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Kaur R, Pandey S, Gupta S, Singh J. Harnessing the potential of long non-coding RNAs in the pathophysiology of Alzheimer's disease. Exp Neurol 2025; 385:115134. [PMID: 39740737 DOI: 10.1016/j.expneurol.2024.115134] [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: 07/02/2024] [Revised: 12/08/2024] [Accepted: 12/27/2024] [Indexed: 01/02/2025]
Abstract
Alzheimer's disease (AD), a diverse neurodegenerative disease, is the leading cause of dementia, accounting for 60-80 % of all cases. The pathophysiology of Alzheimer's disease is unknown, and there is no cure at this time. Recent developments in transcriptome-wide profiling have led to the identification of a number of non-coding RNAs (ncRNAs). Among these, long non-coding RNAs (lncRNAs)-long transcripts that don't seem to be able to code for proteins-have drawn attention because they function as regulatory agents in a variety of biological processes. Recent research suggests that lncRNAs play a role in the pathogenesis of Alzheimer's disease by modulating tau hyperphosphorylation, amyloid production, synaptic impairment, neuroinflammation, mitochondrial dysfunction, and oxidative stress, though their precise effects on the disorder are unknown. The biology and modes of action of the best-characterized lncRNAs in AD will be outlined here, with an emphasis on their possible involvement in the pathophysiology of the disease. As lncRNAs may offer prospective prognostic/diagnostic biomarkers and therapeutic targets for the treatment of AD, a greater comprehension of the molecular processes and the intricate network of interactions in which they are implicated could pave the way for future research.
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Affiliation(s)
- Rasanpreet Kaur
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Chaumuhan, Mathura 281406, Uttar Pradesh, India; Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam, India
| | - Swadha Pandey
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Chaumuhan, Mathura 281406, Uttar Pradesh, India
| | - Saurabh Gupta
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Chaumuhan, Mathura 281406, Uttar Pradesh, India.
| | - Jitendra Singh
- Department of Translational Medicine, All India Institute of Medical Sciences (AIIMS)Bhopal, Saket Nagar, Bhopal 462020, Madhya Pradesh, India
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Alizadeh M, Ghasemi H, Bazhan D, Mohammadi Bolbanabad N, Rahdan F, Arianfar N, Vahedi F, Khatami SH, Taheri-Anganeh M, Aiiashi S, Armand N. MicroRNAs in disease States. Clin Chim Acta 2025; 569:120187. [PMID: 39938625 DOI: 10.1016/j.cca.2025.120187] [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: 11/24/2024] [Revised: 02/08/2025] [Accepted: 02/08/2025] [Indexed: 02/14/2025]
Abstract
This review highlights the role of miRNAs in various diseases affecting major organ systems. miRNAs are small, non-coding RNA molecules that regulate numerous genes. Dysregulation of miRNAs is linked to many pathological conditions due to their involvement in gene silencing and cellular pathways. We discuss miRNA expression patterns, their physiological and pathological roles, and how changes in miRNA levels contribute to disease. Notably, miRNAs like miR-499 and miR-21 are implicated in heart failure and atherosclerosis. miRNA dysregulation is also associated with colorectal and gastric cancers, influencing tumorigenesis and chemoresistance. In neurological diseases, miRNAs exhibit diverse profiles that affect neurodevelopment and degeneration. Additionally, miRNAs modulate cell function in reproductive organs, impacting fertility and cancer progression. miRNAs such as miR-192 and miR-204 serve as biomarkers for nephropathy and acute kidney injury. These miRNAs are involved in skeletal muscle diseases, contributing to conditions like osteoporosis and sarcopenia. miRNAs function as oncogenes or tumor suppressors in cancer, highlighting their potential in diagnostics and therapy. Further research is needed to develop miRNA-based diagnostics and treatments.
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Affiliation(s)
- Mehdi Alizadeh
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Ghasemi
- Research Center for Environmental Contaminants (RCEC), Abadan University of Medical Sciences, Abadan, Iran
| | - Donya Bazhan
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Fereshteh Rahdan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Arianfar
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farzaneh Vahedi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Seyyed Hossein Khatami
- Student Research Committee, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Saleh Aiiashi
- Abadan University of Medical Sciences, Abadan, Iran.
| | - Nezam Armand
- Dietary Supplements and Probiotic Research Center, Alborz University of Medical Sciences, Karaj, Iran.
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3
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Rahman MA, Islam MM, Ripon MAR, Islam MM, Hossain MS. Regulatory Roles of MicroRNAs in the Pathogenesis of Metabolic Syndrome. Mol Biotechnol 2024; 66:1599-1620. [PMID: 37393414 DOI: 10.1007/s12033-023-00805-z] [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: 04/13/2023] [Accepted: 06/17/2023] [Indexed: 07/03/2023]
Abstract
Metabolic syndrome refers to a group of several disease conditions together with high glucose triglyceride levels, high blood pressure, lower high-density lipoprotein level, and large waist circumference. About 400 million people worldwide, one-third of the Euro-American population and 27% Chinese population over age 50 have it. microRNAs, an abundant novel class of endogenous small, non-coding RNAs in eukaryotic cells, act as negative controllers of gene expression by promoting either degradation/translational repression of target messenger RNA. More than 2000 microRNAs in the human genome have been identified and they are implicated in various biological & pathophysiological processes, including glucose homeostasis, inflammatory response, and angiogenesis. Destruction of microRNAs has a crucial role in the pathogenesis of obesity, cardiovascular disease, and diabetes. Recently the discovery of circulating microRNAs in human serum may help to promote metabolic crosstalk between organs and serves as a novel approach for the identification of various diseases, like Type 2 diabetes & atherosclerosis. In this review, we will discuss the most recent and up-to-date research on the pathophysiology and histopathology of metabolic syndrome besides their historical background and epidemiological highlight. As well as search the methodologies employed in this field of research and the potential role of microRNAs as novel biomarkers and therapeutic targets for metabolic syndrome in the human body. Furthermore, the significance of microRNAs in promising strategies, like stem cell therapy, which holds enormous promise for regenerative medicine in the treatment of metabolic disorders will also be discussed.
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Affiliation(s)
- Md Abdur Rahman
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Md Mahmodul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Md Abdur Rahman Ripon
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Md Monirul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Mohammad Salim Hossain
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh.
- Bangladesh Obesity Research Network (BORN), Noakhali, 3814, Bangladesh.
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Watanabe F, Suzuki K, Noda H, Rikiyama T. Liquid biopsy leads to a paradigm shift in the treatment of pancreatic cancer. World J Gastroenterol 2022; 28:6478-6496. [PMID: 36569270 PMCID: PMC9782840 DOI: 10.3748/wjg.v28.i46.6478] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/25/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most cancers. Its 5-year survival rate is very low. The recent induction of neoadjuvant chemotherapy and improvements in chemotherapy for patients with pancreatic cancer have resulted in improved survival outcomes. However, the prognosis of pancreatic cancer is still poor. To dramatically improve the prognosis, we need to develop more tools for early diagnosis, treatment selection, disease monitoring, and response rate evaluation. Recently, liquid biopsy (circulating free DNA, circulating tumor DNA, circulating tumor cells, exosomes, and microRNAs) has caught the attention of many researchers as a new biomarker that is minimally invasive, confers low-risk, and displays an overall state of the tumor. Thus, liquid biopsy does not employ the traditional difficulties of obtaining tumor samples from patients with advanced PDAC to investigate their molecular biological status. In addition, it allows for long-term monitoring of the molecular profile of tumor progression. These could help in identifying tumor-specific alterations that use the target structure for tailor-made therapy. Through this review, we highlighted the latest discoveries and advances in liquid biopsy technology in pancreatic cancer research and showed how it can be applied in clinical practice.
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Affiliation(s)
- Fumiaki Watanabe
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Koichi Suzuki
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Hiroshi Noda
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
| | - Toshiki Rikiyama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
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The neurobiology of non-coding RNAs and Alzheimer's disease pathogenesis: Pathways, mechanisms and translational opportunities. Ageing Res Rev 2021; 71:101425. [PMID: 34384901 DOI: 10.1016/j.arr.2021.101425] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 12/13/2022]
Abstract
In the past two decades, advances in sequencing technology and analysis of the human and mouse genome have led to the discovery of many non-protein-coding RNAs (ncRNAs) including: microRNA, small-interfering RNAs, piwi-associated small RNAs, transfer RNA-derived small RNAs, long-non-coding RNAs and circular RNAs. Compared with healthy controls, levels of some ncRNAs are significantly altered in the central nervous system and blood of patients affected by neurodegenerative disorders like Alzheimer's disease (AD). Although the mechanisms are still not fully elucidated, studies have revealed that these highly conserved ncRNAs are important modulators of gene expression, amyloid-β production, tau phosphorylation, inflammation, synaptic plasticity and neuronal survival, all features considered central to AD pathogenesis. Despite considerable difficulties due to their large heterogeneity, and the complexity of their regulatory pathways, research in this rapidly growing field suggests that ncRNAs hold great potential as biomarkers and therapeutic targets against AD. Herein, we summarize the current knowledge regarding the neurobiology of ncRNA in the context of AD pathophysiology.
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Abstract
Sensitive skin Syndrome (SSS) is a complex global clinical phenomenon that is defined by the self-reported presence of different sensory perceptions, including tightness, stinging, burning, tingling, pain and pruritus and often without objective signs. Due to the subjective nature of this clinical condition, the diagnosis is complex and there is often a disconnect between what subjects feel and what medical professionals can observe. This chapter reviews the known underlying physiology, some of the triggering factors associated with SSS, co-morbidities as well as the psychological impact on individuals suffering from this condition. The goal is to bridge the gap between the physicians’ understanding and the subjects’ perceptions of this real-life condition that affects so many.
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Baraniak D, Boryski J. Triazole-Modified Nucleic Acids for the Application in Bioorganic and Medicinal Chemistry. Biomedicines 2021; 9:628. [PMID: 34073038 PMCID: PMC8229351 DOI: 10.3390/biomedicines9060628] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/26/2021] [Accepted: 05/26/2021] [Indexed: 02/07/2023] Open
Abstract
This review covers studies which exploit triazole-modified nucleic acids in the range of chemistry and biology to medicine. The 1,2,3-triazole unit, which is obtained via click chemistry approach, shows valuable and unique properties. For example, it does not occur in nature, constitutes an additional pharmacophore with attractive properties being resistant to hydrolysis and other reactions at physiological pH, exhibits biological activity (i.e., antibacterial, antitumor, and antiviral), and can be considered as a rigid mimetic of amide linkage. Herein, it is presented a whole area of useful artificial compounds, from the clickable monomers and dimers to modified oligonucleotides, in the field of nucleic acids sciences. Such modifications of internucleotide linkages are designed to increase the hybridization binding affinity toward native DNA or RNA, to enhance resistance to nucleases, and to improve ability to penetrate cell membranes. The insertion of an artificial backbone is used for understanding effects of chemically modified oligonucleotides, and their potential usefulness in therapeutic applications. We describe the state-of-the-art knowledge on their implications for synthetic genes and other large modified DNA and RNA constructs including non-coding RNAs.
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Affiliation(s)
- Dagmara Baraniak
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland;
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Wang B, Zhang K, Meng S, Shao X, Zhou Z, Mao H, Zhu Z, Chen H, Yang H, Chen K. LncRNA-NONHSAT024778 promote the proliferation and invasion of chordoma cell by regulating miR-1290/Robo1 axis. Int J Biol Sci 2021; 17:796-806. [PMID: 33767589 PMCID: PMC7975704 DOI: 10.7150/ijbs.54091] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Chordoma is a malignant bone tumor originating from the embryonic remnants of the notochord. lncRNAs act as competing endogenous RNAs (ceRNAs) and play a critical role in tumor pathology. However, the biological role of lncRNA-NONHSAT024778 and the underlying molecular mechanism in chordoma remains unknown. qRT-PCR was used to analyze the expression changes of NONHSAT024778 and miR-1290 in chordoma tissues and cell lines. Bioinformatics analysis and luciferase reporter assay were applied to detect the targeting binding effect between NONHSAT024778 and miR-1290, and between Robo1 and miR-1290. The effect of NONHSAT024778 on chordoma cell proliferation and invasion and its regulation of miR-1290 by acting as a ceRNA were also investigated. An increased NONHSAT024778 expression was correlated with a decreased miR-1290 level in chordoma tissues. NONHSAT024778 knockdown suppressed the proliferation and invasion of chordoma cells. miR-1290 restored expression rescued the carcinogenic function of NONHSAT024778. Bioinformatics analysis showed that NONHSAT024778 acted as ceRNA to regulate Robo1 via sponging miR-1290 in chordoma cells, thereby promoting chordoma cell malignant progression. In vivo results confirmed the anti-tumor effects of NONHSAT024778 knockdown activating miR-1290 to inhibit the oncogene Robo1. NONHSAT024778 is substantially overexpressed, whereas miR-1290 is decreased in chordoma tissue. NONHSAT024778-miR-1290-Robo1 axis plays a critical role in chordoma tumorigenesis and might be a potential predictive biomarker for the diagnosis and therapeutic target among patients with chordoma.
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Affiliation(s)
- Bin Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou, Jiangsu, China
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Kai Zhang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou, Jiangsu, China
| | - Sen Meng
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiaofeng Shao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou, Jiangsu, China
| | - Zhangzhe Zhou
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou, Jiangsu, China
| | - Haiqing Mao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou, Jiangsu, China
| | - Ziqiang Zhu
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hao Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou, Jiangsu, China
| | - Huilin Yang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou, Jiangsu, China
| | - Kangwu Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou, Jiangsu, China
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Liu X, Zhang P, Li Y, Zhao N, Han H. The AMPK-mTOR axis requires increased MALAT1 expression for promoting granulosa cell proliferation in endometriosis. Exp Ther Med 2021; 21:21. [PMID: 33235630 PMCID: PMC7678598 DOI: 10.3892/etm.2020.9453] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 08/12/2020] [Indexed: 02/07/2023] Open
Abstract
Endometriosis is a common reproductive disorder in women, with a global prevalence of 10-15%. Long noncoding RNAs (lncRNAs) are critical to gene transcription, cell cycle modulation and immune response. The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) reportedly mediates autophagy of endometrial stromal cells in endometriosis. The present study aimed to evaluate the role and mechanism of MALAT1 in granulosa cells (GCs) in endometriosis. Consequently, MALAT1 expression was upregulated in GCs obtained from patients with endometriosis and in the steroidogenic human granulosa-like tumor cell line KGN. However, MALAT1 knockdown consequently decreased the proliferation and viability of these cells, as determined by MTT and 5-ethynyl-2'-deoxyuridine staining assays. Both Annexin V-fluorescein isothiocyanate/propidium iodide flow cytometry and western blotting performed to detect proapoptotic factors indicated that MALAT1 depletion might promote KGN cell apoptosis. Furthermore, MALAT1 knockdown increased GC autophagy, as evidenced by microtubule-associated protein 1A/1B-light chain 3 (LC3) cleavage upregulation and p62 degradation. In addition, although 5'-AMP-activated protein kinase (AMPK) mRNA expression and protein levels decreased in GCs obtained from patients with endometriosis and KGN cells, MALAT1 knockdown restored AMPK levels. However, addition of BML-275 (MALAT1 inhibitor) to MALAT1-knockdown KGN cells recovered their viability and proliferative capacity and simultaneously reduced their apoptotic and autophagic capacity. Therefore, MALAT1 may regulate GC proliferation via AMPK-mTOR-mediated cell apoptosis and autophagy.
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Affiliation(s)
- Xuejie Liu
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261000, P.R. China
| | - Ping Zhang
- Department of Obstetrics, Zhucheng People's Hospital, Zhucheng, Shandong 262200, P.R. China
| | - Yanmin Li
- Department of Obstetrics and Gynecology, Liaocheng Second People's Hospital, Liaocheng, Shandong 252000, P.R. China
| | - Na Zhao
- Department of Obstetrics and Gynecology, Dezhou People's Hospital, Dezhou, Shandong 253000, P.R. China
| | - Haiyan Han
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261000, P.R. China
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Diagnostic value of microRNA panel in endometrial cancer: A systematic review. Oncotarget 2020; 11:2010-2023. [PMID: 32523655 PMCID: PMC7260115 DOI: 10.18632/oncotarget.27601] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 04/03/2020] [Indexed: 12/14/2022] Open
Abstract
PURPOSE We conducted a systematic review to evaluate the overall diagnostic accuracy of miRNAs in detecting endometrial cancer. MATERIALS AND METHODS A systematic search of Medline, Embase, Cinahl and the Cochrane Controlled Register of Trials was performed to identify studies reporting on the diagnostic value of miRNA in EC patients. Included were diagnostic studies looking at miRNA expression in women diagnosed with endometrial cancer. Two reviewers independently selected studies and assessed quality of studies using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) score system. Data extraction was completed and the vote-counting strategy was used to rank miRNAs. RESULTS 26 studies were included with a total number of 1,400 EC patients reporting on 106 differentially expressed miRNAs. The most frequently found up-regulated miRNA was miR-205 followed by miR-200c, -223, -182, -183 and -200a. In addition, miR-135b, miR-429, miR-141 and miR-200b were also frequently up-regulated. There was less consensus on down-regulated miRNAs. CONCLUSIONS miRNAs yield a promising diagnostic biomarker potential in endometrial cancer, especially miR-205, the miR-200 family and miR-135b, -182, -183 and -223. However, no sufficient high quality data are available to draw hard conclusions. More research is needed to validate the diagnostic potential of these miRNAs in larger studies. In addition, the potential of urine as a non-invasive biofluid should be investigated in more detail.
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Maimaitiming A, Wusiman A, Aimudula A, Kuerban X, Su P. MicroRNA-152 Inhibits Cell Proliferation, Migration, and Invasion in Breast Cancer. Oncol Res 2020; 28:13-19. [PMID: 30982494 PMCID: PMC7851537 DOI: 10.3727/096504019x15519249902838] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The aim of the present study was to investigate the roles of microRNA-152 (miR-152) in the initiation and progression of breast cancer. The expression level of miR-152 was detected in human breast cancer tissue and a panel of human breast cancer cell lines using qRT-PCR. Results found that miR-152 expression was significantly downregulated in breast cancer tissue samples compared to adjacent noncancerous tissues as well as in breast cancer cell lines. Overexpression of miR-152 significantly suppressed breast cancer cell proliferation, migration, and invasion. Luciferase reporter assay results found that ROCK1 is a direct and functional target gene of miR-152 in breast cancer. In addition, downexpression of ROCK1 could inhibit breast cancer cell proliferation, migration, and invasion. These findings indicate that miR-152 inhibited breast cancer growth and metastasis through negative regulation of ROCK1 expression. These data suggest that miR-152/ROCK1 pathway may be a useful therapeutic target for breast cancer treatment.
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Affiliation(s)
- Adilijiang Maimaitiming
- *Department of Breast and Thyroid Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, P.R. China
| | - Ailijiang Wusiman
- †Department of Surgery, Hospital of Xinjiang Traditional Uyghur, Urumqi, P.R. China
| | - Abulajiang Aimudula
- †Department of Surgery, Hospital of Xinjiang Traditional Uyghur, Urumqi, P.R. China
| | - Xuekelaiti Kuerban
- *Department of Breast and Thyroid Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, P.R. China
| | - Pengcheng Su
- *Department of Breast and Thyroid Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, P.R. China
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Ebrahimi R, Toolabi K, Jannat Ali Pour N, Mohassel Azadi S, Bahiraee A, Zamani-Garmsiri F, Emamgholipour S. Adipose tissue gene expression of long non-coding RNAs; MALAT1, TUG1 in obesity: is it associated with metabolic profile and lipid homeostasis-related genes expression? Diabetol Metab Syndr 2020; 12:36. [PMID: 32368256 PMCID: PMC7191796 DOI: 10.1186/s13098-020-00544-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 04/22/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Recent studies point toward the possible regulatory roles of two lncRNAs; metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and taurine upregulated gene 1 (TUG1) in the pathogenesis of obesity-related disorders and regulation of lipogenesis and adipogenesis. In an attempt to understand the molecules involved in human obesity pathogenesis, we aimed to evaluate the expression of MALAT1 and TUG1 in visceral adipose tissues (VAT) and subcutaneous adipose tissues (SAT) of obese women, as compared to normal-weight women. The mRNA expression of possible target genes including peroxisome proliferator-activated receptor gamma (PPARγ), PPARγ coactivator-1 alpha (PGC1α), sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) which are involved in adipogenesis and lipogenesis were also examined. METHODS This study was conducted on 20 obese [body mass index (BMI) ≥ 30 kg/m 2] female participants and 19 normal-weight (BMI < 25 kg/m 2) female participants. Real-time PCR was performed to investigate the mRNA expression of the above-mentioned genes in VAT and SAT from all participants. RESULTS The results showed lower mRNA levels of TUG1 in both the VAT and SAT of obese women, compared to normal-weight women. Furthermore, TUG1 expression in SAT positively correlated with BMI, waist circumference (WC), hip circumference, HOMA-IR, and insulin levels, eGFR value, creatinine levels, and hs-CRP in all participants independent of age and HOMA-IR. However, VAT mRNA expression of TUG1 had a positive correlation with obesity indices and HOMA-IR and insulin levels in the whole population. Moreover, SAT mRNA level of TUG1 was positively correlated with SAT gene expression of PGC1α, SREBP-1c, FAS, and ACC independent of age and HOMA-IR. Although mRNA expression of MALAT1 did not differ between two groups for any tissue, it was positively correlated with SAT mRNA levels of SREBP-1c, PPARγ, and their targets; FAS and ACC, as well as with VAT mRNA levels of PGC1α. CONCLUSIONS It seems likely that TUG1 with distinct expression pattern in VAT and SAT are involved in the regulation of lipogenic and adipogenic genes and obesity-related parameters. However, more studies are necessary to establish this concept.
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Affiliation(s)
- Reyhane Ebrahimi
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Karamollah Toolabi
- Department of Surgery, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Naghmeh Jannat Ali Pour
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samaneh Mohassel Azadi
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Bahiraee
- Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Zamani-Garmsiri
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Solaleh Emamgholipour
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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LncRNA SNHG7 contributes to tumorigenesis and progression in breast cancer by interacting with miR-34a through EMT initiation and the Notch-1 pathway. Eur J Pharmacol 2019; 856:172407. [DOI: 10.1016/j.ejphar.2019.172407] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 05/22/2019] [Accepted: 05/22/2019] [Indexed: 01/01/2023]
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Qi J, Chu Y, Zhang G, Li H, Yang D, Wang Q. Down-regulated LncR-MALAT1 suppressed cell proliferation and migration by inactivating autophagy in bladder cancer. RSC Adv 2018; 8:31019-31027. [PMID: 35548736 PMCID: PMC9085497 DOI: 10.1039/c8ra04876b] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 07/10/2018] [Indexed: 01/07/2023] Open
Abstract
Long non-coding RNA-metastasis-associated lung adenocarcinoma transcript (LncR-MALAT) is highly expressed in a variety of tumors, which can affect the progression of tumor cells. LncR-MALAT1 was reported to affect the proliferation of pancreatic cancer and glioma cells by regulating autophagy, but how LncR-MALAT1 affects the proliferation and invasion of various cancer cells by regulating autophagy in bladder cancer has not been reported. Therefore, in this study, we aimed to investigate the effect of LncR-MALAT1 on cell proliferation, apoptosis, invasion and autophagy of bladder cancer and the possible mechanism in vitro. The results showed that LncR-MALAT1 was highly expressed in bladder cancer tissues and cells. The silence of LncR-MALAT1 inhibited the proliferation and invasion and promoted apoptosis in bladder cancer cells. In addition, MALAT1 shRNA down-regulated the expression of Beclin1 and the LC3 II/I ratio, enhanced the expression of p62 and played a significant role in autophagy inhibition. By further investigating the relevant regulatory mechanisms, we found that MALATI shRNA reduced the phosphorylation of AMPK and increased the phosphorylation level of mTOR, thereby inhibiting the activation of the AMPK/mTOR pathway. It is noteworthy that the AMPK/mTOR pathway activator, metformin, partially reversed the effect of MALAT1 shRNA on the inhibition of autophagy in bladder cancer cells. At the same time, the proliferation and invasion ability of HT-1376 cells inhibited by MALAT1 shRNA were also enhanced. The results showed that down-regulation of LncR-MALAT1 could inhibit the proliferation and invasion of bladder cancer cells by attenuating autophagy via the regulation of the AMPK/mTOR pathway. Long non-coding RNA-metastasis-associated lung adenocarcinoma transcript (LncR-MALAT) is highly expressed in a variety of tumors, which can affect the progression of tumor cells.![]()
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Affiliation(s)
- Jiude Qi
- Department of Oncology, People's Hospital of Laiwu Shandong 271100 China
| | - Yanfeng Chu
- Department of Laboratory, Yantaishan Hospital Shandong 264000 China
| | - Guangyan Zhang
- Department of Laboratory, People's Hospital of Zhangqiu District Shandong 250200 China
| | - Hongjun Li
- Department of EGG Laboratory, Traditional Chinese Medicine Hospital of Zhangqiu Dirtrict Shandong 250200 China
| | - Dongdong Yang
- Department of Nursing, People's Hospital of Zhangqiu District Shandong 250000 China
| | - Qi Wang
- Department of Urology, Qingdao Municipal Hospital No. 5 Donghai Middle Road Shinan District Qingdao Shandong 266001 China +86-0523-82789159
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15
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Chen L, Wang Y, He J, Zhang C, Chen J, Shi D. Long Noncoding RNA H19 Promotes Proliferation and Invasion in Human Glioma Cells by Downregulating miR-152. Oncol Res 2018; 26:1419-1428. [PMID: 29422115 PMCID: PMC7844716 DOI: 10.3727/096504018x15178768577951] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
miR-152 and lncRNA H19 have been frequently implicated in various cellular processes including cell proliferation, invasion, angiogenesis, and apoptosis. However, the interaction between miR-152 and H19 in glioma has never been reported. RT-qPCR was used to examine the expression of miR-152 and H19 in human glioma cell lines and normal human astrocytes (NHAs). The interaction between miR-152 and lncRNA H19 was assessed by dual-luciferase reporter assay. MTT assay and Transwell invasion assay were used to determine the proliferation and invasion of U251 and U87 cells. A xenograft tumor experiment was performed to confirm the role of H19 in vivo. The results showed that H19 expression was upregulated and miR-152 expression was downregulated in human glioma cell lines. H19 downregulation or miR-152 upregulation suppressed glioma cell proliferation and invasion in vitro. Moreover, H19 and miR-152 directly regulated each other. Furthermore, decreased miR-152 expression alleviated si-H19-induced inhibitory effects on proliferation and invasion in glioma cells. As expected, H19 silencing hindered glioma growth in vivo. Taken together, H19 promoted glioma cell proliferation and invasion by negatively regulating miR-152 expression, providing evidence for the potential application of H19 as a biomarker and therapy target for glioma.
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Affiliation(s)
- Lei Chen
- Department of Neurosurgery, 101st Hospital of PLA (Wuxi Taihu Hospital), Clinical Medical School of Anhui Medical University, Wuxi, P.R. China
| | - Yuhai Wang
- Department of Neurosurgery, 101st Hospital of PLA (Wuxi Taihu Hospital), Clinical Medical School of Anhui Medical University, Wuxi, P.R. China
| | - Jianqing He
- Department of Neurosurgery, 101st Hospital of PLA (Wuxi Taihu Hospital), Clinical Medical School of Anhui Medical University, Wuxi, P.R. China
| | - Chunlei Zhang
- Department of Neurosurgery, 101st Hospital of PLA (Wuxi Taihu Hospital), Clinical Medical School of Anhui Medical University, Wuxi, P.R. China
| | - Junhui Chen
- Department of Neurosurgery, 101st Hospital of PLA (Wuxi Taihu Hospital), Clinical Medical School of Anhui Medical University, Wuxi, P.R. China
| | - Dongliang Shi
- Department of Neurosurgery, 101st Hospital of PLA (Wuxi Taihu Hospital), Clinical Medical School of Anhui Medical University, Wuxi, P.R. China
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16
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Li Y, Zhang J, Pan J, Feng X, Duan P, Yin X, Xu Y, Wang X, Zou S. Insights into the roles of lncRNAs in skeletal and dental diseases. Cell Biosci 2018; 8:8. [PMID: 29441193 PMCID: PMC5800063 DOI: 10.1186/s13578-018-0208-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 01/30/2018] [Indexed: 02/05/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) are a class of non-protein-coding transcripts with the length longer than 200 nucleotides. Growing evidence suggests that lncRNAs, which were initially thought to be merely transcriptional “noise”, participate in a wide repertoire of biological processes. It has been well established that lncRNAs not only play important roles in genomic regulation, transcription, posttranscriptional processes but are also implicated in the pathogenesis of human diseases including cardiovascular diseases, diabetes, neurodegenerative disorders, and cancer. However, the pathological role of lncRNAs in skeletal and dental diseases is just beginning to be uncovered. In the present review, we outline the current understanding of the established functions and underlying mechanisms of lncRNAs in various cellular processes. Furthermore, we discuss new findings on the role of lncRNAs in osteoblastogenesis and osteoclastogenesis as well as their involvement in skeletal and dental diseases. This review intends to provide a general framework for the actions of lncRNAs and highlight the emerging evidence for the functions of lncRNAs in skeletal and dental diseases.
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Affiliation(s)
- Yuyu Li
- 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China.,2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China
| | - Jiawei Zhang
- 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China.,2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China
| | - Jie Pan
- 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China.,2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China
| | - Xu Feng
- 3Department of Pathology, University of Alabama at Birmingham, 1670 University Blvd., VH G019E, Birmingham, AL 35294 USA
| | - Peipei Duan
- 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China.,2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China
| | - Xing Yin
- 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China.,2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China
| | - Yang Xu
- 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China.,2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China
| | - Xin Wang
- 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China.,2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China
| | - Shujuan Zou
- 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China.,2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu, 610041 China
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17
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Gong X, Wei W, Chen L, Xia Z, Yu C. Comprehensive analysis of long non-coding RNA expression profiles in hepatitis B virus-related hepatocellular carcinoma. Oncotarget 2018; 7:42422-42430. [PMID: 27285756 PMCID: PMC5173145 DOI: 10.18632/oncotarget.9880] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 05/09/2016] [Indexed: 12/30/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common kinds of malignancies and is closely correlated with hepatitis B virus (HBV) infection. Recent evidence has proved that long non-coding RNAs (lncRNAs) are implicated in development and progression of cancer. However, the contributions of lncRNAs to HBV-related HCC remain largely unknown. Here, we comprehensively investigated lncRNA expression profiles in HBV-related HCC by annotating and analyzing microarray datasets. By analyzing 42 HCC tissue samples with different etiology (HBV-related, alcohol-related, and primary HCC) and 15 normal liver tissues, we identified 182 lncRNAs that were specifically differentially expressed in HBV-related HCC, namely HBV-related HCC specific lncRNAs(HH-lncRNAs). Using an online function annotation tool, we found these HH-lncRNAs were associated many oncogenes and immunity related biological processes. 6 candidate HH-lncRNAs were selected and further validated by quantitative real-time PCR analysis in a cohort of HCC tissue samples. Function of a candidate HH-lncRNAs, BAIAP2-AS1, was further predicted by co-expression network and gene set enrichment analysis. These findings provide insights into HH-lncRNAs and offer resource for further search of biomarkers and therapeutic targets of HBV-related HCC.
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Affiliation(s)
- Xianli Gong
- Department of Radiation Oncology, The First Affiliated Hospital, College of Medicine Zhejiang University, Hangzhou 310003, China
| | - Wei Wei
- Department of Radiation Oncology, The First Affiliated Hospital, College of Medicine Zhejiang University, Hangzhou 310003, China
| | - Lan Chen
- Department of Radiation Oncology, The First Affiliated Hospital, College of Medicine Zhejiang University, Hangzhou 310003, China
| | - Zhi Xia
- Department of Radiation Oncology, The First Affiliated Hospital, College of Medicine Zhejiang University, Hangzhou 310003, China
| | - Chengbo Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
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18
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Minotti L, Baldassari F, Galasso M, Volinia S, Bergamini CM, Bianchi N. A long non-coding RNA inside the type 2 transglutaminase gene tightly correlates with the expression of its transcriptional variants. Amino Acids 2018; 50:421-438. [PMID: 29313085 DOI: 10.1007/s00726-017-2528-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 12/10/2017] [Indexed: 12/13/2022]
Abstract
The long non-coding RNAs (lncRNAs) are matter of intense investigation as potential regulators of gene expression. In the case of the transglutaminase 2 gene (TGM2) the databases of genome sequence indicate location of a lncRNA (LOC107987281) within the first intron. This lncRNA is 1000 bp long, arises from 2 exons and starts few nucleotides 3' of the first splicing site of translated TGM2. We have analysed correlations between expression of LOC107987281 lncRNA and TGM2 mRNA by real-time PCR in K562 cell line untreated or treated with the anticancer drugs TPA (12-O-tetradecanoylphorbol-13-acetate), Docetaxel and Doxorubicin. In the treated cells the lncRNA increase follows the trend of TGM2 transcript. To validate this finding we used HumanExon1_0ST Affymetrix; chip data were background-adjusted, quantile-normalized and summarized using robust multi-array average analysis implemented in the R package. The probesets recognize sequences inside each exon, near intronic splicing sites and others located in the untranslated regions of TGM2 gene. The analysis of total RNA samples in GEO datasets from K562, HL-60, THP-1 and U937 cell lines, untreated or treated with TPA in replicated experiments confirmed our earlier results. These demonstrate correlation between LOC107987281 and TGM2 mRNA in the cell lines (K562, HL60 and THP-1) where increased levels of TGM2 mRNA are produced. Additional array study on 358 samples of several normal and paired tumor tissues leads to the same conclusions, indicating a correlation between full-length TGM2 mRNA and LOC107987281 lncRNA in relation to the development of several tumors.
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Affiliation(s)
- Linda Minotti
- Section of Anatomy and Histology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Federica Baldassari
- Section of Anatomy and Histology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Marco Galasso
- Section of Anatomy and Histology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Stefano Volinia
- Section of Anatomy and Histology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Carlo M Bergamini
- Section of Biochemistry, Molecular Biology and Medical Genetics, Department of Biomedical Sciences and Specialist Surgery, University of Ferrara, Via Luigi Borsari 46, 44121, Ferrara, Italy
| | - Nicoletta Bianchi
- Section of Biochemistry, Molecular Biology and Medical Genetics, Department of Biomedical Sciences and Specialist Surgery, University of Ferrara, Via Luigi Borsari 46, 44121, Ferrara, Italy.
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19
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Yang L, Lyu L, Wu W, Lei D, Tu Y, Xu D, Feng J, He L. Genome-wide identification of long non-coding RNA and mRNA profiling using RNA sequencing in subjects with sensitive skin. Oncotarget 2017; 8:114894-114910. [PMID: 29383128 PMCID: PMC5777740 DOI: 10.18632/oncotarget.23147] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 11/14/2017] [Indexed: 12/15/2022] Open
Abstract
Sensitive skin (SS) is a condition of subjective cutaneous hyper-reactivity. The role of long non-coding RNAs (lncRNAs) in subjects with SS is unclear. Therefore, the aim of the present study was to provide a comprehensive profile of the mRNAs and lncRNAs in subjects with SS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis presented the characteristics of associated protein-coding genes. In addition, a co-expression network of lncRNA and mRNA was constructed to identify potential underlying regulation targets; the results were verified by quantitative real-time PCR (qRT-PCR) and RNA-seq analyses in patients with SS and normal samples. Compared with the normal skin group, 266 novel lncRNAs and 6750 annotated lncRNAs were identified in the SS group. A total of 71 lncRNA transcripts and 2615 mRNA transcripts were differentially expressed (P < 0.05). The heat signature of the SS samples could be distinguished from the normal skin samples, whereas the majority of the genes that were present in enriched pathways were those that participated in focal adhesion, PI3K-Akt signaling, and cancer-related pathways. Five transcripts were selected for qRT-PCR analysis and the results were consistent with RNA-seq. The results suggested that LNC_000265 may play a role in the epidermal barrier structure of patient with SS. The data suggest novel genes and pathways that may be involved in the pathogenesis of SS and highlight potential targets that could be used for individualized treatment applications.
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Affiliation(s)
- Li Yang
- Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lechun Lyu
- Technology Transfer Center, Kunming Medical University, Department of Physiology, Kunming Medical University, Kunming, China
| | - Wenjuan Wu
- Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Dongyun Lei
- Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ying Tu
- Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Dan Xu
- Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jiaqi Feng
- Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Li He
- Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
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20
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Ma X, Qi S, Duan Z, Liao H, Yang B, Wang W, Tan J, Li Q, Xia X. Long non-coding RNA LOC554202 modulates chordoma cell proliferation and invasion by recruiting EZH2 and regulating miR-31 expression. Cell Prolif 2017; 50. [PMID: 28963737 DOI: 10.1111/cpr.12388] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Accepted: 08/28/2017] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Chordoma is a rare malignant bone tumour arising from notochordal remnants. Long non-coding RNA LOC554202, as the host gene of miR-31, contributes to various cancer developments. However, little is known about the biological function of LOC554202 in chordoma. Here, the relationship between LncRNA LOC554202, miR-31 and EZH2 was elucidated in chordoma. MATERIALS AND METHODS The levels of LOC554402, miR-31, EZH2, RNF144B, and epithelial-mesenchymal transition (EMT) markers were measured in chordoma tissues and the chordoma cell lines via quantitative real-time PCR (qRT-PCR) or Western blot. FISH assay demonstrated the LOC554402 expression in chordoma tissues. The chordoma cell lines, U-CH1 and JHC7, were transfected with siRNA or miRNA mimics and analysed for cell proliferation ability, apoptosis, cell migration, and invasion. RNA pull down, RIP assay, and Luciferase Reporter Assay were used to analyze the interaction between LOC554202 and EZH2. Animal tumour xenografts were generated, and qRT-PCR was performed to investigate EZH2, miR-31, and RNB144B expression on tumour growth in vivo. RESULTS We found elevated expression of LOC554202 was associated with a decreased level of miR-31 in cancer tissues. Knockdown of LOC554202 or overexpression of miR-31 suppressed the proliferation, migration, and invasion of chordoma cells. Unexpectedly, EZH2 as a binding protein of LOC554202, and it was positively regulated by LOC554202, leading to the reduced expression of miR-31. Furthermore, the impaired function of miR-31 restored expression of the oncogene RNF144B and maintained the metastasis-promoting activity in vitro. The results in vivo confirmed the anti-tumour effects of knockdown of LOC554202, which inhibited EZH2/miR-31 to activate the oncogene RNF144B. CONCLUSION Our results suggest that LOC554202 may play an important role in the progression of chordoma by the direct upregulation of EZH2 and indirect promotion of RNF144B via miR-31.
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Affiliation(s)
- Xianli Ma
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Shengjin Qi
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Zhenying Duan
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Hongzhan Liao
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Baohua Yang
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Wenbo Wang
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Jie Tan
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin, Guangxi, China
| | - Qinghua Li
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin, Guangxi, China
| | - Xuewei Xia
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
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21
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Okajima W, Komatsu S, Ichikawa D, Miyamae M, Ohashi T, Imamura T, Kiuchi J, Nishibeppu K, Arita T, Konishi H, Shiozaki A, Morimura R, Ikoma H, Okamoto K, Otsuji E. Liquid biopsy in patients with hepatocellular carcinoma: Circulating tumor cells and cell-free nucleic acids. World J Gastroenterol 2017; 23:5650-5668. [PMID: 28883691 PMCID: PMC5569280 DOI: 10.3748/wjg.v23.i31.5650] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/14/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), with its high incidence and mortality rate, is one of the most common malignant tumors. Despite recent development of a diagnostic and treatment method, the prognosis of HCC remains poor. Therefore, to provide optimal treatment for each patient with HCC, more precise and effective biomarkers are urgently needed which could facilitate a more detailed individualized decision-making during HCC treatment, including the following; risk assessment, early cancer detection, prediction of treatment or prognostic outcome. In the blood of cancer patients, accumulating evidence about circulating tumor cells and cell-free nucleic acids has suggested their potent clinical utilities as novel biomarker. This concept, so-called "liquid biopsy" is widely known as an alternative approach to cancer tissue biopsy. This method might facilitate a more sensitive diagnosis and better decision-making by obtaining genetic and epigenetic aberrations that are closely associated with cancer initiation and progression. In this article, we review recent developments based on the available literature on both circulating tumor cells and cell-free nucleic acids in cancer patients, especially focusing on Hepatocellular carcinoma.
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Affiliation(s)
- Wataru Okajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Mahito Miyamae
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Ryo Morimura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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22
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Consequences of RNA oxidation on protein synthesis rate and fidelity: implications for the pathophysiology of neuropsychiatric disorders. Biochem Soc Trans 2017; 45:1053-1066. [DOI: 10.1042/bst20160433] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 07/03/2017] [Accepted: 07/05/2017] [Indexed: 12/17/2022]
Abstract
Unlike DNA, oxidative damage to RNA has received little attention presumably due to the assumed transient nature of RNA. However, RNAs including mRNA can persist for several hours to days in certain tissues and are demonstrated to sustain greater oxidative damage than DNA. Because neuronal cells in the brain are continuously exposed to reactive oxygen species due to a high oxygen consumption rate, it is not surprising that neuronal RNA oxidation is observed as a common feature at an early stage in a series of neurodegenerative disorders. A recent study on a well-defined bacterial translation system has revealed that mRNA containing 8-oxo-guanosine (8-oxoGuo) has little effect on fidelity despite the anticipated miscoding. Indeed, 8-oxoGuo-containing mRNA leads to ribosomal stalling with a reduced rate of peptide-bond formation by 3–4 orders of magnitude and is subject to no-go decay, a ribosome-based mRNA surveillance mechanism. Another study demonstrates that transfer RNA oxidation catalyzed by cytochrome c (cyt c) leads to its depurination and cross-linking, which may facilitate cyt c release from mitochondria and subsequently induce apoptosis. Even more importantly, a discovery of oxidized microRNA has been recently reported. The oxidized microRNA causes misrecognizing the target mRNAs and subsequent down-regulation in the protein synthesis. It is noteworthy that oxidative modification to RNA not only interferes with the translational machinery but also with regulatory mechanisms of noncoding RNAs that contribute toward the biological complexity of the mammalian brain. Oxidative RNA damage might be a promising therapeutic target potentially useful for an early intervention of diverse neuropsychiatric disorders.
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23
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Lai Y, Xu P, Liu J, Li Q, Ren D, Zhang J, Wang J. Decreased expression of the long non-coding RNA MLLT4 antisense RNA 1 is a potential biomarker and an indicator of a poor prognosis for gastric cancer. Oncol Lett 2017; 14:2629-2634. [PMID: 28927028 PMCID: PMC5588117 DOI: 10.3892/ol.2017.6478] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 10/14/2016] [Indexed: 01/16/2023] Open
Abstract
In recent years, the identification of long non-coding RNAs (lncRNAs) led to the analysis of their characteristics in cancer biology. However, the expression of lncRNAs in cancer and their clinical significance remain unclear. In the present study, an investigation of lncRNAs that may be involved in the regulation of metastasis using microarray and polymerase chain reaction analyses resulted in the identification of MLLT4 antisense RNA 1 (MLLT4-AS1) as a significantly downregulated lncRNA in gastric cancer tissue compared with normal adjacent tissue (P=0.006). Furthermore, the downregulation of MLL4-AS1 was significantly associated with advanced Tumor-Node-Metastasis stage (P=0.007) and lymph node metastasis (P=0.008). Cox regression analysis showed that MLLT4-AS1 expression was an independent predictor for overall survival (hazard ratio, 13.136; 95% confidence interval, 5.065–34.068; P<0.001). These data suggest that the decreased expression of MLLT4-AS1 is a potential biomarker and a predictor of a poor prognosis for gastric cancer.
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Affiliation(s)
- Yuexing Lai
- Department of Gastroenterology, Shanghai Songjiang Hospital Affiliated to Nanjing Medical University, Shanghai 201600, P.R. China
| | - Ping Xu
- Department of Gastroenterology, Shanghai Songjiang Hospital Affiliated to Nanjing Medical University, Shanghai 201600, P.R. China
| | - Jie Liu
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Qinghua Li
- Department of Gastroenterology, Shanghai Songjiang Hospital Affiliated to Nanjing Medical University, Shanghai 201600, P.R. China
| | - Dabin Ren
- Department of Gastroenterology, Shanghai Songjiang Hospital Affiliated to Nanjing Medical University, Shanghai 201600, P.R. China
| | - Jun Zhang
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jing Wang
- Department of Gastroenterology, Shanghai Songjiang Hospital Affiliated to Nanjing Medical University, Shanghai 201600, P.R. China
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Mumtaz PT, Bhat SA, Ahmad SM, Dar MA, Ahmed R, Urwat U, Ayaz A, Shrivastava D, Shah RA, Ganai NA. LncRNAs and immunity: watchdogs for host pathogen interactions. Biol Proced Online 2017; 19:3. [PMID: 28465674 PMCID: PMC5406993 DOI: 10.1186/s12575-017-0052-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 04/06/2017] [Indexed: 01/23/2023] Open
Abstract
Immune responses combat various infectious agents by inducing inflammatory responses, antimicrobial pathways and adaptive immunity. The polygenic responses to these external stimuli are temporally and coordinately regulated. Specific lncRNAs are induced to modulate innate and adaptive immune responses which can function through various target interactions like RNA-DNA, RNA-RNA, and RNA-protein interaction and hence affect the immunogenic regulation at various stages of gene expression. LncRNA are found to be present in various immune cells like monocytes, macrophages, dendritic cells, neutrophils, T cells and B cells. They have been shown to be involved in many biological processes, including the regulation of the expression of genes, the dosage compensation and genomics imprinting, but the knowledge how lncRNAs are regulated and how they alter cell differentiation/function is still obscure. Further dysregulation of lncRNA has been seen in many diseases, but as yet very less research has been carried out to understand the role of lncRNAs in regulation during host-pathogens interactions. In this review, we summarize the functional developments and mechanism of action of lncRNAs, in immunity and defense of host against pathogens.
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Affiliation(s)
- Peerzada Tajamul Mumtaz
- Division of Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Shuhama, Srinagar, Jammu and Kashmir India
- School of Life Sciences Jaipur National University, Jaipur, Rajasthan India
| | - Shakil Ahmad Bhat
- Division of Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Shuhama, Srinagar, Jammu and Kashmir India
| | - Syed Mudasir Ahmad
- Division of Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Shuhama, Srinagar, Jammu and Kashmir India
| | - Mashooq Ahmad Dar
- Division of Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Shuhama, Srinagar, Jammu and Kashmir India
| | - Raashid Ahmed
- Division of Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Shuhama, Srinagar, Jammu and Kashmir India
| | - Uneeb Urwat
- Division of Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Shuhama, Srinagar, Jammu and Kashmir India
| | - Aadil Ayaz
- Division of Animal Breeding and Genetics, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Shuhama, Srinagar, Jammu and Kashmir India
| | - Divya Shrivastava
- School of Life Sciences Jaipur National University, Jaipur, Rajasthan India
| | - Riaz Ahmad Shah
- Division of Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Shuhama, Srinagar, Jammu and Kashmir India
| | - Nazir Ahmad Ganai
- Division of Animal Breeding and Genetics, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Shuhama, Srinagar, Jammu and Kashmir India
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Zhang H, Zhu C, Zhao Y, Li M, Wu L, Yang X, Wan X, Wang A, Zhang MQ, Sang X, Zhao H. Long non-coding RNA expression profiles of hepatitis C virus-related dysplasia and hepatocellular carcinoma. Oncotarget 2016; 6:43770-8. [PMID: 26540467 PMCID: PMC4791265 DOI: 10.18632/oncotarget.6087] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 10/15/2015] [Indexed: 12/13/2022] Open
Abstract
Recently, long non-coding RNAs (lncRNAs) were found to be implicated in cancer progression. However, the contributions of lncRNAs to Hepatitis C virus-related hepatocellular carcinoma (HCC) remain largely unknown. Here, we characterized lncRNA expression in 73 tissue samples from several different developmental stages of HCV-related hepatocarcinogenesis by repurposing microarray data sets. We found that the expression of 7 lncRNAs in preneoplastic lesions and HCC was significantly different. Among these significantly differently expressed lncRNAs, the lncRNA LINC01419 transcripts were expressed at higher levels in early stage HCC compared to dysplasia and as compared with early stage HCC, lncRNA AK021443 level increase in advanced stage HCC while lncRNA AF070632 level decrease in advanced stage HCC. Using quantitative real-time reverse-transcription PCR, we validated that LINC01419 was significantly overexpressed in HBV-related and HCV-related HCC when compared with matched non-tumor liver tissues. Moreover, functional predictions suggested that LINC01419 and AK021443 regulate cell cycle genes, whereas AF070632 is associated with cofactor binding, oxidation-reduction and carboxylic acid catabolic process. These findings provide the first large-scale survey of lncRNAs associated with the development of hepatocarcinogenesis and may offer new diagnostic biomarkers and therapeutic targets for HCV-related HCC.
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Affiliation(s)
- Haohai Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chengpei Zhu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi Zhao
- School of Medicine, MOE Key Laboratory of Bioinformatics and Bioinformatics Division, Center for Synthetic and System Biology, Tsinghua University, Beijing, China
| | - Ming Li
- Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Liangcai Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaobo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xueshuai Wan
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Anqiang Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Michael Q Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,School of Medicine, MOE Key Laboratory of Bioinformatics and Bioinformatics Division, Center for Synthetic and System Biology, Tsinghua University, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Insights from lncRNAs Profiling of MIN6 Beta Cells Undergoing Inflammation. Mediators Inflamm 2016; 2016:9275106. [PMID: 27698546 PMCID: PMC5028877 DOI: 10.1155/2016/9275106] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 07/12/2016] [Accepted: 07/27/2016] [Indexed: 01/19/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is an organ-specific autoimmune disease characterized by chronic and progressive apoptotic destruction of pancreatic beta cells. During the initial phases of T1DM, cytokines and other inflammatory mediators released by immune cells progressively infiltrate islet cells, induce alterations in gene expression, provoke functional impairment, and ultimately lead to apoptosis. Long noncoding RNAs (lncRNAs) are a new important class of pervasive genes that have a variety of biological functions and play key roles in many diseases. However, whether they have a function in cytokine-induced beta cell apoptosis is still uncertain. In this study, lncRNA microarray technology was used to identify the differently expressed lncRNAs and mRNAs in MIN6 cells exposed to proinflammatory cytokines. Four hundred forty-four upregulated and 279 downregulated lncRNAs were detected with a set filter fold-change ≧2.0. To elucidate the potential functions of these lncRNAs, Gene Ontology (GO) and pathway analyses were used to evaluate the potential functions of differentially expressed lncRNAs. Additionally, a lncRNA-mRNA coexpression network was constructed to predict the interactions between the most strikingly regulated lncRNAs and mRNAs. This study may be utilized as a background or reference resource for future functional studies on lncRNAs related to the diagnosis and development of new therapies for T1DM.
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Imamura T, Komatsu S, Ichikawa D, Kawaguchi T, Miyamae M, Okajima W, Ohashi T, Arita T, Konishi H, Shiozaki A, Morimura R, Ikoma H, Okamoto K, Otsuji E. Liquid biopsy in patients with pancreatic cancer: Circulating tumor cells and cell-free nucleic acids. World J Gastroenterol 2016; 22:5627-5641. [PMID: 27433079 PMCID: PMC4932201 DOI: 10.3748/wjg.v22.i25.5627] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 05/25/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Despite recent advances in surgical techniques and perioperative management, the prognosis of pancreatic cancer (PCa) remains extremely poor. To provide optimal treatment for each patient with Pca, superior biomarkers are urgently needed in all phases of management from early detection to staging, treatment monitoring, and prognosis. In the blood of patients with cancer, circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs), such as DNA, mRNA, and noncoding RNA have been recognized. In the recent years, their presence in the blood has encouraged researchers to investigate their potential use as novel blood biomarkers, and numerous studies have demonstrated their potential clinical utility as a biomarker for certain types of cancer. This concept, called “liquid biopsy” has been focused on as a less invasive, alternative approach to cancer tissue biopsy for obtaining genetic and epigenetic aberrations that contribute to oncogenesis and cancer progression. In this article, we review the available literature on CTCs and cfNAs in patients with cancer, particularly focusing on PCa, and discuss future perspectives in this field.
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Wang G, Li Z, Tian N, Han L, Fu Y, Guo Z, Tian Y. miR-148b-3p inhibits malignant biological behaviors of human glioma cells induced by high HOTAIR expression. Oncol Lett 2016; 12:879-886. [PMID: 27446363 PMCID: PMC4950229 DOI: 10.3892/ol.2016.4743] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 05/26/2016] [Indexed: 01/17/2023] Open
Abstract
Increasing evidence suggests that long non coding (lnc)RNA and microRNA (miRNA/miR) both regulate the expression of key genes in tumorigenesis and have considerable theranostic potential. Rapid advances in bioinformatics indicate that miRNA may potentially interact with lncRNA to modulate their regulatory roles. miR-148b-3p has been reported to have a vital role in regulating tumor progression. However, the expression pattern of miR-148b-3p in glioma remains largely unknown, and interactions between miR-148b-3p and lncRNA has yet to be identified. The aim of the present study was to insight into the regulatory role of miR-148b-3p in glioma. Using online software, the HOTAIR gene was identified as a possible lncRNA target of miR-148b-3p in the present study. siRNA was used to suppress the expression of HOTAIR and reverse transcription-quantitative polymerase chain reaction was used to detect the expression of miR-148b-3p. The results confirmed that HOTAIR mRNA expression was inversely correlated with miR-148b-3p expression in A172 glioma cells. Furthermore, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to detect the viability of cells, flow cytometry was performed to test cell cycle and a matrigel invasion assay was performed to test cell invasion. The results showed that HOTAIR promotes factors associated with malignancy, including cell proliferation, cell cycle progression and invasion, whereas miR-148b-3p suppresses malignancy. Bioinformatics and luciferase reporter assays showed that miR-148b-3p modulates HOTAIR expression by directly targeting the HOTAIR gene sequence. In summary, the results indicated that miR-148b-3p inhibits malignant biological behaviors of glioma cells by directly targeting HOTAIR. The current data provide important evidence for understanding the key roles of the lncRNA miRNA functional network in glioma.
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Affiliation(s)
- Guan Wang
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Zhaohui Li
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Nan Tian
- Department of Cell Biology, College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Liang Han
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Yao Fu
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Zhigang Guo
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Yu Tian
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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Shankar E, Kanwal R, Candamo M, Gupta S. Dietary phytochemicals as epigenetic modifiers in cancer: Promise and challenges. Semin Cancer Biol 2016; 40-41:82-99. [PMID: 27117759 DOI: 10.1016/j.semcancer.2016.04.002] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 04/08/2016] [Accepted: 04/18/2016] [Indexed: 12/21/2022]
Abstract
The influence of diet and environment on human health has been known since ages. Plant-derived natural bioactive compounds (phytochemicals) have acquired an important role in human diet as potent antioxidants and cancer chemopreventive agents. In past few decades, the role of epigenetic alterations such as DNA methylation, histone modifications and non-coding RNAs in the regulation of mammalian genome have been comprehensively addressed. Although the effects of dietary phytochemicals on gene expression and signaling pathways have been widely studied in cancer, the impact of these dietary compounds on mammalian epigenome is rapidly emerging. The present review outlines the role of different epigenetic mechanisms in the regulation and maintenance of mammalian genome and focuses on the role of dietary phytochemicals as epigenetic modifiers in cancer. Above all, the review focuses on summarizing the progress made thus far in cancer chemoprevention with dietary phytochemicals, the heightened interest and challenges in the future.
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Affiliation(s)
- Eswar Shankar
- Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA; Department of Urology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | - Rajnee Kanwal
- Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA; Department of Urology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | - Mario Candamo
- Department of Biology, School of Undergraduate Studies, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Sanjay Gupta
- Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA; Department of Urology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH 44106, USA; Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA; Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
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30
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Yu TT, Xu XM, Hu Y, Deng JJ, Ge W, Han NN, Zhang MX. Long noncoding RNAs in hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol 2015; 21:7208-7217. [PMID: 26109807 PMCID: PMC4476882 DOI: 10.3748/wjg.v21.i23.7208] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 12/26/2014] [Accepted: 03/27/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the expression of long noncoding RNAs (lncRNAs) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).
METHODS: The lncRNA profiles between HBV-related HCC tissues and corresponding normal liver tissues were generated using microarray analysis. Datasets were analyzed using multiple algorithms to depict alterations in gene expression on the basis of gene ontology (GO), pathway analysis, and lncRNA levels.
RESULTS: The microarray revealed that 1772 lncRNAs and 2508 mRNAs were differently expressed. The pathway analysis demonstrated that the cell cycle, cytokine-cytokine receptor interaction, chemokine signaling pathway, and phosphoinositide 3-kinase-protein kinase B signaling pathway may play important roles in HCC. Several GO terms, such as cell cycle, DNA replication, immune response, and signal transduction, were enriched in gene lists, suggesting a potential correlation with HBV-related HCC. The upregulated large intergenic noncoding RNA ULK4P2 was physically combined with enhancer of zeste homolog 2. Therefore, the lncRNAs may participate in regulating HBV-related HCC.
CONCLUSION: lncRNAs play important roles in HCC, future studies should verify whether large intergenic noncoding ULK4P2 functions by combining with enhancer of zeste homolog 2 in HCC.
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31
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Ryu KW, Kim DS, Kraus WL. New facets in the regulation of gene expression by ADP-ribosylation and poly(ADP-ribose) polymerases. Chem Rev 2015; 115:2453-81. [PMID: 25575290 PMCID: PMC4378458 DOI: 10.1021/cr5004248] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Indexed: 12/11/2022]
Affiliation(s)
- Keun Woo Ryu
- Laboratory of Signaling and Gene
Regulation, Cecil H. and Ida Green
Center for Reproductive Biology Sciences, Division of Basic Research, Department
of Obstetrics and Gynecology, and Graduate School of Biomedical Sciences, Program
in Genetics and Development, University
of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Dae-Seok Kim
- Laboratory of Signaling and Gene
Regulation, Cecil H. and Ida Green
Center for Reproductive Biology Sciences, Division of Basic Research, Department
of Obstetrics and Gynecology, and Graduate School of Biomedical Sciences, Program
in Genetics and Development, University
of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - W. Lee Kraus
- Laboratory of Signaling and Gene
Regulation, Cecil H. and Ida Green
Center for Reproductive Biology Sciences, Division of Basic Research, Department
of Obstetrics and Gynecology, and Graduate School of Biomedical Sciences, Program
in Genetics and Development, University
of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
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Guo F, Yu F, Wang J, Li Y, Li Y, Li Z, Zhou Q. Expression of MALAT1 in the peripheral whole blood of patients with lung cancer. Biomed Rep 2015; 3:309-312. [PMID: 26137228 DOI: 10.3892/br.2015.422] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 01/14/2015] [Indexed: 11/06/2022] Open
Abstract
A blood-based biomarker assay is a non-invasive way to screen that can identify lung cancer at an earlier stage to improve the clinical outcome. MALAT1 is a broadly expressed, long non-coding RNA in human tissues and is overexpressed in numerous human carcinomas. The potential of MALAT1 in the whole blood of lung cancer was evaluated. In the present study, blood samples of patients with lung cancer and healthy volunteers (controls) were recruited and analyzed by quantitative polymerase chain reaction (qPCR) for MALAT1 expression and clinicopathological data. Lung cancer tissues were also analyzed by qPCR. The expression of MALAT1 in the whole blood of lung cancer was lower compared to the control. The area under the receiver operator curve was 0.718 (P<0.001). Relatively, the expression of MALAT1 was stronger in the whole blood of lung cancer with metastasis compared to non-metastasis. Additionally, the whole blood with bone or brain metastasis exhibited a higher expression of MALAT1 compared to the blood with lymph node or pleura metastasis. Subsequently, a lower expression of MALAT1 was detected in metastatic lymph node tissues than that of the carcinoma in situ of the lung. Taken together, these results indicate that MALAT1 as a biomarker to screen lung cancer may represent a host response to lung cancer.
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Affiliation(s)
- Fengjie Guo
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Fang Yu
- Department of Laboratories, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Jing Wang
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Yongwen Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Ying Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Zhigang Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China ; Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Qinghua Zhou
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China ; Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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Conte I, Banfi S, Bovolenta P. Non-coding RNAs in the development of sensory organs and related diseases. Cell Mol Life Sci 2013; 70:4141-55. [PMID: 23588489 PMCID: PMC11113508 DOI: 10.1007/s00018-013-1335-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 03/25/2013] [Accepted: 03/27/2013] [Indexed: 12/21/2022]
Abstract
Genomes are transcribed well beyond the conventionally annotated protein-encoding genes and produce many thousands of regulatory non-coding RNAs (ncRNAs). In the last few years, ncRNAs, especially microRNAs and long non-coding RNA, have received increasing attention because of their implication in the function of chromatin-modifying complexes and in the regulation of transcriptional and post-transcriptional events. The morphological events and the genetic networks responsible for the development of sensory organs have been well delineated and therefore sensory organs have provided a useful scenario to address the role of ncRNAs. In this review, we summarize the current information on the importance of microRNAs and long non-coding RNAs during the development of the eye, inner ear, and olfactory system in vertebrates. We will also discuss those cases in which alteration of ncRNA expression has been linked to pathological conditions affecting these organs.
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Affiliation(s)
- Ivan Conte
- Telethon Institute of Genetics and Medicine, Via Pietro Castellino, 111, 80131 Naples, Italy
| | - Sandro Banfi
- Telethon Institute of Genetics and Medicine, Via Pietro Castellino, 111, 80131 Naples, Italy
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Paola Bovolenta
- Centro de Biología Molecular ‘Severo Ochoa’, CSIC–UAM, c/Nicolas Cabrera 1, Cantoblanco, 28049 Madrid, Spain
- CIBER de Enfermedades Raras, ISCIII, Madrid, Spain
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Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, Kim S, Safe S. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene 2012; 32:1616-25. [PMID: 22614017 PMCID: PMC3484248 DOI: 10.1038/onc.2012.193] [Citation(s) in RCA: 675] [Impact Index Per Article: 51.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
HOTAIR is a long intervening non-coding RNA (lincRNA) that associates with the Polycomb Repressive Complex 2 (PRC2) and overexpression is correlated with poor survival for breast, colon and liver cancer patients. In this study, we show that HOTAIR expression is increased in pancreatic tumors compared to non-tumor tissue and is associated with more aggressive tumors. Knockdown of HOTAIR (siHOTAIR) by RNA interference shows that HOTAIR plays an important role in pancreatic cancer cell invasion and as reported in other cancer cell lines. In contrast, HOTAIR knockdown in Panc1 and L3.6pL pancreatic cancer cells that overexpress this lincRNA decreased cell proliferation, altered cell cycle progression, and induced apoptosis, demonstrating an expanded function for HOTAIR in pancreatic cancer cells compared to other cancer cell lines. Results of gene array studies showed that there was minimal overlap between HOTAIR-regulated genes in pancreatic vs. breast cancer cells and HOTAIR uniquely suppressed several interferon-related genes and gene sets related to cell cycle progression in pancreatic cancer cells and tumors. Analysis of selected genes suppressed by HOTAIR in Panc1 and L3.6 pL cells showed by knockdown of EZH2 and chromatin immunoprecipitation assays that HOTAIR-mediated gene repression was both PRC2-dependent and -independent. HOTAIR knockdown in L3.6pL cells inhibited tumor growth in mouse xenograft model, further demonstrating the pro-oncogenic function of HOTAIR in pancreatic cancer.
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Affiliation(s)
- K Kim
- Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA
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35
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Guleria P, Mahajan M, Bhardwaj J, Yadav SK. Plant small RNAs: biogenesis, mode of action and their roles in abiotic stresses. GENOMICS, PROTEOMICS & BIOINFORMATICS 2011; 9:183-99. [PMID: 22289475 PMCID: PMC5054152 DOI: 10.1016/s1672-0229(11)60022-3] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 10/21/2011] [Indexed: 01/01/2023]
Abstract
Small RNAs (sRNAs) are 18-30 nt non-coding regulatory elements found in diverse organisms, which were initially identified as small double-stranded RNAs in Caenorhabditis elegans. With the development of new and improved technologies, sRNAs have also been identified and characterized in plant systems. Among them, micro RNAs (miRNAs) and small interfering RNAs (siRNAs) are found to be very important riboregulators in plants. Various types of sRNAs differ in their mode of biogenesis and in their function of gene regulation. sRNAs are involved in gene regulation at both transcriptional and post-transcriptional levels. They are known to regulate growth and development of plants. Furthermore, sRNAs especially plant miRNAs have been found to be involved in various stress responses, such as oxidative, mineral nutrient deficiency, dehydration, and even mechanical stimulus. Therefore, in the present review, we focus on the current understanding of biogenesis and regulatory mechanisms of plant sRNAs and their responses to various abiotic stresses.
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Affiliation(s)
- Praveen Guleria
- Plant Metabolic Engineering, Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, CSIR, Palampur 176061 (HP), India
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Zong X, Tripathi V, Prasanth KV. RNA splicing control: yet another gene regulatory role for long nuclear noncoding RNAs. RNA Biol 2011; 8:968-77. [PMID: 21941126 DOI: 10.4161/rna.8.6.17606] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The mammalian genome harbors a large number of long non-coding RNAs (lncRNAs) that do not code for proteins, but rather they exert their function directly as RNA molecules. LncRNAs are involved in executing several vital cellular functions. They facilitate the recruitment of proteins to specific chromatin sites, ultimately regulating processes like dosage compensation and genome imprinting. LncRNAs are also known to regulate nucleocytoplasmic transport of macromolecules. A large number of the regulatory lncRNAs are retained within the cell nucleus and constitute a subclass termed nuclear-retained RNAs (nrRNAs). NrRNAs are speculated to be involved in crucial gene regulatory networks, acting as structural scaffolds of subnuclear domains. NrRNAs modulate gene expression by influencing chromatin modification, transcription and post-transcriptional gene processing. The cancer-associated Metastasis-associated lung adenocarcinoma transcript1 (MALAT1) is one such long nrRNA that regulates pre-mRNA processing in mammalian cells. Thus far, our understanding about the roles played by nrRNAs and their relevance in disease pathways is only 'a tip of an iceberg'. It will therefore be crucial to unravel the functions for the vast number of long nrRNAs, buried within the complex mine of the human genome.
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Affiliation(s)
- Xinying Zong
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
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Prasanth KV, Camiolo M, Chan G, Tripathi V, Denis L, Nakamura T, Hübner MR, Spector DL. Nuclear organization and dynamics of 7SK RNA in regulating gene expression. Mol Biol Cell 2010; 21:4184-96. [PMID: 20881057 PMCID: PMC2993747 DOI: 10.1091/mbc.e10-02-0105] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
We have identified 7SK RNA to be enriched in nuclear speckles. Knock-down of 7SK results in the mislocalization of nuclear speckle constituents, and the transcriptional up-regulation of a reporter gene locus. 7SK RNA transiently associates with the locus upon transcriptional down-regulation correlating with the displacement of pTEF-b. Noncoding RNAs play important roles in various aspects of gene regulation. We have identified 7SK RNA to be enriched in nuclear speckles or interchromatin granule clusters (IGCs), a subnuclear domain enriched in pre-mRNA processing factors. 7SK RNA, in association with HEXIM 1 and 2, is involved in the inhibition of transcriptional elongation by RNA polymerase II. Inhibition occurs via sequestration of the active P-TEFb kinase complex (CDK 9 and Cyclin T1/T2a/b or K) that is involved in phosphorylating the C-terminal domain of RNA polymerase II. Our results demonstrate that knock-down of 7SK RNA, by specific antisense oligonucleotides, results in the mislocalization of nuclear speckle constituents in a transcription-dependent manner, and the transcriptional up-regulation of a RNA polymerase II transcribed reporter gene locus. Furthermore, 7SK RNA transiently associates with a stably integrated reporter gene locus upon transcriptional down-regulation and its presence correlates with the efficient displacement of P-TEFb constituents from the locus. Our results suggest that 7SK RNA plays a role in modulating the available level of P-TEFb upon transcriptional down-regulation by sequestering its constituents in nuclear speckles.
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Baratti MO, Moreira YB, Traina F, Costa FF, Verjovski-Almeida S, Olalla-Saad ST. Identification of protein-coding and non-coding RNA expression profiles in CD34+ and in stromal cells in refractory anemia with ringed sideroblasts. BMC Med Genomics 2010; 3:30. [PMID: 20633296 PMCID: PMC2914047 DOI: 10.1186/1755-8794-3-30] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Accepted: 07/15/2010] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Myelodysplastic syndromes (MDS) are a group of clonal hematological disorders characterized by ineffective hematopoiesis with morphological evidence of marrow cell dysplasia resulting in peripheral blood cytopenia. Microarray technology has permitted a refined high-throughput mapping of the transcriptional activity in the human genome. Non-coding RNAs (ncRNAs) transcribed from intronic regions of genes are involved in a number of processes related to post-transcriptional control of gene expression, and in the regulation of exon-skipping and intron retention. Characterization of ncRNAs in progenitor cells and stromal cells of MDS patients could be strategic for understanding gene expression regulation in this disease. METHODS In this study, gene expression profiles of CD34+ cells of 4 patients with MDS of refractory anemia with ringed sideroblasts (RARS) subgroup and stromal cells of 3 patients with MDS-RARS were compared with healthy individuals using 44 k combined intron-exon oligoarrays, which included probes for exons of protein-coding genes, and for non-coding RNAs transcribed from intronic regions in either the sense or antisense strands. Real-time RT-PCR was performed to confirm the expression levels of selected transcripts. RESULTS In CD34+ cells of MDS-RARS patients, 216 genes were significantly differentially expressed (q-value <or= 0.01) in comparison to healthy individuals, of which 65 (30%) were non-coding transcripts. In stromal cells of MDS-RARS, 12 genes were significantly differentially expressed (q-value <or= 0.05) in comparison to healthy individuals, of which 3 (25%) were non-coding transcripts. CONCLUSIONS These results demonstrated, for the first time, the differential ncRNA expression profile between MDS-RARS and healthy individuals, in CD34+ cells and stromal cells, suggesting that ncRNAs may play an important role during the development of myelodysplastic syndromes.
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Affiliation(s)
- Mariana O Baratti
- Department of Internal Medicine, School of Medical Science, Hematology and Hemotherapy Center, University of Campinas, 13083-970 Campinas, SP, Brazil
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Nunomura A, Honda K, Takeda A, Hirai K, Zhu X, Smith MA, Perry G. Oxidative damage to RNA in neurodegenerative diseases. J Biomed Biotechnol 2010; 2006:82323. [PMID: 17047315 PMCID: PMC1559934 DOI: 10.1155/jbb/2006/82323] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Since 1999, oxidative damage to RNA molecules has been described
in several neurological diseases including Alzheimer's
disease, Parkinson's disease, Down syndrome, dementia
with Lewy bodies, prion disease, subacute sclerosing
panencephalitis, and xeroderma pigmentosum. An early involvement
of RNA oxidation of vulnerable neuronal population in the
neurodegenerative diseases has been demonstrated, which is
strongly supported by a recent observation of increased RNA
oxidation in brains of subjects with mild cognitive impairment.
Until recently, little is known about consequences and cellular
handling of the RNA damage. However, increasing body of evidence
suggests detrimental effects of the RNA damage in protein
synthesis and the existence of several coping mechanisms including
direct repair and avoiding the incorporation of the damaged
ribonucleotides into translational machinery. Further
investigations toward understanding of the consequences and
cellular handling mechanisms of the oxidative RNA damage may
provide significant insights into the pathogenesis and therapeutic
strategies of the neurodegenerative diseases.
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Affiliation(s)
- Akihiko Nunomura
- Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa 078-8510, Japan
- *Akihiko Nunomura:
| | - Kazuhiro Honda
- Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Atsushi Takeda
- Department of Neurology, School of Medicine, Tohoku University, Sendai 980-8574, Japan
| | - Keisuke Hirai
- Pharmaceutical Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Limited,
Osaka 532-8686, Japan
| | - Xiongwei Zhu
- Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Mark A. Smith
- Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - George Perry
- Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
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Mercer TR, Qureshi IA, Gokhan S, Dinger ME, Li G, Mattick JS, Mehler MF. Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation. BMC Neurosci 2010; 11:14. [PMID: 20137068 PMCID: PMC2829031 DOI: 10.1186/1471-2202-11-14] [Citation(s) in RCA: 329] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2009] [Accepted: 02/05/2010] [Indexed: 11/21/2022] Open
Abstract
Background Long non-protein-coding RNAs (ncRNAs) are emerging as important regulators of cellular differentiation and are widely expressed in the brain. Results Here we show that many long ncRNAs exhibit dynamic expression patterns during neuronal and oligodendrocyte (OL) lineage specification, neuronal-glial fate transitions, and progressive stages of OL lineage elaboration including myelination. Consideration of the genomic context of these dynamically regulated ncRNAs showed they were part of complex transcriptional loci that encompass key neural developmental protein-coding genes, with which they exhibit concordant expression profiles as indicated by both microarray and in situ hybridization analyses. These included ncRNAs associated with differentiation-specific nuclear subdomains such as Gomafu and Neat1, and ncRNAs associated with developmental enhancers and genes encoding important transcription factors and homeotic proteins. We also observed changes in ncRNA expression profiles in response to treatment with trichostatin A, a histone deacetylase inhibitor that prevents the progression of OL progenitors into post-mitotic OLs by altering lineage-specific gene expression programs. Conclusion This is the first report of long ncRNA expression in neuronal and glial cell differentiation and of the modulation of ncRNA expression by modification of chromatin architecture. These observations explicitly link ncRNA dynamics to neural stem cell fate decisions, specification and epigenetic reprogramming and may have important implications for understanding and treating neuropsychiatric diseases.
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Affiliation(s)
- Tim R Mercer
- Institute for Molecular Bioscience, University of Queensland, 306 Carmody Road, Brisbane, QLD 4072, Australia
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Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 2009; 23:1494-504. [PMID: 19571179 DOI: 10.1101/gad.1800909] [Citation(s) in RCA: 1854] [Impact Index Per Article: 115.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Most of the eukaryotic genome is transcribed, yielding a complex network of transcripts that includes tens of thousands of long noncoding RNAs with little or no protein-coding capacity. Although the vast majority of long noncoding RNAs have yet to be characterized thoroughly, many of these transcripts are unlikely to represent transcriptional "noise" as a significant number have been shown to exhibit cell type-specific expression, localization to subcellular compartments, and association with human diseases. Here, we highlight recent efforts that have identified a myriad of molecular functions for long noncoding RNAs. In some cases, it appears that simply the act of noncoding RNA transcription is sufficient to positively or negatively affect the expression of nearby genes. However, in many cases, the long noncoding RNAs themselves serve key regulatory roles that were assumed previously to be reserved for proteins, such as regulating the activity or localization of proteins and serving as organizational frameworks of subcellular structures. In addition, many long noncoding RNAs are processed to yield small RNAs or, conversely, modulate how other RNAs are processed. It is thus becoming increasingly clear that long noncoding RNAs can function via numerous paradigms and are key regulatory molecules in the cell.
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Affiliation(s)
- Jeremy E Wilusz
- Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
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Abstract
The majority of the genome in animals and plants is transcribed in a developmentally regulated manner to produce large numbers of non-protein-coding RNAs (ncRNAs), whose incidence increases with developmental complexity. There is growing evidence that these transcripts are functional, particularly in the regulation of epigenetic processes, leading to the suggestion that they compose a hitherto hidden layer of genomic programming in humans and other complex organisms. However, to date, very few have been identified in genetic screens. Here I show that this is explicable by an historic emphasis, both phenotypically and technically, on mutations in protein-coding sequences, and by presumptions about the nature of regulatory mutations. Most variations in regulatory sequences produce relatively subtle phenotypic changes, in contrast to mutations in protein-coding sequences that frequently cause catastrophic component failure. Until recently, most mapping projects have focused on protein-coding sequences, and the limited number of identified regulatory mutations have been interpreted as affecting conventional cis-acting promoter and enhancer elements, although these regions are often themselves transcribed. Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction. The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions. There is every possibility that many of these variations will alter the interactions between regulatory RNAs and their targets, a prospect that should be borne in mind in future functional analyses.
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Affiliation(s)
- John S Mattick
- Australian Research Council Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Australia.
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The regulation of non-coding RNA expression in the liver of mice fed DDC. Exp Mol Pathol 2009; 87:12-9. [PMID: 19362547 DOI: 10.1016/j.yexmp.2009.03.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2009] [Accepted: 03/30/2009] [Indexed: 12/13/2022]
Abstract
Mallory-Denk bodies (MDBs) are found in the liver of patients with alcoholic and chronic nonalcoholic liver disease, and hepatocellular carcinoma (HCC). Diethyl 1,4-dihydro-2,4,6,-trimethyl-3,5-pyridinedicarboxylate (DDC) is used as a model to induce the formation of MDBs in mouse liver. Previous studies in this laboratory showed that DDC induced epigenetic modifications in DNA and histones. The combination of these modifications changes the phenotype of the MDB forming hepatocytes, as indicated by the marker FAT10. These epigenetic modifications are partially prevented by adding to the diet S-adenosylmethionine (SAMe) or betaine, both methyl donors. The expression of three imprinted ncRNA genes was found to change in MDB forming hepatocytes, which is the subject of this report. NcRNA expression was quantitated by real-time PCR and RNA FISH in liver sections. Microarray analysis showed that the expression of three ncRNAs was regulated by DDC: up regulation of H19, antisense Igf2r (AIR), and down regulation of GTL2 (also called MEG3). S-adenosylmethionine (SAMe) feeding prevented these changes. Betaine, another methyl group donor, prevented only H19 and AIR up regulation induced by DDC, on microarrays. The results of the SAMe and betaine groups were confirmed by real-time PCR, except for AIR expression. After 1 month of drug withdrawal, the expression of the three ncRNAs tended toward control levels of expression. Liver tumors that developed also showed up regulation of H19 and AIR. The RNA FISH approach showed that the MDB forming cells' phenotype changed the level of expression of AIR, H19 and GTL2, compared to the surrounding cells. Furthermore, over expression of H19 and AIR was demonstrated in tumors formed in mice withdrawn for 9 months. The dysregulation of ncRNA in MDB forming liver cells has been observed for the first time in drug-primed mice associated with liver preneoplastic foci and tumors.
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Wilusz JE, Freier SM, Spector DL. 3' end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell 2008; 135:919-32. [PMID: 19041754 DOI: 10.1016/j.cell.2008.10.012] [Citation(s) in RCA: 566] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2008] [Revised: 07/25/2008] [Accepted: 10/07/2008] [Indexed: 02/06/2023]
Abstract
MALAT1 is a long noncoding RNA known to be misregulated in many human cancers. We have identified a highly conserved small RNA of 61 nucleotides originating from the MALAT1 locus that is broadly expressed in human tissues. Although the long MALAT1 transcript localizes to nuclear speckles, the small RNA is found exclusively in the cytoplasm. RNase P cleaves the nascent MALAT1 transcript downstream of a genomically encoded poly(A)-rich tract to simultaneously generate the 3' end of the mature MALAT1 transcript and the 5' end of the small RNA. Enzymes involved in tRNA biogenesis then further process the small RNA, consistent with its adoption of a tRNA-like structure. Our findings reveal a 3' end processing mechanism by which a single gene locus can yield both a stable nuclear-retained noncoding RNA with a short poly(A) tail-like moiety and a small tRNA-like cytoplasmic RNA.
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Affiliation(s)
- Jeremy E Wilusz
- Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Seim I, Carter SL, Herington AC, Chopin LK. Complex organisation and structure of the ghrelin antisense strand gene GHRLOS, a candidate non-coding RNA gene. BMC Mol Biol 2008; 9:95. [PMID: 18954468 PMCID: PMC2621237 DOI: 10.1186/1471-2199-9-95] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2008] [Accepted: 10/28/2008] [Indexed: 12/13/2022] Open
Abstract
Background The peptide hormone ghrelin has many important physiological and pathophysiological roles, including the stimulation of growth hormone (GH) release, appetite regulation, gut motility and proliferation of cancer cells. We previously identified a gene on the opposite strand of the ghrelin gene, ghrelinOS (GHRLOS), which spans the promoter and untranslated regions of the ghrelin gene (GHRL). Here we further characterise GHRLOS. Results We have described GHRLOS mRNA isoforms that extend over 1.4 kb of the promoter region and 106 nucleotides of exon 4 of the ghrelin gene, GHRL. These GHRLOS transcripts initiate 4.8 kb downstream of the terminal exon 4 of GHRL and are present in the 3' untranslated exon of the adjacent gene TATDN2 (TatD DNase domain containing 2). Interestingly, we have also identified a putative non-coding TATDN2-GHRLOS chimaeric transcript, indicating that GHRLOS RNA biogenesis is extremely complex. Moreover, we have discovered that the 3' region of GHRLOS is also antisense, in a tail-to-tail fashion to a novel terminal exon of the neighbouring SEC13 gene, which is important in protein transport. Sequence analyses revealed that GHRLOS is riddled with stop codons, and that there is little nucleotide and amino-acid sequence conservation of the GHRLOS gene between vertebrates. The gene spans 44 kb on 3p25.3, is extensively spliced and harbours multiple variable exons. We have also investigated the expression of GHRLOS and found evidence of differential tissue expression. It is highly expressed in tissues which are emerging as major sites of non-coding RNA expression (the thymus, brain, and testis), as well as in the ovary and uterus. In contrast, very low levels were found in the stomach where sense, GHRL derived RNAs are highly expressed. Conclusion GHRLOS RNA transcripts display several distinctive features of non-coding (ncRNA) genes, including 5' capping, polyadenylation, extensive splicing and short open reading frames. The gene is also non-conserved, with differential and tissue-restricted expression. The overlapping genomic arrangement of GHRLOS with the ghrelin gene indicates that it is likely to have interesting regulatory and functional roles in the ghrelin axis.
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Affiliation(s)
- Inge Seim
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
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Sublethal RNA oxidation as a mechanism for neurodegenerative disease. Int J Mol Sci 2008; 9:789-806. [PMID: 19325784 PMCID: PMC2635712 DOI: 10.3390/ijms9050789] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2008] [Revised: 05/15/2008] [Accepted: 05/16/2008] [Indexed: 12/27/2022] Open
Abstract
Although cellular RNA is subjected to the same oxidative insults as DNA and other cellular macromolecules, oxidative damage to RNA has not been a major focus in investigations of the biological consequences of free radical damage. In fact, because it is largely single-stranded and its bases lack the protection of hydrogen bonding and binding by specific proteins, RNA may be more susceptible to oxidative insults than is DNA. Oxidative damage to protein-coding RNA or non-coding RNA will, in turn, potentially cause errors in proteins and/or dysregulation of gene expression. While less lethal than mutations in the genome, such sublethal insults to cells might be associated with underlying mechanisms of several chronic diseases, including neurodegenerative disease. Recently, oxidative RNA damage has been described in several neurodegenerative diseases including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and prion diseases. Of particular interest, oxidative RNA damage can be demonstrated in vulnerable neurons early in disease, suggesting that RNA oxidation may actively contribute to the onset of the disease. An increasing body of evidence suggests that, mechanistically speaking, the detrimental effects of oxidative RNA damage to protein synthesis are attenuated, at least in part, by the existence of protective mechanisms that prevent the incorporation of the damaged ribonucleotides into the translational machinery. Further investigations aimed at understanding the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative and other degenerative diseases and lead to better therapeutic strategies.
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Gilbert SD, Love CE, Edwards AL, Batey RT. Mutational analysis of the purine riboswitch aptamer domain. Biochemistry 2007; 46:13297-309. [PMID: 17960911 DOI: 10.1021/bi700410g] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The purine riboswitch is one of a number of mRNA elements commonly found in the 5'-untranslated region capable of controlling expression in a cis-fashion via its ability to directly bind small-molecule metabolites. Extensive biochemical and structural analysis of the nucleobase-binding domain of the riboswitch, referred to as the aptamer domain, has revealed that the mRNA recognizes its cognate ligand using an intricately folded three-way junction motif that completely encapsulates the ligand. High-affinity binding of the purine nucleobase is facilitated by a distal loop-loop interaction that is conserved between both the adenine and guanine riboswitches. To understand the contribution of conserved nucleotides in both the three-way junction and the loop-loop interaction of this RNA, we performed a detailed mutagenic survey of these elements in the context of an adenine-responsive variant of the xpt-pbuX guanine riboswitch from Bacillus subtilis. The varying ability of these mutants to bind ligand as measured by isothermal titration calorimetry uncovered the conserved nucleotides whose identity is required for purine binding. Crystallographic analysis of the bound form of five mutants and chemical probing of their free state demonstrate that the identity of several universally conserved nucleotides is not essential for formation of the RNA-ligand complex but rather for maintaining a binding-competent form of the free RNA. These data show that conservation patterns in riboswitches arise from a combination of formation of the ligand-bound complex, promoting an open form of the free RNA, and participating in the secondary structural switch with the expression platform.
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Affiliation(s)
- Sunny D Gilbert
- Department of Chemistry and Biochemistry, University of Colorado at Boulder, Campus Box 215, Boulder, Colorado 80309-0215, USA
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Abstract
The noncoding RNA database (ncRNAdb) was created as a source of information on RNA molecules, which do not possess protein-coding capacity. It is now widely accepted that, in addition to constitutively expressed, housekeeping or infrastructural RNAs, there is a wide variety of RNAs participating in mechanisms involved in regulation of gene expression at all levels of transmission of genetic information from DNA to proteins. Noncoding RNAs' activities include chromatin structure remodeling, transcriptional and translational regulation of gene expression, modulation of protein function and regulation of subcellular distribution of RNAs as well as proteins. Noncoding transcripts have been identified in organisms belonging to all domains of life. Currently, the ncRNAdb contains >30 000 ncRNA sequences from Eukaryotes, Eubacteria and Archaea, but does not include housekeeping transcripts or microRNAs and snoRNAs for which more specialized databases are available. The contents of the database can be accessed via the WWW at .
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Affiliation(s)
- Maciej Szymanski
- Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Noskowskiego 12 61-704 Poznan, Poland.
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Kaplan JC. Ni gènes, ni junk, mais des TAR/TUF ! Med Sci (Paris) 2005; 21:1005. [PMID: 16274656 DOI: 10.1051/medsci/200521111005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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