to protein coding genes, on the other hand, lncRNA could interact with enzymes involved in DNA methylation to affect the methylation pattern of downstream genes, thus regulating their expression. In addition, circular RNAs (circRNAs) being an important class of noncoding RNA are also found to participate in this complex regulatory network. In this review, we summarize recent research progress on this crosstalk between lncRNA, circRNA, and DNA methylation as well as their potential functions in complex diseases including cancer. This work reveals a hidden layer for gene transcriptional regulation and enhances our understanding for epigenetics regarding detailed mechanisms on lncRNA regulatory function in human cancers.
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Affiliation(s)
- Zhen Yang
- Center for Medical Research and Innovation of Pudong Hospital, The Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Feng Xu
- Center for Medical Research and Innovation of Pudong Hospital, The Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Andrew E. Teschendorff
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yi Zhao
- Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Lei Yao
- Experiment Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Jian Li
- Center for Medical Research and Innovation of Pudong Hospital, The Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yungang He
- Center for Medical Research and Innovation of Pudong Hospital, The Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
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12
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Yu TX, Kalakonda S, Liu X, Han N, Chung HK, Xiao L, Rao JN, He TC, Raufman JP, Wang JY. Long noncoding RNA uc.230/CUG-binding protein 1 axis sustains intestinal epithelial homeostasis and response to tissue injury. JCI Insight 2022; 7:156612. [PMID: 36214222 PMCID: PMC9675575 DOI: 10.1172/jci.insight.156612] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 08/31/2022] [Indexed: 01/16/2023] Open
Abstract
Intestinal epithelial integrity is commonly disrupted in patients with critical disorders, but the exact underlying mechanisms are unclear. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control different cell functions and are involved in pathologies. Here, we investigated the role of T-UCRs in intestinal epithelial homeostasis and identified T-UCR uc.230 as a major regulator of epithelial renewal, apoptosis, and barrier function. Compared with controls, intestinal mucosal tissues from patients with ulcerative colitis and from mice with colitis or fasted for 48 hours had increased levels of uc.230. Silencing uc.230 inhibited the growth of intestinal epithelial cells (IECs) and organoids and caused epithelial barrier dysfunction. Silencing uc.230 also increased IEC vulnerability to apoptosis, whereas increasing uc.230 levels protected IECs against cell death. In mice with colitis, reduced uc.230 levels enhanced mucosal inflammatory injury and delayed recovery. Mechanistic studies revealed that uc.230 increased CUG-binding protein 1 (CUGBP1) by acting as a natural decoy RNA for miR-503, which interacts with Cugbp1 mRNA and represses its translation. These findings indicate that uc.230 sustains intestinal mucosal homeostasis by promoting epithelial renewal and barrier function and that it protects IECs against apoptosis by serving as a natural sponge for miR-503, thereby preserving CUGBP1 expression.
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Affiliation(s)
- Ting-Xi Yu
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Sudhakar Kalakonda
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Xiangzheng Liu
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Naomi Han
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Hee K. Chung
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Lan Xiao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, USA
| | - Jaladanki N. Rao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, USA
| | - Tong-Chuan He
- Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois, USA
| | - Jean-Pierre Raufman
- Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, USA.,Department of Medicine and
| | - Jian-Ying Wang
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, USA.,Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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13
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Uddin MDM, Nguyen NQH, Yu B, Brody JA, Pampana A, Nakao T, Fornage M, Bressler J, Sotoodehnia N, Weinstock JS, Honigberg MC, Nachun D, Bhattacharya R, Griffin GK, Chander V, Gibbs RA, Rotter JI, Liu C, Baccarelli AA, Chasman DI, Whitsel EA, Kiel DP, Murabito JM, Boerwinkle E, Ebert BL, Jaiswal S, Floyd JS, Bick AG, Ballantyne CM, Psaty BM, Natarajan P, Conneely KN. Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease. Nat Commun 2022; 13:5350. [PMID: 36097025 PMCID: PMC9468335 DOI: 10.1038/s41467-022-33093-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 09/01/2022] [Indexed: 12/15/2022] Open
Abstract
Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.
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Affiliation(s)
- M D Mesbah Uddin
- Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Ngoc Quynh H Nguyen
- Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Bing Yu
- Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Jennifer A Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA
| | - Akhil Pampana
- Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
| | - Tetsushi Nakao
- Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Myriam Fornage
- Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
- Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Jan Bressler
- Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
- Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA
| | - Joshua S Weinstock
- Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA
| | - Michael C Honigberg
- Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Daniel Nachun
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Romit Bhattacharya
- Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Gabriel K Griffin
- Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Varuna Chander
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Genetics and Genomics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Richard A Gibbs
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Genetics and Genomics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA
| | - Chunyu Liu
- Department of Biostatistics, School of Public Health, Boston University, Boston, MA, 02118, USA
- Framingham Heart Study, Boston University and NHLBI/NIH, Framingham, MA, 01702, USA
| | - Andrea A Baccarelli
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA
| | - Daniel I Chasman
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA
| | - Eric A Whitsel
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27516, USA
- Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, 27516, USA
| | - Douglas P Kiel
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
- Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, 02131, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
| | - Joanne M Murabito
- Framingham Heart Study, Boston University and NHLBI/NIH, Framingham, MA, 01702, USA
- Department of Medicine, Section of General Internal Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA, 02118, USA
| | - Eric Boerwinkle
- Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
- Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Benjamin L Ebert
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Howard Hughes Medical Institute, Boston, MA, 20815, USA
| | - Siddhartha Jaiswal
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - James S Floyd
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA
- Department of Epidemiology, University of Washington, Seattle, WA, 98101, USA
| | - Alexander G Bick
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Bruce M Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA
- Department of Epidemiology, University of Washington, Seattle, WA, 98101, USA
- Department of Health Systems and Population Health, University of Washington, Seattle, WA, 98101, USA
| | - Pradeep Natarajan
- Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
| | - Karen N Conneely
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
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14
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Li N, Zeng A, Wang Q, Chen M, Zhu S, Song L. Regulatory function of DNA methylation mediated lncRNAs in gastric cancer. Cancer Cell Int 2022; 22:227. [PMID: 35810299 PMCID: PMC9270757 DOI: 10.1186/s12935-022-02648-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 06/28/2022] [Indexed: 12/31/2022] Open
Abstract
As one of the most common malignancies worldwide, gastric cancer contributes to cancer death with a high mortality rate partly responsible for its out-of-control progression as well as limited diagnosis. DNA methylation, one of the epigenetic events, plays an essential role in the carcinogenesis of many cancers, including gastric cancer. Long non-coding RNAs have emerged as the significant factors in the cancer progression functioned as the oncogene genes, the suppressor genes and regulators of signaling pathways over the decade. Intriguingly, increasing reports, recently, have claimed that abnormal DNA methylation regulates the expression of lncRNAs as tumor suppressor genes in gastric cancer and lncRNAs as regulators could exert the critical influence on tumor progression through acting on DNA methylation of other cancer-related genes. In this review, we summarized the DNA methylation-associated lncRNAs in gastric cancer which play a large impact on tumor progression, such as proliferation, invasion, metastasis and so on. Furthermore, the underlying molecular mechanism and signaling pathway might be developed as key points of gastric cancer range from diagnosis to prognosis and treatment in the future.
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Affiliation(s)
- Nan Li
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Anqi Zeng
- Institute of Translational Pharmacology and Clinical Application, Sichuan Academy of Chinese Medical Science, Chengdu, Sichuan, 610041, People's Republic of China
| | - Qian Wang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Maohua Chen
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Shaomi Zhu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China.
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China.
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15
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Gao SS, Zhang ZK, Wang XB, Ma Y, Yin GQ, Guo XB. Role of transcribed ultraconserved regions in gastric cancer and therapeutic perspectives. World J Gastroenterol 2022; 28:2900-2909. [PMID: 35978878 PMCID: PMC9280734 DOI: 10.3748/wjg.v28.i25.2900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/08/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the fourth leading cause of cancer-related death. The occurrence and development of GC is a complex process involving multiple biological mechanisms. Although traditional regulation modulates molecular functions related to the occurrence and development of GC, the comprehensive mechanisms remain unclear. Ultraconserved region (UCR) refers to a genome sequence that is completely conserved in the homologous regions of the human, rat and mouse genomes, with 100% identity, without any insertions or deletions, and often located in fragile sites and tumour-related genes. The transcribed UCR (T-UCR) is transcribed from the UCR and is a new type of long noncoding RNA. Recent studies have found that the expression level of T-UCRs changes during the occurrence and development of GC, revealing a new mechanism underlying GC. Therefore, this article aims to review the relevant research on T-UCRs in GC, as well as the function of T-UCRs and their regulatory role in the occurrence and development of GC, to provide new strategies for GC diagnosis and treatment.
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Affiliation(s)
- Shen-Shuo Gao
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
| | - Zhi-Kai Zhang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
| | - Xu-Bin Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Yan Ma
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Guo-Qing Yin
- Department of Anus and Intestine Surgery, Qingzhou Hospital Affiliated to Shandong First Medical University, Qingzhou 262500, Shandong Province, China
| | - Xiao-Bo Guo
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
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16
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Gibert MK, Sarkar A, Chagari B, Roig-Laboy C, Saha S, Bednarek S, Kefas B, Hanif F, Hudson K, Dube C, Zhang Y, Abounader R. Transcribed Ultraconserved Regions in Cancer. Cells 2022; 11:1684. [PMID: 35626721 PMCID: PMC9139194 DOI: 10.3390/cells11101684] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/11/2022] [Accepted: 05/17/2022] [Indexed: 11/25/2022] Open
Abstract
Transcribed ultraconserved regions are putative lncRNA molecules that are transcribed from DNA that is 100% conserved in human, mouse, and rat genomes. This is notable, as lncRNAs are typically poorly conserved. TUCRs remain very understudied in many diseases, including cancer. In this review, we summarize the current literature on TUCRs in cancer with respect to expression deregulation, functional roles, mechanisms of action, and clinical perspectives.
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Affiliation(s)
- Myron K. Gibert
- Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; (M.K.G.J.); (A.S.); (B.C.); (C.R.-L.); (S.S.); (S.B.); (B.K.); (F.H.); (K.H.); (C.D.); (Y.Z.)
| | - Aditya Sarkar
- Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; (M.K.G.J.); (A.S.); (B.C.); (C.R.-L.); (S.S.); (S.B.); (B.K.); (F.H.); (K.H.); (C.D.); (Y.Z.)
| | - Bilhan Chagari
- Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; (M.K.G.J.); (A.S.); (B.C.); (C.R.-L.); (S.S.); (S.B.); (B.K.); (F.H.); (K.H.); (C.D.); (Y.Z.)
| | - Christian Roig-Laboy
- Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; (M.K.G.J.); (A.S.); (B.C.); (C.R.-L.); (S.S.); (S.B.); (B.K.); (F.H.); (K.H.); (C.D.); (Y.Z.)
| | - Shekhar Saha
- Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; (M.K.G.J.); (A.S.); (B.C.); (C.R.-L.); (S.S.); (S.B.); (B.K.); (F.H.); (K.H.); (C.D.); (Y.Z.)
| | - Sylwia Bednarek
- Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; (M.K.G.J.); (A.S.); (B.C.); (C.R.-L.); (S.S.); (S.B.); (B.K.); (F.H.); (K.H.); (C.D.); (Y.Z.)
| | - Benjamin Kefas
- Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; (M.K.G.J.); (A.S.); (B.C.); (C.R.-L.); (S.S.); (S.B.); (B.K.); (F.H.); (K.H.); (C.D.); (Y.Z.)
| | - Farina Hanif
- Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; (M.K.G.J.); (A.S.); (B.C.); (C.R.-L.); (S.S.); (S.B.); (B.K.); (F.H.); (K.H.); (C.D.); (Y.Z.)
| | - Kadie Hudson
- Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; (M.K.G.J.); (A.S.); (B.C.); (C.R.-L.); (S.S.); (S.B.); (B.K.); (F.H.); (K.H.); (C.D.); (Y.Z.)
| | - Collin Dube
- Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; (M.K.G.J.); (A.S.); (B.C.); (C.R.-L.); (S.S.); (S.B.); (B.K.); (F.H.); (K.H.); (C.D.); (Y.Z.)
| | - Ying Zhang
- Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; (M.K.G.J.); (A.S.); (B.C.); (C.R.-L.); (S.S.); (S.B.); (B.K.); (F.H.); (K.H.); (C.D.); (Y.Z.)
| | - Roger Abounader
- Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; (M.K.G.J.); (A.S.); (B.C.); (C.R.-L.); (S.S.); (S.B.); (B.K.); (F.H.); (K.H.); (C.D.); (Y.Z.)
- Department of Neurology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
- NCI Designated Comprehensive Cancer Center, University of Virginia, Charlottesville, VA 22908, USA
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17
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Yoon JH, Byun H, Ivan C, Calin GA, Jung D, Lee S. lncRNAs UC.145 and PRKG1-AS1 Determine the Functional Output of DKK1 in Regulating the Wnt Signaling Pathway in Gastric Cancer. Cancers (Basel) 2022; 14:2369. [PMID: 35625973 PMCID: PMC9140071 DOI: 10.3390/cancers14102369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/06/2022] [Accepted: 05/09/2022] [Indexed: 11/16/2022] Open
Abstract
DKK1 inhibits the canonical Wnt signaling pathway that is known to be involved in various cancers. However, whether DKK1 acts as an oncogene or tumor suppressor gene remains controversial. Furthermore, the DKK1-regulating mechanism in gastric cancer has not yet been defined. The aim of this study was to explore whether the ultraconserved region UC.145 regulates epigenetic changes in DKK1 expression in gastric cancer. Microarray analysis revealed that UC.145 exhibited the highest binding affinity to EZH2, a histone methyltransferase. The effects of UC.145 inactivation were assessed in gastric cancer cell lines using siRNA. The results indicated that UC.145 triggers DKK1 methylation via interaction with EZH2 and is involved in the canonical Wnt signaling pathway. Additionally, interaction between UC.145 and another long non-coding RNA adjacent to DKK1, PRKG1-AS1, induced a synergistic effect on Wnt signaling. The regulation of these three genes was closely associated with patient overall survival. Inactivation of UC.145 induced apoptosis and inhibited the growth and migratory, invasive, and colony-forming abilities of gastric cancer cells. The study findings provide insights into Wnt signaling in gastric cancer and support UC.145 as a potential novel predictive biomarker for the disease.
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Affiliation(s)
- Jung-ho Yoon
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Severance Hospital, Seoul 03722, Korea; (J.-h.Y.); (H.B.)
| | - Hyojoo Byun
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Severance Hospital, Seoul 03722, Korea; (J.-h.Y.); (H.B.)
| | - Cristina Ivan
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - George A. Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Dahyun Jung
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Severance Hospital, Seoul 03722, Korea; (J.-h.Y.); (H.B.)
| | - Sangkil Lee
- Division of Gastroenterology, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Severance Hospital, Seoul 03722, Korea; (J.-h.Y.); (H.B.)
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18
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Bozgeyik I. The dark matter of the human genome and its role in human cancers. Gene 2022; 811:146084. [PMID: 34843880 DOI: 10.1016/j.gene.2021.146084] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/06/2021] [Accepted: 11/23/2021] [Indexed: 12/26/2022]
Abstract
The transcribed ultra-conserved regions (T-UCRs) are a novel family of non-coding RNAs which are absolutely conserved (100%) across orthologous regions of the human, mouse, and rat genomes. T-UCRs represent a small portion of the human genome that is likely to be functional but does not code for proteins and is referred to as the "dark matter" of the human genome. Although T-UCRs are ubiquitously expressed, tissue- and disease-specific expression of T-UCRs have also been observed. Accumulating evidence suggests that T-UCRs are differentially expressed and involved in the malignant transformation of human tumors through various genetic and epigenetic regulatory mechanisms. Therefore, T-UCRs are novel candidate predisposing biomarkers for cancer development. T-UCRs have shown to drive malignant transformation of human cancers through regulating non-coding RNAs and/or protein coding genes. However, the functions and fate of most T-UCRs remain mysterious. Here, we review and highlight the current knowledge on these ultra-conserved elements in the formation and progression of human cancers.
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Affiliation(s)
- Ibrahim Bozgeyik
- Department of Medical Biology, Faculty of Medicine, Adiyaman University, Adiyaman, Turkey.
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19
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Noble AJ, Purcell RV, Adams AT, Lam YK, Ring PM, Anderson JR, Osborne AJ. A Final Frontier in Environment-Genome Interactions? Integrated, Multi-Omic Approaches to Predictions of Non-Communicable Disease Risk. Front Genet 2022; 13:831866. [PMID: 35211161 PMCID: PMC8861380 DOI: 10.3389/fgene.2022.831866] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/19/2022] [Indexed: 12/26/2022] Open
Abstract
Epidemiological and associative research from humans and animals identifies correlations between the environment and health impacts. The environment-health inter-relationship is effected through an individual's underlying genetic variation and mediated by mechanisms that include the changes to gene regulation that are associated with the diversity of phenotypes we exhibit. However, the causal relationships have yet to be established, in part because the associations are reduced to individual interactions and the combinatorial effects are rarely studied. This problem is exacerbated by the fact that our genomes are highly dynamic; they integrate information across multiple levels (from linear sequence, to structural organisation, to temporal variation) each of which is open to and responds to environmental influence. To unravel the complexities of the genomic basis of human disease, and in particular non-communicable diseases that are also influenced by the environment (e.g., obesity, type II diabetes, cancer, multiple sclerosis, some neurodegenerative diseases, inflammatory bowel disease, rheumatoid arthritis) it is imperative that we fully integrate multiple layers of genomic data. Here we review current progress in integrated genomic data analysis, and discuss cases where data integration would lead to significant advances in our ability to predict how the environment may impact on our health. We also outline limitations which should form the basis of future research questions. In so doing, this review will lay the foundations for future research into the impact of the environment on our health.
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Affiliation(s)
- Alexandra J. Noble
- Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, United Kingdom
| | - Rachel V. Purcell
- Department of Surgery, University of Otago Christchurch, Christchurch, New Zealand
| | - Alex T. Adams
- Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, United Kingdom
| | - Ying K. Lam
- Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, United Kingdom
| | - Paulina M. Ring
- School of Biological Sciences, University of Canterbury, Christchurch, New Zealand
| | - Jessica R. Anderson
- School of Biological Sciences, University of Canterbury, Christchurch, New Zealand
| | - Amy J. Osborne
- School of Biological Sciences, University of Canterbury, Christchurch, New Zealand
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20
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Shi X, Huang X, Chen R, Li Y, Xu Y, Zhang W, Zhu Q, Zha X, Wang J. The transcribed ultraconserved element uc.51 promotes the proliferation and metastasis of breast cancer by stabilizing NONO. Clin Exp Metastasis 2021; 38:551-571. [PMID: 34714466 DOI: 10.1007/s10585-021-10128-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/15/2021] [Indexed: 12/22/2022]
Abstract
Long noncoding RNAs have recently emerged as significant contributors to cancers, including breast cancer (BC). One class of long noncoding RNAs called transcribed ultraconserved regions (T-UCRs) is highly conserved in many species and closely related to diverse physiological and pathological processes. However, the function of T-UCRs in BC remains largely unclear. In this study, we identified uc.51, a T-UCR that is overexpressed in both BC tissues and cell lines and is correlated with larger tumor size. Loss- and gain-of-function assays were performed in vitro and demonstrated that uc.51 promotes the proliferation, migration, and invasion of BC cells. Mechanistically, non-POU domain-containing octamer-binding protein (NONO) was found to physically interact with uc.51 by RNA pulldown followed by mass spectrometry. This interaction was further verified by RNA immunoprecipitation. Moreover, uc.51 positively regulated the expression of NONO, maintained its stability through the ubiquitin-proteasome system, and activated the phosphorylation of CREB. Rescue experiments demonstrated that NONO overexpression compensated for the attenuated influence on BC progression resulting from downregulation of uc.51, indicating that NONO functions downstream of uc.51. In vivo functional experiments also revealed a positive correlation between uc.51 expression and tumor size. Ki-67 and NONO levels in the lv-uc.51-shRNA group were decreased compared with those in the lv-con-shRNA group, according to the immunohistochemical staining results, and a decreased incidence of distant metastasis was observed in the lv-uc.51-shRNA group in the xenograft model. Collectively, our results reveal a substantial role for the uc.51-NONO axis in BC progression and indicate that the uc.51-NONO axis has potential to be a therapeutic target for BC.
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Affiliation(s)
- Xiaoqing Shi
- Department of Breast Disease, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210000, China
| | - Xiaofeng Huang
- Department of Breast Disease, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210000, China
| | - Rui Chen
- Department of Breast Disease, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210000, China
| | - Yan Li
- Department of Breast Disease, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210000, China
| | - Yinggang Xu
- Department of Breast Disease, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210000, China
| | - Weiwei Zhang
- Department of Breast Disease, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210000, China
| | - Qiannan Zhu
- Department of Breast Disease, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210000, China
| | - Xiaoming Zha
- Department of Breast Disease, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210000, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210000, China.
| | - Jue Wang
- Department of Breast Disease, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210000, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210000, China.
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21
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EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors. Int J Mol Sci 2021; 22:ijms222011292. [PMID: 34681949 PMCID: PMC8539543 DOI: 10.3390/ijms222011292] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 10/09/2021] [Indexed: 02/08/2023] Open
Abstract
Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors.
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22
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Soler M, Davalos V, Sánchez-Castillo A, Mora-Martinez C, Setién F, Siqueira E, Castro de Moura M, Esteller M, Guil S. The transcribed ultraconserved region uc.160+ enhances processing and A-to-I editing of the miR-376 cluster: hypermethylation improves glioma prognosis. Mol Oncol 2021; 16:648-664. [PMID: 34665919 PMCID: PMC8807354 DOI: 10.1002/1878-0261.13121] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 10/01/2021] [Accepted: 10/15/2021] [Indexed: 11/11/2022] Open
Abstract
Transcribed ultraconserved regions (T‐UCRs) are noncoding RNAs derived from DNA sequences that are entirely conserved across species. Their expression is altered in many tumor types, and, although a role for T‐UCRs as regulators of gene expression has been proposed, their functions remain largely unknown. Herein, we describe the epigenetic silencing of the uc.160+ T‐UCR in gliomas and mechanistically define a novel RNA–RNA regulatory network in which uc.160+ modulates the biogenesis of several members of the miR‐376 cluster. This includes the positive regulation of primary microRNA (pri‐miRNA) cleavage and an enhanced A‐to‐I editing on its mature sequence. As a consequence, the expression of uc.160+ affects the downstream, miR‐376‐regulated genes, including the transcriptional coregulators RING1 and YY1‐binding protein (RYBP) and forkhead box P2 (FOXP2). Finally, we elucidate the clinical impact of our findings, showing that hypermethylation of the uc.160+ CpG island is an independent prognostic factor associated with better overall survival in lower‐grade gliomas, highlighting the importance of T‐UCRs in cancer pathophysiology.
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Affiliation(s)
- Marta Soler
- Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
| | - Veronica Davalos
- Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
| | - Anaís Sánchez-Castillo
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, The Netherlands
| | - Carlos Mora-Martinez
- Centre of Excellence in Experimental and Computational Developmental Biology, Institute of Biotechnology, University of Helsinki, Finland
| | - Fernando Setién
- Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
| | - Edilene Siqueira
- Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain.,Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq), Brasilia, Brazil
| | | | - Manel Esteller
- Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain.,Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.,Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Spain
| | - Sonia Guil
- Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain.,Germans Trias i Pujol Health Science Research Institute, Barcelona, Spain
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23
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Abballe L, Miele E. Epigenetic modulators for brain cancer stem cells: Implications for anticancer treatment. World J Stem Cells 2021; 13:670-684. [PMID: 34367473 PMCID: PMC8316861 DOI: 10.4252/wjsc.v13.i7.670] [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: 03/13/2021] [Revised: 04/26/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Primary malignant brain tumors are a major cause of morbidity and mortality in both adults and children, with a dismal prognosis despite multimodal therapeutic approaches. In the last years, a specific subpopulation of cells within the tumor bulk, named cancer stem cells (CSCs) or tumor-initiating cells, have been identified in brain tumors as responsible for cancer growth and disease progression. Stemness features of tumor cells strongly affect treatment response, leading to the escape from conventional therapeutic approaches and subsequently causing tumor relapse. Recent research efforts have focused at identifying new therapeutic strategies capable of specifically targeting CSCs in cancers by taking into consideration their complex nature. Aberrant epigenetic machinery plays a key role in the genesis and progression of brain tumors as well as inducing CSC reprogramming and preserving CSC characteristics. Thus, reverting the cancer epigenome can be considered a promising therapeutic strategy. Three main epigenetic mechanisms have been described: DNA methylation, histone modifications, and non-coding RNA, particularly microRNAs. Each of these mechanisms has been proven to be targetable by chemical compounds, known as epigenetic-based drugs or epidrugs, that specifically target epigenetic marks. We review here recent advances in the study of epigenetic modulators promoting and sustaining brain tumor stem-like cells. We focus on their potential role in cancer therapy.
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Affiliation(s)
- Luana Abballe
- Department of Pediatric Hematology/Oncology and Cellular and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome 00165, Italy
| | - Evelina Miele
- Department of Pediatric Hematology/Oncology and Cellular and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome 00165, Italy.
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24
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Torcivia JP, Mazumder R. Scanning window analysis of non-coding regions within normal-tumor whole-genome sequence samples. Brief Bioinform 2021; 22:bbaa203. [PMID: 32940334 PMCID: PMC8138877 DOI: 10.1093/bib/bbaa203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 08/08/2020] [Accepted: 08/10/2020] [Indexed: 11/15/2022] Open
Abstract
Genomics has benefited from an explosion in affordable high-throughput technology for whole-genome sequencing. The regulatory and functional aspects in non-coding regions may be an important contributor to oncogenesis. Whole-genome tumor-normal paired alignments were used to examine the non-coding regions in five cancer types and two races. Both a sliding window and a binning strategy were introduced to uncover areas of higher than expected variation for additional study. We show that the majority of cancer associated mutations in 154 whole-genome sequences covering breast invasive carcinoma, colon adenocarcinoma, kidney renal papillary cell carcinoma, lung adenocarcinoma and uterine corpus endometrial carcinoma cancers and two races are found outside of the coding region (4 432 885 in non-gene regions versus 1 412 731 in gene regions). A pan-cancer analysis found significantly mutated windows (292 to 3881 in count) demonstrating that there are significant numbers of large mutated regions in the non-coding genome. The 59 significantly mutated windows were found in all studied races and cancers. These offer 16 regions ripe for additional study within 12 different chromosomes-2, 4, 5, 7, 10, 11, 16, 18, 20, 21 and X. Many of these regions were found in centromeric locations. The X chromosome had the largest set of universal windows that cluster almost exclusively in Xq11.1-an area linked to chromosomal instability and oncogenesis. Large consecutive clusters (super windows) were found (19 to 114 in count) providing further evidence that large mutated regions in the genome are influencing cancer development. We show remarkable similarity in highly mutated non-coding regions across both cancer and race.
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Affiliation(s)
- J P Torcivia
- The Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, Washington, DC, USA
| | - R Mazumder
- The Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, Washington, DC, USA
- McCormick Genomic and Proteomic Center, The George Washington University, Washington, DC, USA
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25
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New insights into long non-coding RNAs in non-small cell lung cancer. Biomed Pharmacother 2020; 131:110775. [PMID: 33152934 DOI: 10.1016/j.biopha.2020.110775] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 09/09/2020] [Accepted: 09/17/2020] [Indexed: 12/14/2022] Open
Abstract
Lung cancer is a malignant tumor that seriously threatens human life and health. Non-small cell lung cancer (NSCLC) accounts for 85 % of all lung cancer cases, and its global 5-year survival rate is only approximately 5%. Thus, the identification of new prognostic biomarkers has become one of the most urgent challenges in NSCLC research. Long noncoding RNAs (LncRNAs) are a kind of noncoding RNA whose length exceeds 200 nucleotides (nt). LncRNAs are transcribed by RNA pol II and can be subjected to posttranscriptional modifications such as blocking, polyadenylation and splicing; moreover, their expression profiles are more specific than those of mRNAs. Emerging evidence confirms that lncRNAs are associated with the occurrence and development of NSCLC and play an important role in NSCLC drug resistance. The purpose of this review was to describe the roles of lncRNAs in the development, diagnosis and prognosis of NSCLC and to explore new evidence of lncRNAs in the treatment of NSCLC drug resistance. This review provides a new perspective of lncRNAs in the treatment of NSCLC.
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26
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An Evolutionary Cancer Epigenetic Approach Revealed DNA Hypermethylation of Ultra-Conserved Non-Coding Elements in Squamous Cell Carcinoma of Different Mammalian Species. Cells 2020; 9:cells9092092. [PMID: 32933205 PMCID: PMC7565279 DOI: 10.3390/cells9092092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/09/2020] [Accepted: 09/10/2020] [Indexed: 12/15/2022] Open
Abstract
Background: Ultra-conserved non-coding elements (UCNEs) are genomic sequences that exhibit > 95% sequence identity between humans, mammals, birds, reptiles, and fish. Recent findings reported their functional role in cancer. The aim of this study was to evaluate the DNA methylation modifications of UNCEs in squamous cell carcinoma (SCC) from different mammal species. Methods: Fifty SCCs from 26 humans, 17 cats, 3 dogs, 1 horse, 1 bovine, 1 badger, and 1 porcupine were investigated. Fourteen feline stomatitis and normal samples from 36 healthy human donors, 7 cats, 5 dogs, 5 horses, 2 bovines and 1 badger were collected as normal controls. Bisulfite next generation sequencing evaluated the DNA methylation level from seven UCNEs (uc.160, uc.283, uc.416, uc.339, uc.270, uc.299, and uc.328). Results: 57/59 CpGs were significantly different according to the Kruskal–Wallis test (p < 0.05) comparing normal samples with SCC. A common DNA hypermethylation pattern was observed in SCCs from all the species evaluated in this study, with an increasing trend of hypermethylation starting from normal mucosa, through stomatitis to SCC. Conclusions: Our findings indicate that UCNEs are hypermethylated in human SCC, and this behavior is also conserved among different species of mammals.
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27
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Sakamoto N, Sekino Y, Fukada K, Pham QT, Honma R, Taniyama D, Ukai S, Takashima T, Hattori T, Naka K, Tanabe K, Ohdan H, Yasui W. Uc.63+ contributes to gastric cancer progression through regulation of NF-kB signaling. Gastric Cancer 2020; 23:863-873. [PMID: 32323025 DOI: 10.1007/s10120-020-01070-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 04/02/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The transcribed ultraconserved regions (T-UCRs) are a novel class of long non-coding RNAs and are involved in the development of several types of cancer. Although several different papers have described the oncogenic role of Uc.63+, there are no reports mentioning its importance in gastric cancer (GC) biology. METHODS In this study, we evaluated Uc.63+ expression using clinical samples of GC by qRT-PCR, and also assessed the correlation between Uc.63+ expression and clinico-pathological factors. RESULTS The upregulation of Uc.63+ was significantly correlated with advanced clinico-pathological features. Knockdown of Uc.63+ significantly repressed GC cell growth and migration, whereas overexpression of Uc.63+ conversely promoted those of GC cells. In situ hybridization of Uc.63+ revealed its preferential expression in poorly differentiated adenocarcinoma. We further conducted a microarray analysis using MKN-1 cells overexpressing Uc.63- and found that NF-κB signaling was significantly upregulated in accordance with Uc.63+ expression. CONCLUSION Our results suggest that Uc.63+ could be involved in GC progression by regulating GC cell growth and migration via NF-κB signaling.
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Affiliation(s)
- Naoya Sakamoto
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yohei Sekino
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kaho Fukada
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Quoc Thang Pham
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Ririno Honma
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Daiki Taniyama
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shoichi Ukai
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Tsuyoshi Takashima
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Takuya Hattori
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kazuhito Naka
- Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Tanabe
- Department of Health Care for Adults, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Health Care for Adults, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
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Wang Y, Zhou D, Feng Y, Chen G, Li N. T-UCRs with digestive and respiratory diseases. Bioorg Med Chem Lett 2020; 30:127306. [PMID: 32631526 DOI: 10.1016/j.bmcl.2020.127306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/31/2020] [Accepted: 06/01/2020] [Indexed: 12/23/2022]
Abstract
From the perspective of histoembryology, the lung, gaster, and intestines that derived from the endoderm of the gastrula are structurally homologous. The interplay of intestines and lung in many pathologic changes is called the gut-lung axis. RNAs transcribed from ultraconserved regions (T-UCRs) are highly evolutionarily conserved in many mammalian genomes and have been found to be important in the pathogenesis and diagnosis of many diseases. More and more studies in recent years have shown that T-UCRs play important roles both in digestive and respiratory diseases. Taking the gut-lung axis as the entry point, this review summarizes the T-UCRs related to digestive and respiratory diseases in recent years. Meanwhile, these T-UCRs and their targets can lay a foundation for future drug research.
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Affiliation(s)
- Yajun Wang
- School of Traditional Chinese Materia Medica, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Di Zhou
- School of Traditional Chinese Materia Medica, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yuan Feng
- School of Traditional Chinese Materia Medica, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Gang Chen
- School of Traditional Chinese Materia Medica, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug, Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Ning Li
- School of Traditional Chinese Materia Medica, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug, Shenyang Pharmaceutical University, Shenyang 110016, China.
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Kottorou AE, Dimitrakopoulos FID, Antonacopoulou AG, Diamantopoulou G, Tsoumas D, Koutras A, Makatsoris T, Stavropoulos M, Thomopoulos KC, Hulbert A, Tzelepi V, Kalofonos HP. Differentially Methylated Ultra-Conserved Regions Uc160 and Uc283 in Adenomas and Adenocarcinomas Are Associated with Overall Survival of Colorectal Cancer Patients. Cancers (Basel) 2020; 12:895. [PMID: 32272654 PMCID: PMC7226527 DOI: 10.3390/cancers12040895] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/20/2020] [Accepted: 03/25/2020] [Indexed: 12/18/2022] Open
Abstract
: Deregulation of the transcribed ultra-conserved regions (T-UCRs) Uc160, Uc283, and Uc346 has been reported in colorectal cancer (CRC) recently. Here, we investigated promoter methylation of these T-UCRs during the adenoma-carcinoma sequence and their clinical significance in CRC patients. Methylation levels were assessed in CRC, adenomas, infiltrated lymph nodes, and metastatic tissue specimens. In situ hybridization was performed in representative tissue specimens. T-UCRs expression levels were also evaluated in HT-29 colon cancer cells before and after the acquired resistance to 5-fluorouracil (5-FU) and oxaliplatin. A gradual increase in T-UCRs methylation levels from hyperplastic polyps to adenomas and to in situ carcinomas (ISC) and a gradual decrease from ISC to infiltrative and metastatic carcinomas was observed (p < 0.001 for Uc160 and Uc283, p = 0.018 for Uc346). Uc160 and Uc283 methylation was associated with the grade of dysplasia in adenoma specimens (p = 0.034 and p = 0.019, respectively). Furthermore, higher Uc160 methylation, mainly in stage III and IV patients, was related to improved overall survival (OS) in univariate (p = 0.009; HR, 0.366) and multivariate analysis (p = 0.005; HR, 0.240). Similarly, higher methylation of Uc283 was associated with longer OS (p = 0.030). Finally, T-UCRs expression was significantly reduced in HT-29 cells after resistance to chemotherapy. This study suggests that promoter methylation of Uc160, Uc283, and Uc346 is altered during CRC development and that Uc160 and Uc283 methylation may have prognostic significance for CRC patients.
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Affiliation(s)
- Anastasia E. Kottorou
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, 26504 Rio, Greece; (A.E.K.); (F.-I.D.D.); (A.G.A.); (D.T.); (A.K.); (T.M.)
| | - Foteinos-Ioannis D. Dimitrakopoulos
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, 26504 Rio, Greece; (A.E.K.); (F.-I.D.D.); (A.G.A.); (D.T.); (A.K.); (T.M.)
| | - Anna G. Antonacopoulou
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, 26504 Rio, Greece; (A.E.K.); (F.-I.D.D.); (A.G.A.); (D.T.); (A.K.); (T.M.)
| | - Georgia Diamantopoulou
- Division of Gastroenterology, University Hospital of Patras, 26504 Rio, Greece; (G.D.); (K.C.T.)
| | - Dimitrios Tsoumas
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, 26504 Rio, Greece; (A.E.K.); (F.-I.D.D.); (A.G.A.); (D.T.); (A.K.); (T.M.)
| | - Angelos Koutras
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, 26504 Rio, Greece; (A.E.K.); (F.-I.D.D.); (A.G.A.); (D.T.); (A.K.); (T.M.)
- Division of Oncology, Department of Internal Medicine, University Hospital of Patras, 26504 Rio, Greece
| | - Thomas Makatsoris
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, 26504 Rio, Greece; (A.E.K.); (F.-I.D.D.); (A.G.A.); (D.T.); (A.K.); (T.M.)
- Division of Oncology, Department of Internal Medicine, University Hospital of Patras, 26504 Rio, Greece
| | | | | | - Alicia Hulbert
- Cancer Center, University of Illinois at Chicago School of Medicine, Chicago, IL 60612, USA;
- Department of Surgery, University of Illinois at Chicago School of Medicine, Chicago, IL 60612, USA
| | - Vassiliki Tzelepi
- Department of Pathology, Medical School, University of Patras, 26504 Rio, Greece;
| | - Haralabos P. Kalofonos
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, 26504 Rio, Greece; (A.E.K.); (F.-I.D.D.); (A.G.A.); (D.T.); (A.K.); (T.M.)
- Division of Oncology, Department of Internal Medicine, University Hospital of Patras, 26504 Rio, Greece
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Navarro E, Mallén A, Cruzado JM, Torras J, Hueso M. Unveiling ncRNA regulatory axes in atherosclerosis progression. Clin Transl Med 2020; 9:5. [PMID: 32009226 PMCID: PMC6995802 DOI: 10.1186/s40169-020-0256-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 01/05/2020] [Indexed: 02/06/2023] Open
Abstract
Completion of the human genome sequencing project highlighted the richness of the cellular RNA world, and opened the door to the discovery of a plethora of short and long non-coding RNAs (the dark transcriptome) with regulatory or structural potential, which shifted the balance of pathological gene alterations from coding to non-coding RNAs. Thus, disease risk assessment currently has to also evaluate the expression of new RNAs such as small micro RNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), competing endogenous RNAs (ceRNAs), retrogressed elements, 3'UTRs of mRNAs, etc. We are interested in the pathogenic mechanisms of atherosclerosis (ATH) progression in patients suffering Chronic Kidney Disease, and in this review, we will focus in the role of the dark transcriptome (non-coding RNAs) in ATH progression. We will focus in miRNAs and in the formation of regulatory axes or networks with their mRNA targets and with the lncRNAs that function as miRNA sponges or competitive inhibitors of miRNA activity. In this sense, we will pay special attention to retrogressed genomic elements, such as processed pseudogenes and Alu repeated elements, that have been recently seen to also function as miRNA sponges, as well as to the use or miRNA derivatives in gene silencing, anti-ATH therapies. Along the review, we will discuss technical developments associated to research in lncRNAs, from sequencing technologies to databases, repositories and algorithms to predict miRNA targets, as well as new approaches to miRNA function, such as integrative or enrichment analysis and their potential to unveil RNA regulatory networks.
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Affiliation(s)
- Estanislao Navarro
- Independent Researcher, Barcelona, Spain. .,Department of Nephrology, Hospital Universitari Bellvitge and Bellvitge Research Institute (IDIBELL), C/Feixa Llarga, s/n; L'Hospitalet de Llobregat, 08907, Barcelona, Spain.
| | - Adrian Mallén
- Department of Nephrology, Hospital Universitari Bellvitge and Bellvitge Research Institute (IDIBELL), C/Feixa Llarga, s/n; L'Hospitalet de Llobregat, 08907, Barcelona, Spain
| | - Josep M Cruzado
- Department of Nephrology, Hospital Universitari Bellvitge and Bellvitge Research Institute (IDIBELL), C/Feixa Llarga, s/n; L'Hospitalet de Llobregat, 08907, Barcelona, Spain
| | - Joan Torras
- Department of Nephrology, Hospital Universitari Bellvitge and Bellvitge Research Institute (IDIBELL), C/Feixa Llarga, s/n; L'Hospitalet de Llobregat, 08907, Barcelona, Spain
| | - Miguel Hueso
- Department of Nephrology, Hospital Universitari Bellvitge and Bellvitge Research Institute (IDIBELL), C/Feixa Llarga, s/n; L'Hospitalet de Llobregat, 08907, Barcelona, Spain.
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Zeng F, Heng J, Guo X, Wang Y, Wu W, Tang L, Chen M, Wang S, Deng H, Wang J. The novel TP53 3'-end methylation pattern associated with its expression would be a potential biomarker for breast cancer detection. Breast Cancer Res Treat 2020; 180:237-245. [PMID: 31983017 DOI: 10.1007/s10549-020-05536-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 01/14/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Deficiency or silence of TP53 is an early event in breast tumorigenesis. Aberrant methylation and mutation in regulatory regions were considered as crucial regulators of gene expression. METHODS Using multiplex-PCR and next-generation sequencing technology, we analyzed TP53 mutation spectrum in its promoter region. Using PCR target sequence enrichment and next-generation bisulfite sequencing technology, we analyzed the methylation profile of the promoter and 3'-end regions of TP53 gene in paired breast tumor and normal tissues from 120 breast cancer patients. The expression of TP53 and the flanking gene ATP1B2 was explored with qPCR method in the same cohort. RESULTS No promoter mutation of TP53 gene was found in the cohort of the 120 breast cancer patients. The 3'-end of TP53 gene was hyper-methylated (average 78.71%) compared with the promoter region (average less than 1%) in breast tumor tissues. TP53 was significantly lower expressed (P = 1.68E-15) and hyper-methylated in 3'-end (P = 1.82E-18) in tumor. Negative cis correlation was found between the TP53 expression and its 3'-end methylation (P = 9.02E-8, R = 0.337). TP53 expression was significantly associated with PR status (P = 0.0128), Ki67 level (P = 0.0091), and breast cancer subtypes (P = 0.0109). TP53 3'-end methylation and expression showed a good performance in discriminating breast cancer and normal tissues with an AUC of 0.930. CONCLUSIONS The 3'-end methylation of TP53 might be a crucial regulator for its expression in breast cancer, suggesting that TP53 3'-end hyper-methylation associated with its lower expression could be a potential biomarker for breast cancer diagnosis.
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Affiliation(s)
- Feng Zeng
- Department of Emergency, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jianfu Heng
- Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, China
- School of Life Sciences, Central South University, Changsha, 410013, Hunan, China
| | - Xinwu Guo
- Sansure Biotech Inc., Changsha, 410205, Hunan, China
| | - Yue Wang
- School of Life Sciences, Central South University, Changsha, 410013, Hunan, China
| | - Wenhan Wu
- School of Life Sciences, Central South University, Changsha, 410013, Hunan, China
| | - Lili Tang
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Min Chen
- Sansure Biotech Inc., Changsha, 410205, Hunan, China
| | - Shouman Wang
- Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Hongyu Deng
- Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, 410013, China
| | - Jun Wang
- School of Life Sciences, Central South University, Changsha, 410013, Hunan, China.
- Sansure Biotech Inc., Changsha, 410205, Hunan, China.
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Wang LY, Shen H, Yang Q, Min J, Wang Q, Xi W, Yin L, Le SG, Zhang YF, Xiao J, Wang ZN, Ji GY. LncRNA-LINC00472 contributes to the pathogenesis of atrial fibrillation (Af) by reducing expression of JP2 and RyR2 via miR-24. Biomed Pharmacother 2019; 120:109364. [DOI: 10.1016/j.biopha.2019.109364] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 07/31/2019] [Accepted: 08/14/2019] [Indexed: 12/31/2022] Open
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Pereira Zambalde E, Mathias C, Rodrigues AC, Souza Fonseca Ribeiro EM, Fiori Gradia D, Calin GA, Carvalho de Oliveira J. Highlighting transcribed ultraconserved regions in human diseases. WILEY INTERDISCIPLINARY REVIEWS-RNA 2019; 11:e1567. [DOI: 10.1002/wrna.1567] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 08/02/2019] [Accepted: 08/13/2019] [Indexed: 12/18/2022]
Affiliation(s)
| | - Carolina Mathias
- Department of Genetics Universidade Federal do Paraná Curitiba Brazil
| | | | | | | | - George A. Calin
- Department of Experimental Therapeutics, MD Anderson Cancer Center University of Texas Houston Texas
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The Transcribed-Ultra Conserved Regions: Novel Non-Coding RNA Players in Neuroblastoma Progression. Noncoding RNA 2019; 5:ncrna5020039. [PMID: 31167408 PMCID: PMC6631508 DOI: 10.3390/ncrna5020039] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/30/2019] [Accepted: 06/03/2019] [Indexed: 12/15/2022] Open
Abstract
The Transcribed-Ultra Conserved Regions (T-UCRs) are a class of novel non-coding RNAs that arise from the dark matter of the genome. T-UCRs are highly conserved between mouse, rat, and human genomes, which might indicate a definitive role for these elements in health and disease. The growing body of evidence suggests that T-UCRs contribute to oncogenic pathways. Neuroblastoma is a type of childhood cancer that is challenging to treat. The role of non-coding RNAs in the pathogenesis of neuroblastoma, in particular for cancer development, progression, and therapy resistance, has been documented. Exosmic non-coding RNAs are also involved in shaping the biology of the tumor microenvironment in neuroblastoma. In recent years, the involvement of T-UCRs in a wide variety of pathways in neuroblastoma has been discovered. Here, we present an overview of the involvement of T-UCRs in various cellular pathways, such as DNA damage response, proliferation, chemotherapy response, MYCN (v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian)) amplification, gene copy number, and immune response, as well as correlate it to patient survival in neuroblastoma.
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Abstract
While only a small part of the human genome encodes for proteins, biological functions for the so-called junk genome are increasingly being recognized through high-throughput technologies and mechanistic experimental studies. Indeed, novel mechanisms of gene regulation are being discovered that require coordinated interaction between DNA, RNA, and proteins. Therefore, interdisciplinary efforts are still needed to decipher these complex transcriptional networks. In this review, we discuss how non-coding RNAs (ncRNAs) are epigenetically regulated in cancer and metastases and consequently how ncRNAs participate in the sculpting of the epigenetic profile of a cancer cell, thus modulating the expression of other RNA molecules. In the latter case, ncRNAs not only affect the DNA methylation status of certain genomic loci but also interact with histone-modifying complexes, changing the structure of the chromatin itself. We present several examples of epigenetic changes causing aberrant expression of ncRNAs in the context of tumor progression. Interestingly, there are also important epigenetic changes and transcriptional regulatory effects derived from their aberrant expression. As ncRNAs can also be used as biomarkers for diagnosis and prognosis or explored as potential targets, we present insights into the use of ncRNAs for targeted cancer therapy.
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36
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Yuan L, Zhou M, Lv H, Qin X, Zhou J, Mao X, Li X, Xu Y, Liu Y, Xing H. Involvement of NEAT1/miR‐133a axis in promoting cervical cancer progression via targeting SOX4. J Cell Physiol 2019; 234:18985-18993. [PMID: 30932200 DOI: 10.1002/jcp.28538] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 02/25/2019] [Accepted: 03/05/2019] [Indexed: 12/31/2022]
Affiliation(s)
- Li‐Yun Yuan
- Department of Obstetrics and Gynecology Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science Xiangyang Hubei China
| | - Min Zhou
- Department of Obstetrics and Gynecology Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science Xiangyang Hubei China
| | - Huabing Lv
- Department of Obstetrics and Gynecology Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science Xiangyang Hubei China
| | - Xiaomin Qin
- Department of Obstetrics and Gynecology Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science Xiangyang Hubei China
| | - Jinting Zhou
- Department of Obstetrics and Gynecology Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science Xiangyang Hubei China
| | - Xiaogang Mao
- Department of Obstetrics and Gynecology Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science Xiangyang Hubei China
| | - Xianxian Li
- Department of Obstetrics and Gynecology Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science Xiangyang Hubei China
| | - Ying Xu
- Department of Obstetrics and Gynecology Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science Xiangyang Hubei China
| | - Yun Liu
- Department of Nephrology Huai'an Second People's Hospital and the Affiliated Huai'an Hospital of Xuzhou Medical University Huai'an China
| | - Hui Xing
- Department of Obstetrics and Gynecology Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science Xiangyang Hubei China
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Fico A, Fiorenzano A, Pascale E, Patriarca EJ, Minchiotti G. Long non-coding RNA in stem cell pluripotency and lineage commitment: functions and evolutionary conservation. Cell Mol Life Sci 2019; 76:1459-1471. [PMID: 30607432 PMCID: PMC6439142 DOI: 10.1007/s00018-018-3000-z] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 11/13/2018] [Accepted: 12/17/2018] [Indexed: 02/07/2023]
Abstract
LncRNAs have recently emerged as new and fundamental transcriptional and post-transcriptional regulators acting at multiple levels of gene expression. Indeed, lncRNAs participate in a wide variety of stem cell and developmental processes, acting in cis and/or in trans in the nuclear and/or in the cytoplasmic compartments, and generating an intricate network of interactions with RNAs, enhancers, and chromatin-modifier complexes. Given the versatility of these molecules to operate in different subcellular compartments, via different modes of action and with different target specificity, the interest in this research field is rapidly growing. Here, we review recent progress in defining the functional role of lncRNAs in stem cell biology with a specific focus on the underlying mechanisms. We also discuss recent findings on a new family of evolutionary conserved lncRNAs transcribed from ultraconserved elements, which show perfect conservation between human, mouse, and rat genomes, and that are emerging as new player in this complex scenario.
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Affiliation(s)
- Annalisa Fico
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131, Naples, Italy.
- Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131, Naples, Italy.
| | - Alessandro Fiorenzano
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131, Naples, Italy
- Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131, Naples, Italy
- Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, 22184, Lund, Sweden
| | - Emilia Pascale
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131, Naples, Italy
- Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131, Naples, Italy
| | - Eduardo Jorge Patriarca
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131, Naples, Italy
- Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131, Naples, Italy
| | - Gabriella Minchiotti
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131, Naples, Italy
- Institute of Genetics and Biophysics "A. Buzzati-Traverso", CNR, 80131, Naples, Italy
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Yuan L, Qin X, Li L, Zhou J, Zhou M, Li X, Xu Y, Cheng L, Xing H. Overexpression of LINC00037 represses cervical cancer progression by activating mTOR signaling pathway. J Cell Physiol 2019; 234:13353-13360. [PMID: 30613967 DOI: 10.1002/jcp.28012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 12/11/2018] [Indexed: 12/14/2022]
Affiliation(s)
- Li‐Yun Yuan
- Department of Obstetrics and Gynecology Xiangyang Central Hospital,Hubei University of Arts and Science Xiangyang Hubei China
| | - Xiaomin Qin
- Department of Obstetrics and Gynecology Xiangyang Central Hospital,Hubei University of Arts and Science Xiangyang Hubei China
| | - Lin Li
- Department of Obstetrics and Gynecology Xiangyang Central Hospital,Hubei University of Arts and Science Xiangyang Hubei China
| | - Jinting Zhou
- Department of Obstetrics and Gynecology Xiangyang Central Hospital,Hubei University of Arts and Science Xiangyang Hubei China
| | - Min Zhou
- Department of Obstetrics and Gynecology Xiangyang Central Hospital,Hubei University of Arts and Science Xiangyang Hubei China
| | - Xianxian Li
- Department of Obstetrics and Gynecology Xiangyang Central Hospital,Hubei University of Arts and Science Xiangyang Hubei China
| | - Ying Xu
- Department of Obstetrics and Gynecology Xiangyang Central Hospital,Hubei University of Arts and Science Xiangyang Hubei China
| | - Li Cheng
- Department of Obstetrics Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University Huai'an China
| | - Hui Xing
- Department of Obstetrics and Gynecology Xiangyang Central Hospital,Hubei University of Arts and Science Xiangyang Hubei China
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Trzybulska D, Vergadi E, Tsatsanis C. miRNA and Other Non-Coding RNAs as Promising Diagnostic Markers. EJIFCC 2018; 29:221-226. [PMID: 30479608 PMCID: PMC6247131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Since the discovery of non-coding RNAs (ncRNAs) a new area has emerged in the field of biomarkers. NcRNAs are RNA molecules of different sizes that are transcribed as independent genes or as part of protein coding genes and are not translated, therefore they do not produce proteins. They have been classified according to their size and function and include microRNAs (miRNAs), piwiRNAs (piRNAs), snoRNAs and long non-coding RNAs (lncRNAs). These non-coding RNAs are present in different cell compartments participating in multiple cell functions, but they have also been identified in biological fluids, also known as cell-free or circulating ncRNAs, where they can be detected in exosomes, bound on lipoproteins as well as free circulating molecules. The role of circulating ncRNAs is still under investigation but are believed to be paracrine or endocrine messengers to systematically deliver signals between cells and tissues. Detecting ncRNAs in biological fluids has opened a new field in Clinical Chemistry utilizing them as biomarkers of diseases or prognostic markers for different pathological conditions. Herein, the different types of ncRNAs and their potential in the field of diagnostics are outlined.
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Affiliation(s)
- Dorota Trzybulska
- Molecular Reproductive Medicine, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Eleni Vergadi
- Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Greece
| | - Christos Tsatsanis
- Molecular Reproductive Medicine, Department of Translational Medicine, Lund University, Malmö, Sweden, Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion, Greece,Corresponding author: Christos Tsatsanis Medical School University of Crete Voutes, 70013 Heraklion, Crete Greece Phone: +30 2810394833 E-mail:
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40
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Mo XB, Wu LF, Cai XM, Tang ZX, Lu X, Zhang YH, Deng FY, Lei SF. Integrative analysis identified mediation effects of lncRNAs on the correlations between methylation and mRNA. Int J Biochem Cell Biol 2018; 104:66-72. [PMID: 30227253 DOI: 10.1016/j.biocel.2018.09.005] [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: 05/03/2018] [Revised: 08/22/2018] [Accepted: 09/12/2018] [Indexed: 02/01/2023]
Abstract
The aim of this study was to construct DNA methylation-lncRNA-mRNA interaction trios in peripheral blood mononuclear cells. We first conducted eQTL analyses using genome-wide methylation, lncRNA and mRNA expression data from 43 Chinese females. Next, causal inference test (CIT) was used to detect the lncRNA mediation effects on methylation and mRNA. Methylation-lncRNA cis-eQTL analysis identified 11 significant cis-methylation-lncRNA pairs. Combined with the results from the next lncRNA-mRNA eQTL and methylation-mRNA eQTL analyses, the 11 significant pairs and their corresponding 11,204 target e-mRNAs formed 12,245 trios. Further CIT identified six lncRNAs as mediators in regulating the corresponding pairs between methylation and mRNA. This study detected lncRNAs with mediation effects on the correlations between DNA methylations and a large number of mRNAs.
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Affiliation(s)
- Xing-Bo Mo
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, 215123, PR China
| | - Long-Fei Wu
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, 215123, PR China
| | - Xiao-Ming Cai
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, 215123, PR China
| | - Zai-Xiang Tang
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, 215123, PR China
| | - Xin Lu
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, 215123, PR China
| | - Yong-Hong Zhang
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, 215123, PR China
| | - Fei-Yan Deng
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, 215123, PR China
| | - Shu-Feng Lei
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, 215123, PR China.
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Pang L, Li Q, Zhang Y, Deng B, Wu F, Wang J, Wu K, Ding Y, Yu D. Transcribed ultraconserved noncoding RNA uc.160 acts as a negative regulator in gastric cancer. Am J Transl Res 2018; 10:2822-2833. [PMID: 30323869 PMCID: PMC6176235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 08/18/2018] [Indexed: 06/08/2023]
Abstract
BACKGROUND Transcribed ultraconserved regions (T-UCRs) are a subset of long noncoding RNAs. It has been reported that T-UCRs are dysregulated in cancers and play an important role in the development and progression of malignancies. uc.160 was found to be a suppressive factor of cancer development, but its role has not been fully elucidated. METHODS The uc.160 expression was examined in gastric cancer tissues and established cell lines by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The biological function of gastric cancer cells with uc.160 over-expression were investigated, and the interaction between uc.160 and microRNA miR-155 was examined by dual-luciferase reporter assay. PTEN levels were detected by Western blotting. Anti-tumor effects of uc.160 were further explored in tumor transplantation models. RESULTS uc.160 expression was significantly down-regulated in gastric cancer tissues and gastric cell lines as compared to adjacent normal tissues and immortalized gastric epithelial cell line (GES-1), respectively. Over-expression of uc.160 in SGC-7901 and AGS gastric cancer cells significantly suppressed their proliferation in vitro and in vivo. Moreover, uc.160 positively regulated the tumor suppressor protein PTEN. Interestingly, uc.160 was inhibited by microRNA miR-155 that is also a negative regulator of gastric cancer. CONCLUSION uc.160 is significantly down-regulated in gastric carcinomas and can inhibit the tumor growth both in vitro and in vivo, suggesting that uc.160 may be used as a diagnostic marker and therapeutic target of gastric malignancies.
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Affiliation(s)
- Lei Pang
- Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou University School of MedicineYangzhou 225001, China
- Department of Gastroenterology, Affiliated Hospital, Yangzhou UniversityYangzhou 225000, China
| | - Qiang Li
- Department of General Surgery, Affiliated Hospital, Yangzhou UniversityYangzhou 225000, China
| | - Yanqing Zhang
- Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou University School of MedicineYangzhou 225001, China
| | - Bin Deng
- Department of Gastroenterology, Affiliated Hospital, Yangzhou UniversityYangzhou 225000, China
| | - Fan Wu
- Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou University School of MedicineYangzhou 225001, China
| | - Jijun Wang
- Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou University School of MedicineYangzhou 225001, China
| | - Keyan Wu
- Department of Gastroenterology, Affiliated Hospital, Yangzhou UniversityYangzhou 225000, China
| | - Yanbing Ding
- Department of Gastroenterology, Affiliated Hospital, Yangzhou UniversityYangzhou 225000, China
| | - Duonan Yu
- Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou University School of MedicineYangzhou 225001, China
- Department of Gastroenterology, Affiliated Hospital, Yangzhou UniversityYangzhou 225000, China
- Institute of Translational Medicine, Yangzhou UniversityYangzhou 225001, China
- Institute of Comparative Medicine, Yangzhou UniversityYangzhou 225001, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou UniversityYangzhou 225009, China
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The emerging role of lncRNAs in the regulation of cancer stem cells. Cell Oncol (Dordr) 2018; 41:585-603. [PMID: 30218296 DOI: 10.1007/s13402-018-0406-4] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Tumors contain a functional subpopulation of cells that exhibit stem cell properties. These cells, named cancer stem cells (CSCs), play significant roles in the initiation and progression of cancer. Long non-coding RNAs (lncRNAs) can act at the transcriptional, posttranscriptional and translational level. As such, they may be involved in various biological processes such as DNA damage repair, inflammation, metabolism, cell survival, cell signaling, cell growth and differentiation. Accumulating evidence indicates that lncRNAs are key regulators of the CSC subpopulation, thereby contributing to cancer progression. The aim of this review is to overview current knowledge about the functional role and the mechanisms of action of lncRNAs in the initiation, maintenance and regulation of CSCs derived from different neoplasms. These lncRNAs include CTCF7, ROR, DILC, HOTAIR, H19, HOTTIP, ATB, HIF2PUT, SOX2OT, MALAT-1, CUDR, Lnc34a, Linc00617, DYNC2H1-4, PVT1, SOX4 and ARSR Uc.283-plus. Furthermore, we will illustrate how lncRNAs may regulate asymmetric CSC division and contribute to self-renewal, drug resistance and EMT, thus affecting the metastasis and recurrence of different cancers. In addition, we will highlight the implications of targeting lncRNAs to improve the efficacy of conventional drug therapies and to hamper CSC survival and proliferation. CONCLUSIONS lncRNAs are valuable tools in the search for new targets to selectively eliminate CSCs and improve clinical outcomes. LncRNAs may serve as excellent therapeutic targets because they are stable, easily detectable and expressed in tissue-specific contexts.
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Wang Z, Katsaros D, Biglia N, Shen Y, Fu Y, Loo LWM, Jia W, Obata Y, Yu H. High expression of long non-coding RNA MALAT1 in breast cancer is associated with poor relapse-free survival. Breast Cancer Res Treat 2018; 171:261-271. [PMID: 29845475 PMCID: PMC6488226 DOI: 10.1007/s10549-018-4839-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 05/25/2018] [Indexed: 12/14/2022]
Abstract
PURPOSE Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been identified as a prognostic marker for the metastasis of early-stage non-small cell lung cancer (NSCLCs). We studied MALAT1 expression in breast cancer in relation to disease features and patient survival. METHODS Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to measure MALAT1 expression in tumor samples of 509 breast cancer patients. Hazards ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the association between MALAT1 expression and breast cancer survival using the Cox proportional hazards regression model, and the analysis was adjusted for age at surgery, tumor grade, disease stage, and hormone receptor status. Meta-analysis of multiple microarray datasets from online databases and our own study was performed to evaluate the association of MALAT1 with breast cancer survival. RESULTS Patients with low-grade or ER-positive tumors had higher expression of MALAT1 compared to those with high-grade (p = 0.013) or ER-negative (p = 0.0002) tumors. Patients with PR-positive tumors also had higher MALAT1 expression than those with PR-negative tumors (p < 0.0001). In patients with positive hormone receptors or low tumor grade, tumors with high MALAT1 expression were more likely to recur. Survival analysis showed that patients with high expression of MALAT1 had a twofold increase in risk of relapse (p = 0.0083) compared to those with low expression. This association remained significant after adjustment for age at surgery, disease stage, tumor grade, and hormone receptor status. Meta-analysis showed that high MALAT1 expression was associated with poor relapse-free survival in patients with hormone receptor-positive tumors (HR 1.44, 95% CI 1.08-1.92). CONCLUSIONS High expression of lncRNA MALAT1 is associated with breast cancer relapse and may play a role in tumor progression.
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Affiliation(s)
- Zhanwei Wang
- Cancer Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA
| | - Dionyssios Katsaros
- Department of Surgical Sciences, Gynecology, AOU Città della Salute, University of Torino School of Medicine, Turin, Italy
| | - Nicoletta Biglia
- Department of Surgical Sciences, Division of Obstetrics and Gynecology, University of Torino School of Medicine, Mauriziano Hospital, Turin, Italy
| | - Yi Shen
- Cancer Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA
| | - Yuanyuan Fu
- Cancer Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA
- Department of Molecular Biosciences & Bioengineering, University of Hawaii at Manoa, Honolulu, HI, USA
| | - Lenora W M Loo
- Cancer Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA
| | - Wei Jia
- Cancer Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA
| | - Yuki Obata
- College of Pharmacy, Kinjo Gakuin University, Nagoya, Aichi, Japan
| | - Herbert Yu
- Cancer Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
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Circular RNA CpG island hypermethylation-associated silencing in human cancer. Oncotarget 2018; 9:29208-29219. [PMID: 30018746 PMCID: PMC6044373 DOI: 10.18632/oncotarget.25673] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 06/12/2018] [Indexed: 12/31/2022] Open
Abstract
Noncoding RNAs (ncRNAs), such as microRNAs and long noncoding RNAs (lncRNAs), participate in cellular transformation. Work done in the last decade has also demonstrated that ncRNAs with growth-inhibitory functions can undergo promoter CpG island hypermethylation-associated silencing in tumorigenesis. Herein, we wondered whether circular RNAs (circRNAs), a type of RNA transcripts lacking 5′-3′ ends and forming closed loops that are gaining relevance in cancer biology, are also a target of epigenetic inactivation in tumors. To tackle this issue, we have used cancer cells genetically deficient for the DNA methyltransferase enzymes in conjuction with circRNA expression microarrays. We have found that the loss of DNA methylation provokes a release of circRNA silencing. In particular, we have identified that promoter CpG island hypermethylation of the genes TUSC3 (tumor suppressor candidate 3), POMT1 (protein O-mannosyltransferase 1), ATRNL1 (attractin-like 1) and SAMD4A (sterile alpha motif domain containing 4A) is linked to the transcriptional downregulation of both linear mRNA and the hosted circRNA. Although some circRNAs regulate the linear transcript, we did not observe changes in TUSC3 mRNA levels upon TUSC3 circ104557 overexpression. Interestingly, we found circRNA-mediated regulation of target miRNAs and an in vivo growth inhibitory effect upon TUSC3 circ104557 transduction. Data mining for 5′-end CpG island methylation of TUSC3, ATRNL1, POMT1 and SAMD4A in cancer cell lines and primary tumors showed that the epigenetic defect was commonly observed among different tumor types in association with the diminished expression of the corresponding transcript. Our findings support a role for circRNA DNA methylation-associated loss in human cancer.
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Hong Y, Hong SH, Oh YM, Shin SH, Choi SS, Kim WJ. Identification of lung cancer specific differentially methylated regions using genome-wide DNA methylation study. Mol Cell Toxicol 2018. [DOI: 10.1007/s13273-018-0034-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Satake Y, Kuwano Y, Nishikawa T, Fujita K, Saijo S, Itai M, Tanaka H, Nishida K, Rokutan K. Nucleolin facilitates nuclear retention of an ultraconserved region containing TRA2β4 and accelerates colon cancer cell growth. Oncotarget 2018; 9:26817-26833. [PMID: 29928487 PMCID: PMC6003563 DOI: 10.18632/oncotarget.25510] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 05/12/2018] [Indexed: 01/06/2023] Open
Abstract
Transcribed-ultraconserved regions (T-UCRs), which contain conserved sequences with 100% identity across human, rat and mouse species, are a novel category of functional RNAs. The human transformer 2β gene (TRA2B) encodes a UCR that spans exon 2 (276 bp) and its neighboring introns. Among five spliced RNA variants (TRA2β1-5) transcribed from the TRA2B gene, only TRA2β4 contains the conserved exon 2. TRA2β4 is overexpressed in colon cancer cells and accelerates cell growth by blocking the transcription of CDKN1A. However, the mechanisms underlying the overexpression of TRA2β4 in colon cancer cells are unknown. Using biotinylated RNA pull-down assays followed by liquid chromatography-mass spectrometric analysis, we identified nucleolin as a TRA2β4-binding protein. Knockdown of nucleolin reduced the nuclear retention of TRA2β4 and accelerated its degradation in the cytoplasm, whereas nucleolin overexpression increased TRA2β4 levels and its mitogenic activity. Nucleolin directly bound to TRA2β4 exon 2 via the glycine/arginine-rich (GAR) domain. Overexpression of GAR-deficient nucleolin failed to increase TRA2β4 expression and growth of colon cancer cells. RNA fluorescence in situ hybridization showed that TRA2β4 co-localized with nucleolin in nuclei but not with the mutant lacking GAR. Our results suggest that specific interactions between nucleolin and UCR-containing TRA2β4 may be associated with abnormal growth of colon cancer cells.
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Affiliation(s)
- Yuzuru Satake
- Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Yuki Kuwano
- Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Tatsuya Nishikawa
- Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Kinuyo Fujita
- Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Saki Saijo
- Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Miki Itai
- Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Hiroki Tanaka
- Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Kensei Nishida
- Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Kazuhito Rokutan
- Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
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Sziráki A, Tyshkovskiy A, Gladyshev VN. Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction. Aging Cell 2018; 17:e12738. [PMID: 29575528 PMCID: PMC5946071 DOI: 10.1111/acel.12738] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2018] [Indexed: 01/08/2023] Open
Abstract
Aging is characterized by numerous molecular changes, such as accumulation of molecular damage and altered gene expression, many of which are linked to DNA methylation. Here, we characterize the blood DNA methylome across 16 age groups of mice and report numerous global, region‐ and site‐specific features, as well as the associated dynamics of methylation changes. Transition of the methylome throughout lifespan was not uniform, with many sites showing accelerated changes in late life. The associated genes and promoters were enriched for aging‐related pathways, pointing to a fundamental link between DNA methylation and control of the aging process. Calorie restriction both shifted the overall methylation pattern and was accompanied by its gradual age‐related remodeling, the latter contributing to the lifespan‐extending effect. With age, both highly and poorly methylated sites trended toward intermediate levels, and aging was accompanied by an accelerated increase in entropy, consistent with damage accumulation. However, the entropy effects differed for the sites that increased, decreased and did not change methylation with age. Many sites trailed behind, whereas some followed or even exceeded the entropy trajectory and altered the developmental DNA methylation pattern. The patterns we observed in certain genomic regions were conserved between humans and mice, suggesting common principles of functional DNA methylome remodeling and its critical role in aging. The highly resolved DNA methylome remodeling provides an excellent model for understanding systemic changes that characterize the aging process.
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Affiliation(s)
- András Sziráki
- Division of Genetics; Department of Medicine; Brigham and Women's Hospital and Harvard Medical School; Boston MA USA
| | - Alexander Tyshkovskiy
- Division of Genetics; Department of Medicine; Brigham and Women's Hospital and Harvard Medical School; Boston MA USA
- Center for Data-Intensive Biomedicine and Biotechnology; Skolkovo Institute of Science and Technology; Moscow Russia
| | - Vadim N. Gladyshev
- Division of Genetics; Department of Medicine; Brigham and Women's Hospital and Harvard Medical School; Boston MA USA
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Kottorou AE, Antonacopoulou AG, Dimitrakopoulos FID, Diamantopoulou G, Sirinian C, Kalofonou M, Theodorakopoulos T, Oikonomou C, Katsakoulis EC, Koutras A, Makatsoris T, Demopoulos N, Stephanou G, Stavropoulos M, Thomopoulos KC, Kalofonos HP. Deregulation of methylation of transcribed-ultra conserved regions in colorectal cancer and their value for detection of adenomas and adenocarcinomas. Oncotarget 2018; 9:21411-21428. [PMID: 29765549 PMCID: PMC5940382 DOI: 10.18632/oncotarget.25115] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 03/02/2018] [Indexed: 02/06/2023] Open
Abstract
Expression of Transcribed Ultraconserved Regions (T-UCRs) is often deregulated in cancer. The present study assesses the expression and methylation of three T-UCRs (Uc160, Uc283 and Uc346) in colorectal cancer (CRC) and explores the potential of T-UCR methylation in circulating DNA for the detection of adenomas and adenocarcinomas. Expression levels of Uc160, Uc283 and Uc346 were lower in neoplastic tissues from 64 CRC patients (statistically significant for Uc160, p<0.001), compared to non-malignant tissues, while methylation levels displayed the inverse pattern (p<0.001, p=0.001 and p=0.004 respectively). In colon cancer cell lines, overexpression of Uc160 and Uc346 led to increased proliferation and migration rates. Methylation levels of Uc160 in plasma of 50 CRC, 59 adenoma patients, 40 healthy subjects and 12 patients with colon inflammation or diverticulosis predicted the presence of CRC with 35% sensitivity and 89% specificity (p=0.016), while methylation levels of the combination of all three T-UCRs resulted in 45% sensitivity and 74.3% specificity (p=0.013). In conclusion, studied T-UCRs' expression and methylation status are deregulated in CRC while Uc160 and Uc346 appear to have a complicated role in CRC progression. Moreover their methylation status appears a promising non-invasive screening test for CRC, provided that the sensitivity of the assay is improved.
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Affiliation(s)
- Anastasia E. Kottorou
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, Patras, Greece
| | - Anna G. Antonacopoulou
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, Patras, Greece
| | - Foteinos-Ioannis D. Dimitrakopoulos
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, Patras, Greece
- Division of Oncology, University Hospital of Patras, Patras, Greece
| | | | - Chaido Sirinian
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, Patras, Greece
| | - Melpomeni Kalofonou
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, Patras, Greece
- Institute of Biomedical Engineering, Imperial College London, London, UK
| | | | - Chrysa Oikonomou
- Division of Oncology, University Hospital of Patras, Patras, Greece
| | | | - Angelos Koutras
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, Patras, Greece
- Division of Oncology, University Hospital of Patras, Patras, Greece
| | - Thomas Makatsoris
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, Patras, Greece
- Division of Oncology, University Hospital of Patras, Patras, Greece
| | - Nikos Demopoulos
- Division of Genetics, Cell and Developmental Biology, Department of Biology, University of Patras, Patras, Greece
| | - Georgia Stephanou
- Division of Genetics, Cell and Developmental Biology, Department of Biology, University of Patras, Patras, Greece
| | | | | | - Haralabos P. Kalofonos
- Clinical and Molecular Oncology Laboratory, Division of Oncology, Medical School, University of Patras, Patras, Greece
- Division of Oncology, University Hospital of Patras, Patras, Greece
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Irimie AI, Zimta AA, Ciocan C, Mehterov N, Dudea D, Braicu C, Berindan-Neagoe I. The Unforeseen Non-Coding RNAs in Head and Neck Cancer. Genes (Basel) 2018; 9:genes9030134. [PMID: 29494516 PMCID: PMC5867855 DOI: 10.3390/genes9030134] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 02/21/2018] [Accepted: 02/22/2018] [Indexed: 12/18/2022] Open
Abstract
Previously ignored non-coding RNAs (ncRNAs) have become the subject of many studies. However, there is an imbalance in the amount of consideration that ncRNAs are receiving. Some transcripts such as microRNAs (miRNAs) or small interfering RNAs (siRNAs) have gained much attention, but it is necessary to investigate other “pieces of the RNA puzzle”. These can offer a more complete view over normal and pathological cell behavior. The other ncRNA species are less studied, either due to their recent discovery, such as stable intronic sequence RNA (sisRNA), YRNA, miRNA-offset RNAs (moRNA), telomerase RNA component (TERC), natural antisense transcript (NAT), transcribed ultraconserved regions (T-UCR), and pseudogene transcript, or because they are still largely seen as non-coding transcripts with no relevance to pathogenesis. Moreover, some are still considered housekeeping RNAs, for instance small nucleolar RNAs (snoRNAs) and TERC. Our review summarizes the biogenesis, mechanism of action and potential role of less known ncRNAs in head and neck cancer, with a particular focus on the installment and progress for this particular cancer type.
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Affiliation(s)
- Alexandra Iulia Irimie
- Department of Prosthetic Dentistry and Dental Materials, Division Dental Propaedeutic, Aesthetic, "IuliuHatieganu" University of Medicine and Pharmacy, Cluj-Napoca, 23 Marinescu Street, 40015 Cluj-Napoca, Romania.
| | - Alina-Andreea Zimta
- MEDFUTURE-Research Center for Advanced Medicine, University of Medicine and Pharmacy Iuliu-Hatieganu, 23 Marinescu Street, 40015 Cluj-Napoca, Romania.
| | - Cristina Ciocan
- MEDFUTURE-Research Center for Advanced Medicine, University of Medicine and Pharmacy Iuliu-Hatieganu, 23 Marinescu Street, 40015 Cluj-Napoca, Romania.
| | - Nikolay Mehterov
- Department of Medical Biology, Medical University Plovdiv, BulVasilAprilov 15-А, Plovdiv 4002, Bulgaria.
- Technological Center for Emergency Medicine, BulVasilAprilov 15-А, Plovdiv 4002, Bulgaria.
| | - Diana Dudea
- Department of Prosthetic Dentistry and Dental Materials, Division Dental Propaedeutic, Aesthetic, "IuliuHatieganu" University of Medicine and Pharmacy, Cluj-Napoca, 23 Marinescu Street, 40015 Cluj-Napoca, Romania.
| | - Cornelia Braicu
- Research Center for Functional Genomics and Translational Medicine, "IuliuHatieganu" University of Medicine and Pharmacy, 23 Marinescu Street, 40015 Cluj-Napoca, Romania.
| | - Ioana Berindan-Neagoe
- MEDFUTURE-Research Center for Advanced Medicine, University of Medicine and Pharmacy Iuliu-Hatieganu, 23 Marinescu Street, 40015 Cluj-Napoca, Romania.
- Research Center for Functional Genomics and Translational Medicine, "IuliuHatieganu" University of Medicine and Pharmacy, 23 Marinescu Street, 40015 Cluj-Napoca, Romania.
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute "Prof. Dr. Ion Chiricuta", Republicii 34 Street, 400015 Cluj-Napoca, Romania.
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