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John A, Almulla N, Elboughdiri N, Gacem A, Yadav KK, Abass AM, Alam MW, Wani AW, Bashir SM, Rab SO, Kumar A, Wani AK. Non-coding RNAs in Cancer: Mechanistic insights and therapeutic implications. Pathol Res Pract 2024; 266:155745. [PMID: 39637712 DOI: 10.1016/j.prp.2024.155745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/23/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024]
Abstract
Non-coding RNAs have gathered significant attention for their unique roles in biological regulation. Across a broad spectrum of developmental processes and diseases, particularly in human malignancies, ncRNAs play pivotal roles in regulatory mechanisms. MicroRNAs, long noncoding RNAs, and small nucleolar RNAs stand out among the diverse forms of ncRNAs that have been implicated in cancer. MiRNAs, classified as short non-coding RNAs, modulate gene expression by binding to messenger RNA molecules, thereby inhibiting their translation. Altered miRNA expression has been associated with the onset and progression of various malignancies, including lung, breast, and prostate cancer. In contrast, lncRNAs, characterized as longer ncRNAs, exert control over gene expression through various mechanisms, such as chromatin remodelling and gene silencing. This review offers a comprehensive examination of the numerous ncRNAs that have emerged as crucial regulators of gene expression, playing implicated roles in the initiation and progression of diverse cancers.
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Affiliation(s)
- Arjumand John
- School of Bioengineering and Biosciences, Lovely Professional University, Jalandhar, Punjab 144411, India
| | - Nuha Almulla
- Department of Biology, Adham University College, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Noureddine Elboughdiri
- Chemical Engineering Department, College of Engineering, University of Ha'il, P.O. Box 2440, Ha'il 81441, Saudi Arabia
| | - Amel Gacem
- Department of Physics, Faculty of Sciences, University 20 Aout, Skikda 1955, Algeria
| | - Krishna Kumar Yadav
- Department of VLSI Microelectronics, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai - 602105, Tamil Nadu, India; Environmental and Atmospheric Sciences Research Group, Scientific Research Center, Al-Ayen University, Thi-Qar, Nasiriyah 64001, Iraq
| | - Anass M Abass
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia
| | - Mir Waqas Alam
- Department of Physics, College of Science, King Faisal University, Al Ahsa 31982, Saudi Arabia.
| | - Ab Waheed Wani
- Department of Horticulture, School of Agriculture, Lovely Professional University, Jalandhar, Punjab 144411, India
| | - Showkeen Muzamil Bashir
- Biochemistry & Molecular Biology Lab, Division of Veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology, Srinagar, Jammu and Kashmir 190006, India
| | - Safia Obaidur Rab
- Central Labs, King Khalid University, AlQura'a, P.O. Box 960, Abha, Saudi Arabia; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Abhinav Kumar
- Department of Nuclear and Renewable Energy, Ural Federal University Named after the First President of Russia Boris Yeltsin, Ekaterinburg 620002, Russia; Department of Technical Sciences, Western Caspian University, Baku, Azerbaijan; Department of Mechanical Engineering, Karpagam Academy of Higher Education, Coimbatore 641021, India
| | - Atif Khurshid Wani
- School of Bioengineering and Biosciences, Lovely Professional University, Jalandhar, Punjab 144411, India.
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2
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Sakuraba Y, Yang M, Yanagisawa S. HASTY-mediated miRNA dynamics modulate nitrogen starvation-induced leaf senescence in Arabidopsis. Nat Commun 2024; 15:7913. [PMID: 39256370 PMCID: PMC11387735 DOI: 10.1038/s41467-024-52339-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 08/30/2024] [Indexed: 09/12/2024] Open
Abstract
Nitrogen (N) deficiency responses are essential for plant survival and reproduction. Here, via an expression genome-wide association study (eGWAS), we reveal a mechanism that regulates microRNA (miRNA) dynamics necessary for N deficiency responses in Arabidopsis. Differential expression levels of three NAC transcription factor (TF) genes involved in leaf N deficiency responses among Arabidopsis accessions are most significantly associated with polymorphisms in HASTY (HST), which encodes an importin/exportin family protein responsible for the generation of mature miRNAs. HST acts as a negative regulator of N deficiency-induced leaf senescence, and the disruption and overexpression of HST differently modifies miRNA dynamics in response to N deficiency, altering levels of miRNAs targeting transcripts. Interestingly, N deficiency prevents the interaction of HST with HST-interacting proteins, DCL1 and RAN1, and some miRNAs. This suggests that HST-mediated regulation of miRNA dynamics collectively controls regulations mediated by multiple N deficiency response-associated NAC TFs, thereby being central to the N deficiency response network.
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Affiliation(s)
- Yasuhito Sakuraba
- Plant Functional Biotechnology, Agro-Biotechnology Research Center, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Mailun Yang
- Plant Functional Biotechnology, Agro-Biotechnology Research Center, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Shuichi Yanagisawa
- Plant Functional Biotechnology, Agro-Biotechnology Research Center, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo, 113-8657, Japan.
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Zhang J, Yang L, Sun Y, Zhang L, Wang Y, Liu M, Li X, Liang Y, Zhao H, Liu Z, Qiu Z, Zhang T, Xie J. Up-regulation of miR-10a-5p expression inhibits the proliferation and differentiation of neural stem cells by targeting Chl1. Acta Biochim Biophys Sin (Shanghai) 2024; 56:1483-1497. [PMID: 38841745 PMCID: PMC11532229 DOI: 10.3724/abbs.2024078] [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: 01/30/2024] [Accepted: 03/07/2024] [Indexed: 06/07/2024] Open
Abstract
Neural tube defects (NTDs) are characterized by the failure of neural tube closure during embryogenesis and are considered the most common and severe central nervous system anomalies during early development. Recent microRNA (miRNA) expression profiling studies have revealed that the dysregulation of several miRNAs plays an important role in retinoic acid (RA)-induced NTDs. However, the molecular functions of these miRNAs in NTDs remain largely unidentified. Here, we show that miR-10a-5p is significantly upregulated in RA-induced NTDs and results in reduced cell growth due to cell cycle arrest and dysregulation of cell differentiation. Moreover, the cell adhesion molecule L1-like ( Chl1) is identified as a direct target of miR-10a-5p in neural stem cells (NSCs) in vitro, and its expression is reduced in RA-induced NTDs. siRNA-mediated knockdown of intracellular Chl1 affects cell proliferation and differentiation similar to those of miR-10a-5p overexpression, which further leads to the inhibition of the expressions of downstream ERK1/2 MAPK signaling pathway proteins. These cellular responses are abrogated by either increased expression of the direct target of miR-10a-5p ( Chl1) or an ERK agonist such as honokiol. Overall, our study demonstrates that miR-10a-5p plays a major role in the process of NSC growth and differentiation by directly targeting Chl1, which in turn induces the downregulation of the ERK1/2 cascade, suggesting that miR-10a-5p and Chl1 are critical for NTD formation in the development of embryos.
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Affiliation(s)
- Juan Zhang
- Department of Biochemistry and Molecular BiologySchool of Basic Medical ScienceShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
- of Cell Biology and GeneticsSchool of Basic Medical ScienceShanxi Medical UniversityTaiyuan030001China
| | - Lihong Yang
- Department of Biochemistry and Molecular BiologySchool of Basic Medical ScienceShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Yuqing Sun
- Department of Biochemistry and Molecular BiologySchool of Basic Medical ScienceShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Li Zhang
- Department of Biochemistry and Molecular BiologySchool of Basic Medical ScienceShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Yufei Wang
- Department of Biochemistry and Molecular BiologySchool of Basic Medical ScienceShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Ming Liu
- of Cell Biology and GeneticsSchool of Basic Medical ScienceShanxi Medical UniversityTaiyuan030001China
| | - Xiujuan Li
- Department of Biochemistry and Molecular BiologySchool of Basic Medical ScienceShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Yuxiang Liang
- Department of Biochemistry and Molecular BiologySchool of Basic Medical ScienceShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Hong Zhao
- Department of Biochemistry and Molecular BiologySchool of Basic Medical ScienceShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Zhizhen Liu
- Department of Biochemistry and Molecular BiologySchool of Basic Medical ScienceShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Zhiyong Qiu
- Beijing Municipal Key Laboratory of Child Development and NutriomicsCapital Institute of PediatricsBeijing100020China
| | - Ting Zhang
- Beijing Municipal Key Laboratory of Child Development and NutriomicsCapital Institute of PediatricsBeijing100020China
| | - Jun Xie
- Department of Biochemistry and Molecular BiologySchool of Basic Medical ScienceShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
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Fattahi M, Rahdan F, Shaterabadi D, Zamani Sani M, Alizadeh M, Khatami SH, Taheri-Anganeh M, Movahedpour A, Ghasemi H. MicroRNA biosensors for the detection of liver cancer. Clin Chim Acta 2024; 554:117796. [PMID: 38272250 DOI: 10.1016/j.cca.2024.117796] [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: 12/07/2023] [Revised: 01/21/2024] [Accepted: 01/22/2024] [Indexed: 01/27/2024]
Abstract
Liver cancer is one of the deadliest types worldwide and early diagnosis is highly important for successful treatment. Therefore, it is necessary to develop rapid, sensitive, simple, and inexpensive analytical tools for its detection. MicroRNAs (miRNA) represent unique biomarkers whose expression in biofluids is strongly associated with cancer in general and miR-21, -31, -122, -145, -146a, -200c, -221, -222, and -223 in liver cancer, specifically. Various biosensors for miRNA detection have been developed. These include electrochemical biosensors based on amperometric, potentiometric, conductometric and impedimetric technology. Furthermore, the use of advanced nanomaterials with enhanced chemical stability, conductivity and electrocatalytic activity have greatly increased the sensitivity and specificity of these devices. The present review focuses on recent advances in electrochemical biosensors for miRNA detection in liver cancer.
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Affiliation(s)
- Mehdi Fattahi
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam; School of Engineering & Technology, Duy Tan University, Da Nang, Vietnam
| | - Fereshteh Rahdan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Donya Shaterabadi
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Zamani Sani
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Alizadeh
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyyed Hossein Khatami
- 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
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Bassal MA. The Interplay between Dysregulated Metabolism and Epigenetics in Cancer. Biomolecules 2023; 13:944. [PMID: 37371524 DOI: 10.3390/biom13060944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/21/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023] Open
Abstract
Cellular metabolism (or energetics) and epigenetics are tightly coupled cellular processes. It is arguable that of all the described cancer hallmarks, dysregulated cellular energetics and epigenetics are the most tightly coregulated. Cellular metabolic states regulate and drive epigenetic changes while also being capable of influencing, if not driving, epigenetic reprogramming. Conversely, epigenetic changes can drive altered and compensatory metabolic states. Cancer cells meticulously modify and control each of these two linked cellular processes in order to maintain their tumorigenic potential and capacity. This review aims to explore the interplay between these two processes and discuss how each affects the other, driving and enhancing tumorigenic states in certain contexts.
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Affiliation(s)
- Mahmoud Adel Bassal
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA
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Liu H, Guan H, He F, Song Y, Li F, Sun-Waterhouse D, Li D. Therapeutic actions of tea phenolic compounds against oxidative stress and inflammation as central mediators in the development and progression of health problems: A review focusing on microRNA regulation. Crit Rev Food Sci Nutr 2023; 64:8414-8444. [PMID: 37074177 DOI: 10.1080/10408398.2023.2202762] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2023]
Abstract
Many health problems including chronic diseases are closely associated with oxidative stress and inflammation. Tea has abundant phenolic compounds with various health benefits including antioxidant and anti-inflammatory properties. This review focuses on the present understanding of the impact of tea phenolic compounds on the expression of miRNAs, and elucidates the biochemical and molecular mechanisms underlying the transcriptional and post-transcriptional protective actions of tea phenolic compounds against oxidative stress- and/or inflammation-mediated diseases. Clinical studies showed that drinking tea or taking catechin supplement on a daily basis promoted the endogenous antioxidant defense system of the body while inhibiting inflammatory factors. The regulation of chronic diseases based on epigenetic mechanisms, and the epigenetic-based therapies involving different tea phenolic compounds, have been insufficiently studied. The molecular mechanisms and application strategies of miR-27 and miR-34 involved in oxidative stress response and miR-126 and miR-146 involved in inflammation process were preliminarily investigated. Some emerging evidence suggests that tea phenolic compounds may promote epigenetic changes, involving non-coding RNA regulation, DNA methylation, histone modification, ubiquitin and SUMO modifications. However, epigenetic mechanisms and epigenetic-based disease therapies involving phenolic compounds from different teas, and the potential cross-talks among the epigenetic events, remain understudied.
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Affiliation(s)
- Hui Liu
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, P.R. China
| | - Hui Guan
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, P.R. China
| | - Fatao He
- All-China Federation of Supply & Marketing Co-operatives, Jinan Fruit Research Institute, Jinan, P.R. China
| | - Ye Song
- All-China Federation of Supply & Marketing Co-operatives, Jinan Fruit Research Institute, Jinan, P.R. China
| | - Feng Li
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, P.R. China
| | - Dongxiao Sun-Waterhouse
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, P.R. China
- School of Chemical Sciences, The University of Auckland, Auckland, New Zealand
| | - Dapeng Li
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, P.R. China
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Chen J, Lin Y, Sun Z. Inhibition of miR-101-3p prevents human aortic valve interstitial cell calcification through regulation of CDH11/SOX9 expression. Mol Med 2023; 29:24. [PMID: 36809926 PMCID: PMC9945614 DOI: 10.1186/s10020-023-00619-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 02/10/2023] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND Calcific aortic valve disease (CAVD) is the second leading cause of adult heart diseases. The purpose of this study is to investigate whether miR-101-3p plays a role in the human aortic valve interstitial cells (HAVICs) calcification and the underlying mechanisms. METHODS Small RNA deep sequencing and qPCR analysis were used to determine changes in microRNA expression in calcified human aortic valves. RESULTS The data showed that miR-101-3p levels were increased in the calcified human aortic valves. Using cultured primary HAVICs, we demonstrated that the miR-101-3p mimic promoted calcification and upregulated the osteogenesis pathway, while anti-miR-101-3p inhibited osteogenic differentiation and prevented calcification in HAVICs treated with the osteogenic conditioned medium. Mechanistically, miR-101-3p directly targeted cadherin-11 (CDH11) and Sry-related high-mobility-group box 9 (SOX9), key factors in the regulation of chondrogenesis and osteogenesis. Both CDH11 and SOX9 expressions were downregulated in the calcified human HAVICs. Inhibition of miR-101-3p restored expression of CDH11, SOX9 and ASPN and prevented osteogenesis in HAVICs under the calcific condition. CONCLUSION miR-101-3p plays an important role in HAVIC calcification through regulation of CDH11/SOX9 expression. The finding is important as it reveals that miR-1013p may be a potential therapeutic target for calcific aortic valve disease.
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Affiliation(s)
- Jianglei Chen
- Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Yi Lin
- Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Zhongjie Sun
- Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. .,Department of Physiology, College of Medicine, UT Cardiovascular Institute, University of Tennessee Health Science Center, 956 Court Avenue, Memphis, TN, 38163, USA.
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Davey MG, McGuire A, Casey MC, Waldron RM, Paganga M, Holian E, Newell J, Heneghan HM, McDermott AM, Keane MM, Lowery AJ, Miller N, Kerin MJ. Evaluating the Role of Circulating MicroRNAs in Predicting Long-Term Survival Outcomes in Breast Cancer: A Prospective, Multicenter Clinical Trial. J Am Coll Surg 2023; 236:317-327. [PMID: 36648259 PMCID: PMC9835657 DOI: 10.1097/xcs.0000000000000465] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 08/06/2022] [Accepted: 08/08/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND While long-term outcomes have improved for patients with breast cancer, 20% to 30% will still develop recurrence, and identifying these patients remains a challenge. MicroRNAs (miRNAs) are small, noncoding molecules that modulate genetic expression and affect oncogenesis. STUDY DESIGN This prospective, multicenter trial (ICORG10/11-NCT01722851) recruited patients undergoing neoadjuvant chemotherapy across 8 Irish centers. Predetermined miRNAs were quantified from patient whole blood using quantitative reverse transcriptase polymerase chain reaction. Venous sampling was performed at diagnosis (timepoint 1) and midway during neoadjuvant chemotherapy (timepoint 2 [T2]). miRNA expression profiles were correlated with recurrence-free survival (RFS), disease-free survival (DFS), and overall survival. Data analysis was performed using R v3.2.3. RESULTS A total of 124 patients were recruited with a median age of 55.0 years. The median follow-up was 103.1 months. Increased miR-145 expression at T2 was associated with improved RFS (hazard ratio 0.00; 95% confidence interval [CI] 0.00 to 0.99; p = 0.050). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved RFS (p = 0.041). Increased miR-145 expression at T2 trended towards significance in predicting improved DFS (hazard ratio 0.00; 95% CI 0.00 to 1.42; p = 0.067). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved DFS (p = 0.012). No miRNAs correlated with overall survival. CONCLUSIONS ICORG10/11 is the first Irish multicenter, translational research trial evaluating circulatory miRNAs as biomarkers predictive of long-term survival and correlated increased miR-145 expression with enhanced outcomes in early-stage breast cancer. Validation of these findings is required in the next generation of translational research trials.
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Affiliation(s)
- Matthew G Davey
- From the Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland (Davey, McGuire, Casey, Waldron, Heneghan, McDermott, Lowery, Miller, Kerin)
| | - Andrew McGuire
- From the Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland (Davey, McGuire, Casey, Waldron, Heneghan, McDermott, Lowery, Miller, Kerin)
| | - Maire Caitlin Casey
- From the Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland (Davey, McGuire, Casey, Waldron, Heneghan, McDermott, Lowery, Miller, Kerin)
| | - Ronan M Waldron
- From the Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland (Davey, McGuire, Casey, Waldron, Heneghan, McDermott, Lowery, Miller, Kerin)
| | - Maxwell Paganga
- From the Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland (Davey, McGuire, Casey, Waldron, Heneghan, McDermott, Lowery, Miller, Kerin)
- the School of Mathematics, Statistics and Applied Mathematics, National University of Ireland Galway, Galway, Ireland (Paganga, Holian, Newell)
| | - Emma Holian
- the School of Mathematics, Statistics and Applied Mathematics, National University of Ireland Galway, Galway, Ireland (Paganga, Holian, Newell)
| | - John Newell
- the School of Mathematics, Statistics and Applied Mathematics, National University of Ireland Galway, Galway, Ireland (Paganga, Holian, Newell)
| | - Helen M Heneghan
- From the Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland (Davey, McGuire, Casey, Waldron, Heneghan, McDermott, Lowery, Miller, Kerin)
| | - Ailbhe M McDermott
- From the Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland (Davey, McGuire, Casey, Waldron, Heneghan, McDermott, Lowery, Miller, Kerin)
| | - Maccon M Keane
- the Department of Medical Oncology, Galway University Hospital, Galway, Ireland (Keane)
| | - Aoife J Lowery
- From the Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland (Davey, McGuire, Casey, Waldron, Heneghan, McDermott, Lowery, Miller, Kerin)
| | - Nicola Miller
- From the Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland (Davey, McGuire, Casey, Waldron, Heneghan, McDermott, Lowery, Miller, Kerin)
| | - Michael J Kerin
- From the Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland (Davey, McGuire, Casey, Waldron, Heneghan, McDermott, Lowery, Miller, Kerin)
- the Cancer Trials Ireland, Innovation House, Dublin, Ireland (Kerin)
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Identification of a Five-MiRNA Expression Assay to Aid Colorectal Cancer Diagnosis. GASTROINTESTINAL DISORDERS 2022. [DOI: 10.3390/gidisord4030018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Introduction: One-third of colorectal cancer (CRC) patients present with advanced disease, and establishing control remains a challenge. Identifying novel biomarkers to facilitate earlier diagnosis is imperative in enhancing oncological outcomes. We aimed to create miRNA oncogenic signature to aid CRC diagnosis. Methods: Tumour and tumour-associated normal (TAN) were extracted from 74 patients during surgery for CRC. RNA was isolated and target miRNAs were quantified using real-time reverse transcriptase polymerase chain reaction. Regression analyses were performed in order to identify miRNA targets capable of differentiating CRC from TAN and compared with two endogenous controls (miR-16 and miR-345) in each sample. Areas under the curve (AUCs) in Receiver Operating Characteristic (ROC) analyses were determined. Results: MiR-21 (β-coefficient:3.661, SE:1.720, p = 0.033), miR-31 (β-coefficient:2.783, SE:0.918, p = 0.002), and miR-150 (β-coefficient:−4.404, SE:0.526, p = 0.004) expression profiles differentiated CRC from TAN. In multivariable analyses, increased miR-31 (β-coefficient:2.431, SE:0.715, p < 0.001) and reduced miR-150 (β-coefficient:−4.620, SE:1.319, p < 0.001) independently differentiated CRC from TAN. The highest AUC generated for miR-21, miR-31, and miR-150 in an oncogenic expression assay was 83.0% (95%CI: 61.7–100.0, p < 0.001). In the circulation of 34 independent CRC patients and 5 controls, the mean expression of miR-21 (p = 0.001), miR-31 (p = 0.001), and miR-150 (p < 0.001) differentiated CRC from controls; however, the median expression of miR-21 (p = 0.476), miR-31 (p = 0.933), and miR-150 (p = 0.148) failed to differentiate these groups. Conclusion: This study identified a five-miRNA signature capable of distinguishing CRC from normal tissues with a high diagnostic test accuracy. Further experimentation with this signature is required to elucidate its diagnostic relevance in the circulation of CRC patients.
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Nothnick WB, Graham A. Dissecting the miR-451a-Mif Pathway in Endometriosis Pathophysiology Using a Syngeneic Mouse Model: Temporal Expression of Lesion Mif Receptors, Cd74 and Cxcr4. Biomedicines 2022; 10:1699. [PMID: 35885004 PMCID: PMC9313350 DOI: 10.3390/biomedicines10071699] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/05/2022] [Accepted: 07/09/2022] [Indexed: 01/08/2023] Open
Abstract
Endometriosis is an enigmatic disease characterized by pain and infertility in which endometrial tissue grows in ectopic locations, predominantly the pelvic cavity. The pathogenesis and pathophysiology of endometriosis is complex and postulated to involve alterations in inflammatory, cell proliferation and post-transcriptional regulatory pathways among others. Our understanding on the pathogenesis and pathophysiology of endometriosis is further complicated by the fact that endometriosis can only be diagnosed by laparoscopy only after the disease has manifested. This makes it difficult to understand the true pathogenesis as a cause-and-effect relationship is difficult to ascertain. To aid in our understanding on endometriosis pathogenesis and pathophysiology, numerous rodent models have been developed. In this case, we discuss further assessment of a miR-451a-macrophage migration inhibitory factor (Mif) pathway which contributes to lesion survival. Specifically, we evaluate the temporal expression of lesion Mif receptors, Cd74 and Cxcr4 using host mice which express wild-type or miR-451a deficient lesions. Similar to that observed in humans and a non-human primate model of endometriosis, Cd74 expression is elevated in lesion tissue in a temporal fashion while that of Cxcr4 shows minimal increase during initial lesion establishment but is reduced later during the lifespan. Absence of miR-451a during initial lesion establishment is associated with an augmentation of Cd74, but no Cxcr4 expression. The data obtained in this study provide further support for a role of Mif receptors, Cd74 and Cxcr4 in the pathophysiology of endometriosis.
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Affiliation(s)
- Warren B. Nothnick
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA;
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Center for Reproductive Sciences, Institute for Reproduction and Perinatal Research, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Amanda Graham
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA;
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11
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Kanoria S, Rennie WA, Carmack CS, Lu J, Ding Y. N 6-methyladenosine enhances post-transcriptional gene regulation by microRNAs. BIOINFORMATICS ADVANCES 2022; 2:vbab046. [PMID: 35098135 PMCID: PMC8792947 DOI: 10.1093/bioadv/vbab046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/09/2021] [Indexed: 01/27/2023]
Abstract
MOTIVATION N 6-methyladenosine (m6A) is the most prevalent modification in eukaryotic messenger RNAs. MicroRNAs (miRNAs) are abundant post-transcriptional regulators of gene expression. Correlation between m6A and miRNA-targeting sites has been reported to suggest possible involvement of m6A in miRNA-mediated gene regulation. However, it is unknown what the regulatory effects might be. In this study, we performed comprehensive analyses of high-throughput data on m6A and miRNA target binding and regulation. RESULTS We found that the level of miRNA-mediated target suppression is significantly enhanced when m6A is present on target mRNAs. The evolutionary conservation for miRNA-binding sites with m6A modification is significantly higher than that for miRNA-binding sites without modification. These findings suggest functional significance of m6A modification in post-transcriptional gene regulation by miRNAs. We also found that methylated targets have more stable structure than non-methylated targets, as indicated by significantly higher GC content. Furthermore, miRNA-binding sites that can be potentially methylated are significantly less accessible without methylation than those that do not possess potential methylation sites. Since either RNA-binding proteins or m6A modification by itself can destabilize RNA structure, we propose a model in which m6A alters local target secondary structure to increase accessibility for efficient binding by Argonaute proteins, leading to enhanced miRNA-mediated regulation. AVAILABILITY AND IMPLEMENTATION N/A.
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Affiliation(s)
- Shaveta Kanoria
- Wadsworth Center, New York State Department of Health, Center for Medical Science, Albany, NY 12208, USA
| | - William A Rennie
- Wadsworth Center, New York State Department of Health, Center for Medical Science, Albany, NY 12208, USA
| | - Charles Steven Carmack
- Wadsworth Center, New York State Department of Health, Center for Medical Science, Albany, NY 12208, USA
| | - Jun Lu
- Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA,To whom correspondence should be addressed. or
| | - Ye Ding
- Wadsworth Center, New York State Department of Health, Center for Medical Science, Albany, NY 12208, USA,To whom correspondence should be addressed. or
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12
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Morales-Pison S, Jara L, Carrasco V, Gutiérrez-Vera C, Reyes JM, Gonzalez-Hormazabal P, Carreño LJ, Tapia JC, Contreras HR. Genetic Variation in MicroRNA-423 Promotes Proliferation, Migration, Invasion, and Chemoresistance in Breast Cancer Cells. Int J Mol Sci 2021; 23:ijms23010380. [PMID: 35008806 PMCID: PMC8745459 DOI: 10.3390/ijms23010380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 12/11/2022] Open
Abstract
MicroRNA-423 (miR-423) is highly expressed in breast cancer (BC). Previously, our group showed that the SNP rs6505162:C>A located in the pre-miR-423 was significantly associated with increased familial BC risk in patients with a strong family history of BC. Therefore, in this study, we evaluated the functional role of rs6505162 in mammary tumorigenesis in vitro to corroborate the association of this SNP with BC risk. We found that rs6505162:C>A upregulated expression of both mature miR-423 sequences (3p and 5p). Moreover, pre-miR-423-A enhanced proliferation, and promoted cisplatin resistance in BC cell lines. We also showed that pre-miR-423-A expression decreased cisplatin-induced apoptosis, and increased BC cell migration and invasion. We propose that the rs6505162-A allele promotes miR-423 overexpression, and that the rs6505162-A allele induces BC cell proliferation, viability, chemoresistance, migration, and invasion, and decreases cell apoptosis as a consequence. We suggest that rs6505162:C>A is a functional SNP site with potential utility as a marker for early diagnosis, prognosis, and treatment efficacy monitoring in BRCA1/2-negative BC patients, as well as a possible therapeutic target.
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Affiliation(s)
- Sebastian Morales-Pison
- Laboratorio de Genética Humana, Programa de Genética Humana, Instituto de Ciencia Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (S.M.-P.); (L.J.); (P.G.-H.)
| | - Lilian Jara
- Laboratorio de Genética Humana, Programa de Genética Humana, Instituto de Ciencia Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (S.M.-P.); (L.J.); (P.G.-H.)
| | - Valentina Carrasco
- Laboratorio de Biología Estructural y Molecular, Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 8380453, Chile;
| | - Cristian Gutiérrez-Vera
- Millennium Institute on Immunology and Immunotherapy, Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (C.G.-V.); (L.J.C.)
| | | | - Patricio Gonzalez-Hormazabal
- Laboratorio de Genética Humana, Programa de Genética Humana, Instituto de Ciencia Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (S.M.-P.); (L.J.); (P.G.-H.)
| | - Leandro J. Carreño
- Millennium Institute on Immunology and Immunotherapy, Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (C.G.-V.); (L.J.C.)
| | - Julio C. Tapia
- Laboratorio de Transformación Celular, Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
- Correspondence: (J.C.T.); (H.R.C.); Tel.: +56-2-9788647 (J.C.T.)
| | - Héctor R. Contreras
- Laboratorio de Biología Celular y Molecular, Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
- Correspondence: (J.C.T.); (H.R.C.); Tel.: +56-2-9788647 (J.C.T.)
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13
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Arancibia T, Morales-Pison S, Maldonado E, Jara L. Association between single-nucleotide polymorphisms in miRNA and breast cancer risk: an updated review. Biol Res 2021; 54:26. [PMID: 34454612 PMCID: PMC8401249 DOI: 10.1186/s40659-021-00349-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/13/2021] [Indexed: 12/27/2022] Open
Abstract
Breast cancer (BC), a heterogeneous, aggressive illness with high mortality, is essentially a genomic disease. While the high-penetrance genes BRCA1 and BRCA2 play important roles in tumorigenesis, moderate- and low-penetrance genes are also involved. Single-nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes have recently been identified as BC risk factors. miRNA genes are currently classified as low-penetrance. SNPs are the most common variations in the human genome. While the role of miRNA SNPs in BC susceptibility has been studied extensively, results have been inconsistent. This review analyzes the results of association studies between miRNA SNPs and BC risk from countries around the world. We conclude that: (a) By continent, the largest proportion of studies to date were conducted in Asia (65.0 %) and the smallest proportion in Africa (1.8 %); (b) Association studies have been completed for 67 different SNPs; (c) 146a, 196a2, 499, 27a, and 423 are the most-studied miRNAs; (d) The SNPs rs2910164 (miRNA-146a), rs11614913 (miRNA-196a2), rs3746444 (miRNA-499) and rs6505162 (miRNA-423) were the most widely associated with increased BC risk; (e) The majority of studies had small samples, which may affect the precision and power of the results; and (f) The effect of an SNP on BC risk depends on the ethnicity of the population. This review also discusses potential explanations for controversial findings.
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Affiliation(s)
- Trinidad Arancibia
- Programa de Genética Humana, Instituto de Ciencia Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, 8380453, Santiago, Chile
| | - Sebastian Morales-Pison
- Programa de Genética Humana, Instituto de Ciencia Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, 8380453, Santiago, Chile
| | - Edio Maldonado
- Programa Biología Celular y Molecular, Facultad de Medicina, Universidad de Chile, 8380453, Santiago, Chile
| | - Lilian Jara
- Programa de Genética Humana, Instituto de Ciencia Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, 8380453, Santiago, Chile.
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14
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Johnson NM, Hoffmann AR, Behlen JC, Lau C, Pendleton D, Harvey N, Shore R, Li Y, Chen J, Tian Y, Zhang R. Air pollution and children's health-a review of adverse effects associated with prenatal exposure from fine to ultrafine particulate matter. Environ Health Prev Med 2021; 26:72. [PMID: 34253165 PMCID: PMC8274666 DOI: 10.1186/s12199-021-00995-5] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 07/01/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Particulate matter (PM), a major component of ambient air pollution, accounts for a substantial burden of diseases and fatality worldwide. Maternal exposure to PM during pregnancy is particularly harmful to children's health since this is a phase of rapid human growth and development. METHOD In this review, we synthesize the scientific evidence on adverse health outcomes in children following prenatal exposure to the smallest toxic components, fine (PM2.5) and ultrafine (PM0.1) PM. We highlight the established and emerging findings from epidemiologic studies and experimental models. RESULTS Maternal exposure to fine and ultrafine PM directly and indirectly yields numerous adverse birth outcomes and impacts on children's respiratory systems, immune status, brain development, and cardiometabolic health. The biological mechanisms underlying adverse effects include direct placental translocation of ultrafine particles, placental and systemic maternal oxidative stress and inflammation elicited by both fine and ultrafine PM, epigenetic changes, and potential endocrine effects that influence long-term health. CONCLUSION Policies to reduce maternal exposure and health consequences in children should be a high priority. PM2.5 levels are regulated, yet it is recognized that minority and low socioeconomic status groups experience disproportionate exposures. Moreover, PM0.1 levels are not routinely measured or currently regulated. Consequently, preventive strategies that inform neighborhood/regional planning and clinical/nutritional recommendations are needed to mitigate maternal exposure and ultimately protect children's health.
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Affiliation(s)
- Natalie M Johnson
- Department of Environmental and Occupational Health, Texas A&M University, College Station, TX, 77843, USA.
| | | | - Jonathan C Behlen
- Department of Environmental and Occupational Health, Texas A&M University, College Station, TX, 77843, USA
| | - Carmen Lau
- Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, 77843, USA
| | - Drew Pendleton
- Department of Environmental and Occupational Health, Texas A&M University, College Station, TX, 77843, USA
| | - Navada Harvey
- Department of Environmental and Occupational Health, Texas A&M University, College Station, TX, 77843, USA
| | - Ross Shore
- Department of Environmental and Occupational Health, Texas A&M University, College Station, TX, 77843, USA
| | - Yixin Li
- Department of Chemistry, Texas A&M University, College Station, TX, 77843, USA
| | - Jingshu Chen
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843, USA
| | - Yanan Tian
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843, USA
| | - Renyi Zhang
- Department of Chemistry, Texas A&M University, College Station, TX, 77843, USA
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15
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Liu D, Huang Y, Nie W, Zhang J, Deng L. SMALF: miRNA-disease associations prediction based on stacked autoencoder and XGBoost. BMC Bioinformatics 2021; 22:219. [PMID: 33910505 PMCID: PMC8082881 DOI: 10.1186/s12859-021-04135-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/14/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Identifying miRNA and disease associations helps us understand disease mechanisms of action from the molecular level. However, it is usually blind, time-consuming, and small-scale based on biological experiments. Hence, developing computational methods to predict unknown miRNA and disease associations is becoming increasingly important. RESULTS In this work, we develop a computational framework called SMALF to predict unknown miRNA-disease associations. SMALF first utilizes a stacked autoencoder to learn miRNA latent feature and disease latent feature from the original miRNA-disease association matrix. Then, SMALF obtains the feature vector of representing miRNA-disease by integrating miRNA functional similarity, miRNA latent feature, disease semantic similarity, and disease latent feature. Finally, XGBoost is utilized to predict unknown miRNA-disease associations. We implement cross-validation experiments. Compared with other state-of-the-art methods, SAMLF achieved the best AUC value. We also construct three case studies, including hepatocellular carcinoma, colon cancer, and breast cancer. The results show that 10, 10, and 9 out of the top ten predicted miRNAs are verified in MNDR v3.0 or miRCancer, respectively. CONCLUSION The comprehensive experimental results demonstrate that SMALF is effective in identifying unknown miRNA-disease associations.
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Affiliation(s)
- Dayun Liu
- School of Computer Science and Engineering, Central South University, Hunan, 410083, China
| | - Yibiao Huang
- School of Computer Science and Engineering, Central South University, Hunan, 410083, China
| | - Wenjuan Nie
- School of Computer Science and Engineering, Central South University, Hunan, 410083, China
| | - Jiaxuan Zhang
- Department of Cognitive Science, University of California San Diego, La Jolla, 92093, USA
| | - Lei Deng
- School of Computer Science and Engineering, Central South University, Hunan, 410083, China.
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16
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Aranda A. MicroRNAs and thyroid hormone action. Mol Cell Endocrinol 2021; 525:111175. [PMID: 33515639 DOI: 10.1016/j.mce.2021.111175] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/29/2020] [Accepted: 01/21/2021] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally repress gene expression by binding generally to the 3'-untranslated regions of their target mRNAs. miRNAs regulate a large fraction of the genome, playing a key role in most physiological and pathological processes. The thyroid hormones (T4 and T3) are major regulators of development, metabolism and cell growth. The thyroid hormones (THs) are synthetized in the thyroid gland and enter the cells through transporter proteins. In the cells, T4 and T3 are metabolized by deiodinase enzymes and bind to nuclear receptors (TRs), which have a higher affinity by T3. TRs act as hormone dependent transcription factors by binding to thyroid hormone response elements (TREs) in the target genes and recruiting transcriptional coregulators. There is increasing evidence that a variety of miRNAs target deiodinases and the receptor, thus regulating TH signaling is different tissues. In turn, the THs have been shown to modulate the expression of specific miRNAs and their mRNA targets in different cell types and organs. In many cases, the existence of TREs in the regulatory regions of these miRNAs has been identified, and the hormone bound receptors transcriptionally regulate expression of these molecules. Changes in the levels of miRNAs have been demonstrated to mediate some of the important actions of the THs in processes such as muscle and heart function, lipid liver metabolism or skin physiology. In addition, miRNA regulation is involved in the effects of TRs on cell proliferation and cancer.
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Affiliation(s)
- Ana Aranda
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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17
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Marchione AD, Thompson Z, Kathrein KL. DNA methylation and histone modifications are essential for regulation of stem cell formation and differentiation in zebrafish development. Brief Funct Genomics 2021:elab022. [PMID: 33782688 DOI: 10.1093/bfgp/elab022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/05/2021] [Accepted: 03/09/2021] [Indexed: 01/21/2023] Open
Abstract
The complex processes necessary for embryogenesis require a gene regulatory network that is complex and systematic. Gene expression regulates development and organogenesis, but this process is altered and fine-tuned by epigenetic regulators that facilitate changes in the chromatin landscape. Epigenetic regulation of embryogenesis adjusts the chromatin structure by modifying both DNA through methylation and nucleosomes through posttranslational modifications of histone tails. The zebrafish is a well-characterized model organism that is a quintessential tool for studying developmental biology. With external fertilization, low cost and high fecundity, the zebrafish are an efficient tool for studying early developmental stages. Genetic manipulation can be performed in vivo resulting in quick identification of gene function. Large-scale genome analyses including RNA sequencing, chromatin immunoprecipitation and chromatin structure all are feasible in the zebrafish. In this review, we highlight the key events in zebrafish development where epigenetic regulation plays a critical role from the early stem cell stages through differentiation and organogenesis.
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18
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Ayachit G, Shaikh I, Pandya H, Das J. Salient Features, Data and Algorithms for MicroRNA Screening from Plants: A Review on the Gains and Pitfalls of Machine Learning Techniques. Curr Bioinform 2021. [DOI: 10.2174/1574893615999200601121756] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The era of big data and high-throughput genomic technology has enabled scientists to
have a clear view of plant genomic profiles. However, it has also led to a massive need for
computational tools and strategies to interpret this data. In this scenario of huge data inflow,
machine learning (ML) approaches are emerging to be the most promising for analysing
heterogeneous and unstructured biological datasets. Extending its application to healthcare and
agriculture, ML approaches are being useful for microRNA (miRNA) screening as well.
Identification of miRNAs is a crucial step towards understanding post-transcriptional gene
regulation and miRNA-related pathology. The use of ML tools is becoming indispensable in
analysing such data and identifying species-specific, non-conserved miRNA. However, these
techniques have their own benefits and lacunas. In this review, we will discuss the current scenario
and pitfalls of ML-based tools for plant miRNA identification and provide some insights into the
important features, the need for deep learning models and direction in which studies are needed.
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Affiliation(s)
- Garima Ayachit
- Department of Botany, Bioinformatics and Climate Change, University School of Sciences, Gujarat University, Navrangpura, Ahmedabad – 380009, India
| | - Inayatullah Shaikh
- Gujarat State Biotechnology Mission, Department of Science and Technology, Government of Gujarat, Gandhinagar, Gujarat 382011, India
| | - Himanshu Pandya
- Department of Botany, Bioinformatics and Climate Change, University School of Sciences, Gujarat University, Navrangpura, Ahmedabad – 380009, India
| | - Jayashankar Das
- Gujarat State Biotechnology Mission, Department of Science and Technology, Government of Gujarat, Gandhinagar, Gujarat 382011, India
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The Role of miRNAs, miRNA Clusters, and isomiRs in Development of Cancer Stem Cell Populations in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22031424. [PMID: 33572600 PMCID: PMC7867000 DOI: 10.3390/ijms22031424] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/17/2021] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs or miRs) have a critical role in regulating stem cells (SCs) during development and altered expression can cause developmental defects and/or disease. Indeed, aberrant miRNA expression leads to wide-spread transcriptional dysregulation which has been linked to many cancers. Mounting evidence also indicates a role for miRNAs in the development of the cancer SC (CSC) phenotype. Our goal herein is to provide a review of: (i) current research on miRNAs and their targets in colorectal cancer (CRC), and (ii) miRNAs that are differentially expressed in colon CSCs. MicroRNAs can work in clusters or alone when targeting different SC genes to influence CSC phenotype. Accordingly, we discuss the specific miRNA cluster classifications and isomiRs that are predicted to target the ALDH1, CD166, BMI1, LRIG1, and LGR5 SC genes. miR-23b and miR-92A are of particular interest because our previously reported studies on miRNA expression in isolated normal versus malignant human colonic SCs showed that miR-23b and miR-92a are regulators of the LGR5 and LRIG1 SC genes, respectively. We also identify additional miRNAs whose expression inversely correlated with mRNA levels of their target genes and associated with CRC patient survival. Altogether, our deliberation on miRNAs, their clusters, and isomiRs in regulation of SC genes could provide insight into how dysregulation of miRNAs leads to the emergence of different CSC populations and SC overpopulation in CRC.
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Abstract
The protein-coding regions of mRNAs have the information to make proteins and hence have been at the center of attention for understanding altered protein functions in disease states, including cancer. Indeed, the discovery of genomic alterations and driver mutations that change protein levels and/or activity has been pivotal in our understanding of cancer biology. However, to better understand complex molecular mechanisms that are deregulated in cancers, we also need to look at non-coding parts of mRNAs, including 3'UTRs (untranslated regions), which control mRNA stability, localization, and translation efficiency. Recently, these rather overlooked regions of mRNAs are gaining attention as mounting evidence provides functional links between 3'UTRs, protein functions, and cancer-related molecular mechanisms. Here, roles of 3'UTRs in cancer biology and mechanisms that result in cancer-specific 3'-end isoform variants will be reviewed. An increased appreciation of 3'UTRs may help the discovery of new ways to explain as of yet unknown oncogene activation and tumor suppressor inactivation cases in cancers, and provide new avenues for diagnostic and therapeutic applications.
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Affiliation(s)
- Ayse Elif Erson-Bensan
- Department of Biological Sciences and Cancer Systems Biology Laboratory, Middle East Technical University (METU, ODTU), Dumlupinar Blv No: 1, Universiteler Mah, 06800, Ankara, Turkey.
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Liu T, Sun Y, Bai W. The Role of Epigenetics in the Chronic Sinusitis with Nasal Polyp. Curr Allergy Asthma Rep 2020; 21:1. [PMID: 33236242 DOI: 10.1007/s11882-020-00976-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common and heterogeneous inflammatory disease. The underlying epigenetic mechanisms and treatment of CRSwNP are partially understood. Of the different epigenetic changes in CRSwNP, histone deacetylases (HDACs), methylation of DNA, and the levels of miRNA are widely studied. Here, we review the human studies of epigenetic mechanisms in CRSwNP. RECENT FINDINGS The promoters of COL18A1, PTGES, PLAT, and TSLP genes are hypermethylated in CRSwNP compared with those of controls, while the promoters of PGDS, ALOX5AP, LTB4R, IL-8, and FZD5 genes are hypomethylated in CRSwNP. Promoter hypermethylation suppresses the gene expression, while promoter hypomethylation increases the gene expression. Studies have shown the elevation in the levels of HDAC2, HDAC4, and H3K4me3 in CRSwNP. In CRSwNP patients, there is also an upregulation of certain miRNAs including miR-125b, miR-155, miR-19a, miR-142-3p, and miR-21 and downregulation of miR-4492. Epigenetics takes part in the immunology of CRSwNP and may give rise to endotypes of CRSwNP. Both HDAC2 and the miRNA including miR-18a, miR-124a, and miR-142-3p may take function in the regulation of glucocorticoid resistance. HDAC inhibitors and KDM2B have shown effectiveness in decreasing nasal polyp, and DNA methyltransferase (DNMT) or HDAC inhibitors may have a potential efficacy for the treatment of CRSwNP. Recent advances in the epigenetics of CRSwNP have led to the identification of several potential therapeutic targets for this disease. The use of epigenetics may provide novel and effective biomarkers and therapies for the treatment of nasal polyp.
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Affiliation(s)
- Tiancong Liu
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Yang Sun
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Weiliang Bai
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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miR-618 rs2682818 C>A polymorphism decreases Hirschsprung disease risk in Chinese children. Biosci Rep 2020; 40:223573. [PMID: 32364585 PMCID: PMC7214396 DOI: 10.1042/bsr20193989] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 04/27/2020] [Accepted: 04/30/2020] [Indexed: 12/02/2022] Open
Abstract
MicroRNAs (miRNAs) are endogenous non-coding small RNAs that play an important role in the development of many malignant tumors. In addition, recent studies have reported that single nucleotide polymorphisms (SNPs) located in the miRNA functional region was inextricably linked to tumor susceptibility. In the present study, we investigated the susceptibility between miR-618 rs2682818 C>A and Hirschsprung disease (HSCR) in the Southern Chinese population (1470 patients and 1473 controls). Odds ratios (ORs) and 95% confidence intervals (CIs) were used for estimating the strength of interrelation between them. We found that the CA/AA genotypes of miR-618 rs2682818 were associated with a decreased risk of HSCR when compared with the CC genotype (OR = 0.84, 95% CI = 0.72–0.99, P=0.032). Based on the stratified analysis of HSCR subtypes, the rs2682818 CA/AA genotypes were able to significantly lessen the risk of HSCR compared with CC genotype in patients with long-segment HSCR (adjusted OR = 0.70, 95% CI = 0.52–0.93, P=0.013). In conclusion, our results indicated that the miR-618 rs2682818 C>A polymorphism was associated with a reduced risk of HSCR in Chinese children, especially in patients with long-segment HSCR (L-HSCR) subtype.
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The role of activated leukocyte cell adhesion molecule (ALCAM) in cancer progression, invasion, metastasis and recurrence: A novel cancer stem cell marker and tumor-specific prognostic marker. Exp Mol Pathol 2020; 115:104443. [PMID: 32380056 DOI: 10.1016/j.yexmp.2020.104443] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 03/17/2020] [Accepted: 04/17/2020] [Indexed: 12/21/2022]
Abstract
Activated leukocyte cell adhesion molecule (ALCAM) or CD166 is a 100 to 105 KDa transmembrane immunoglobulin which is involved in activation of T-cells, hematopoiesis, neutrophils trans-endothelial migration, angiogenesis, inflammation and tumor propagation and invasiveness through formation of homophilic and heterophilic interactions. Recently, many studies have proposed that the expression pattern of ALCAM is highly associated with the grade, stage and invasiveness of tumors. Although ALCAM is a valuable prognostic marker in different carcinomas, similar expression patterns in different tumor types may be associated with completely different prognostic states, making it to be a tumor-type-dependent prognostic marker. In addition, ALCAM isoforms provide ways for primary detection of tumor cells with metastatic potential. More importantly, this prognostic marker has shown to be considerably dependent on the cytoplasmic and membranous expression, indirect and direct regulation of post-transcriptional molecules, pro-apoptotic proteins functionalities and several other oncogenic proteins or signalling pathways. This review mainly focuses on the pathways involved in expression of ALCAM and its prognostic value of in different types of cancers and the way in which it is regulated.
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24
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Chen Z, Hu Y, Lu R, Ge M, Zhang L. MicroRNA-374a-5p inhibits neuroinflammation in neonatal hypoxic-ischemic encephalopathy via regulating NLRP3 inflammasome targeted Smad6. Life Sci 2020; 252:117664. [PMID: 32304765 DOI: 10.1016/j.lfs.2020.117664] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 04/09/2020] [Accepted: 04/09/2020] [Indexed: 12/12/2022]
Abstract
AIMS Neonatal hypoxic-ischemic encephalopathy (HIE) is still an important cause of neurological dysfunction. At present, there is no reliable biochemical index in clinical examination. Increasing evidence demonstrates that microRNAs (miRNAs) are involved in the process of HIE, and miR-374a-5p is down-regulated in HIE infants. In this study, the aim is to investigate the role and mechanism of miR-374a-5p in HIE. MAIN METHODS Sprague-Dawley (SD) rats were used to establish model of neonatal HIE, pathologic changes and inflammatory response of brain tissues were measured. Subsequently, primary microglia were induced by LPS (1 μg/ml) in vitro, the miR-374a-5p mimic, Ad-Smad6 adenovirus vector and NLRP3 siRNA oligo were applied for microglial transfection. Furthermore, the target relationship between miR-374a-5p and Smad6 was analyzed, while microglia activity and inflammatory factor (IL-1β, TNF-α and IL-6) levels were detected. KEY FINDINGS Herein, we found that over-expression of miR-374a-5p significantly attenuated brain injury and strongly inhibited the release of pro-inflammatory cytokines in neonatal rat HIE model. In vitro, miR-374a-5p inhibited LPS-induced microglial pro-inflammatory cytokines production by regulating NLRP3 inflammasome. In addition, Smad6 was identified as a direct target of miR-374a-5p, and miR-374a-5p had a negative regulatory effect on Smad6 expression. By targeting Smad6, miR-374a-5p inhibited the activation of NLRP3 inflammatory signals in microglia and the subsequent release of pro-inflammatory factors. SIGNIFICANCE Our study recognized that miR-374a-5p as a novel regulator of microglial activation in neonatal HIE highlighted potential therapeutic target for the treatment of neonatal hypoxic-ischemic brain injury.
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Affiliation(s)
- Zhong Chen
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, P.R. China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, P.R. China
| | - Yong Hu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, P.R. China
| | - Ruifeng Lu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, P.R. China
| | - Min Ge
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, P.R. China
| | - Li Zhang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, P.R. China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, P.R. China.
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25
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Dai J, Chen Y, Gong Y, Gu D, Chen J. Association of microRNA-27a rs895819 polymorphism with the risk of cancer: An updated meta-analysis. Gene 2019; 728:144185. [PMID: 31838252 DOI: 10.1016/j.gene.2019.144185] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/17/2019] [Accepted: 10/17/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND MiR-27a rs895819 polymorphism is considered as a tumor- related susceptibility gene. Previous meta-analyses evaluated the association the association between miR-27a rs895819 and cancer risk, but the results were inconsistent. The present meta-analysis was carried out to better estimate the correlation of rs895819 and cancer susceptibility. METHODS We searched several databases to identify relevant studies, including PubMed, EMBASE and the Cochrane Controlled Trials Register. The odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the association between miR-27a rs895819 and cancer risk. RESULTS The overall analysis showed the miR-27a rs895819 was not associated with cancer susceptibility in all models (dominant model: OR = 1.02, 95% CI:0.94-1.10, p = 0.632; recessive model: OR = 1.05, 95% CI: 0.92-1.76, p = 0.474; homozygote model: OR = 1.06, 95% CI: 0.91-1.23, p = 0.439; heterozygote model: OR = 1.00, 95% CI: 0.93-1.08, p = 0.934; and allele model: OR = 1.02, 95% CI: 0.96-1.09, p = 0.486). Interestingly, rs895819 A > G was significantly associated with colorectal cancer risk in recessive model (OR = 1.54, 95% CI: 1.29-1.83, p < 0.001), homozygote model (OR = 1.59, 95% CI: 1.31-1.92, p < 0.001), and allele model (OR = 1.22, 95% CI: 1.10-1.34, p < 0.001). In addition, rs895819 polymorphism was correlated with increased risk of breast cancer in the recessive model (OR = 0.81, 95% CI: 0.66-1.00, p = 0.046) and allele model (OR = 0.89, 95% CI: 0.80-0.98, p = 0.021). CONCLUSIONS Our results suggested that rs895819 polymorphism was correlated with increased risk of colorectal cancer and breast cancer, but not all types of cancer.
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Affiliation(s)
- Jiali Dai
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yuetong Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yang Gong
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Dongying Gu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
| | - Jinfei Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; Cancer Center, Taikang Xianlin Drum Tower Hospital, Nanjing University, Nanjing, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
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26
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The shift in the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells mediated by glucocorticoid receptor. Stem Cell Res Ther 2019; 10:377. [PMID: 31805987 PMCID: PMC6896503 DOI: 10.1186/s13287-019-1498-0] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 11/09/2019] [Accepted: 11/18/2019] [Indexed: 12/31/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into several tissues, such as bone, cartilage, and fat. Glucocorticoids affect a variety of biological processes such as proliferation, differentiation, and apoptosis of various cell types, including osteoblasts, adipocytes, or chondrocytes. Glucocorticoids exert their function by binding to the glucocorticoid receptor (GR). Physiological concentrations of glucocorticoids stimulate osteoblast proliferation and promote osteogenic differentiation of MSCs. However, pharmacological concentrations of glucocorticoids can not only induce apoptosis of osteoblasts and osteocytes but can also reduce proliferation and inhibit the differentiation of osteoprogenitor cells. Several signaling pathways, including the Wnt, TGFβ/BMP superfamily and Notch signaling pathways, transcription factors, post-transcriptional regulators, and other regulators, regulate osteoblastogenesis and adipogenesis of MSCs mediated by GR. These signaling pathways target key transcription factors, such as Runx2 and TAZ for osteogenesis and PPARγ and C/EBPs for adipogenesis. Glucocorticoid-induced osteonecrosis and osteoporosis are caused by various factors including dysfunction of bone marrow MSCs. Transplantation of MSCs is valuable in regenerative medicine for the treatment of osteonecrosis of the femoral head, osteoporosis, osteogenesis imperfecta, and other skeletal disorders. However, the mechanism of inducing MSCs to differentiate toward the osteogenic lineage is the key to an efficient treatment. Thus, a better understanding of the molecular mechanisms behind the imbalance between GR-mediated osteoblastogenesis and adipogenesis of MSCs would not only help us to identify the pathogenic causes of glucocorticoid-induced osteonecrosis and osteoporosis but also promote future clinical applications for stem cell-based tissue engineering and regenerative medicine. Here, we primarily review the signaling mechanisms involved in adipogenesis and osteogenesis mediated by GR and discuss the factors that control the adipo-osteogenic balance.
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Abstract
PURPOSE OF REVIEW Asthma is one of the most common chronic respiratory diseases linked with increased morbidity and healthcare utilization. The underlying pathophysiological processes and causal relationships of asthma with epigenetic mechanisms are partially understood. Here we review human studies of epigenetic mechanisms in asthma, with a special focus on DNA methylation. RECENT FINDINGS Epigenetic studies of childhood asthma have identified specific methylation signatures associated with allergic inflammation in the airway and immune cells, demonstrating a regulatory role for methylation in asthma pathogenesis. Despite these novel findings, additional research in the role of epigenetic mechanisms underlying asthma endotypes is needed. Similarly, studies of histone modifications are also lacking in asthma. Future studies of epigenetic mechanisms in asthma will benefit from data integration in well phenotyped cohorts. This review provides an overview of the current literature on epigenetic studies in human asthma, with special emphasis on methylation and childhood asthma.
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Affiliation(s)
- Jose L Gomez
- Pulmonary, Critical Care and Sleep, Yale University School of Medicine, 300 Cedar Street, New Haven, CT, 06520, USA.
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28
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Morgado-Pascual JL, Rayego-Mateos S, Tejedor L, Suarez-Alvarez B, Ruiz-Ortega M. Bromodomain and Extraterminal Proteins as Novel Epigenetic Targets for Renal Diseases. Front Pharmacol 2019; 10:1315. [PMID: 31780938 PMCID: PMC6857099 DOI: 10.3389/fphar.2019.01315] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 10/15/2019] [Indexed: 12/11/2022] Open
Abstract
Epigenetic mechanisms, especially DNA methylation and histone modifications, are dynamic processes that regulate the gene expression transcriptional program in normal and diseased states. The bromodomain and extraterminal (BET) protein family (BRD2, BRD3, BRD4, and BRDT) are epigenetic readers that, via bromodomains, regulate gene transcription by binding to acetylated lysine residues on histones and master transcriptional factors. Experimental data have demonstrated the involvement of some BET proteins in many pathological conditions, including tumor development, infections, autoimmunity, and inflammation. Selective bromodomain inhibitors are epigenetic drugs that block the interaction between BET proteins and acetylated proteins, thus exerting beneficial effects. Recent data have described the beneficial effect of BET inhibition on experimental renal diseases. Emerging evidence underscores the importance of environmental modifications in the origin of pathological features in chronic kidney diseases (CKD). Several cellular processes such as oxidation, metabolic disorders, cytokines, inflammation, or accumulated uremic toxins may induce epigenetic modifications that regulate key processes involved in renal damage and in other pathological conditions observed in CKD patients. Here, we review how targeting bromodomains in BET proteins may regulate essential processes involved in renal diseases and in associated complications found in CKD patients, such as cardiovascular damage, highlighting the potential of epigenetic therapeutic strategies against BET proteins for CKD treatment and associated risks.
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Affiliation(s)
- Jose Luis Morgado-Pascual
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.,Red de Investigación Renal (REDinREN), Madrid, Spain
| | - Sandra Rayego-Mateos
- Red de Investigación Renal (REDinREN), Madrid, Spain.,Vascular and Renal Translational Research Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain
| | - Lucia Tejedor
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.,Red de Investigación Renal (REDinREN), Madrid, Spain
| | - Beatriz Suarez-Alvarez
- Red de Investigación Renal (REDinREN), Madrid, Spain.,Translational Immunology Laboratory, Health Research Institute of the Principality of Asturias (ISPA), Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Marta Ruiz-Ortega
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.,Red de Investigación Renal (REDinREN), Madrid, Spain
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29
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Kwee LC, Neely ML, Grass E, Gregory SG, Roe MT, Ohman EM, Fox KAA, White HD, Armstrong PW, Bowsman LM, Haas JV, Duffin KL, Chan MY, Shah SH. Associations of osteopontin and NT-proBNP with circulating miRNA levels in acute coronary syndrome. Physiol Genomics 2019; 51:506-515. [PMID: 31530226 PMCID: PMC7054637 DOI: 10.1152/physiolgenomics.00033.2019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The genomic regulatory networks underlying the pathogenesis of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) are incompletely understood. As intermediate traits, protein biomarkers report on underlying disease severity and prognosis in NSTE-ACS. We hypothesized that integration of dense microRNA (miRNA) profiling with biomarker measurements would highlight potential regulatory pathways that underlie the relationships between prognostic biomarkers, miRNAs, and cardiovascular phenotypes. We performed miRNA sequencing using whole blood from 186 patients from the TRILOGY-ACS trial. Seven circulating prognostic biomarkers were measured: NH2-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein, osteopontin (OPN), myeloperoxidase, growth differentiation factor 15, monocyte chemoattractant protein, and neopterin. We tested miRNAs for association with each biomarker with generalized linear models and controlled the false discovery rate at 0.05. Ten miRNAs, including known cardiac-related miRNAs 25-3p and 423-3p, were associated with NT-proBNP levels (min. P = 7.5 × 10−4) and 48 miRNAs, including cardiac-related miRNAs 378a-3p, 20b-5p and 320a, -b, and -d, were associated with OPN levels (min. P = 1.6 × 10−6). NT-proBNP and OPN were also associated with time to cardiovascular death, myocardial infarction (MI), or stroke in the sample. By integrating large-scale miRNA profiling with circulating biomarkers as intermediate traits, we identified associations of known cardiac-related and novel miRNAs with two prognostic biomarkers and identified potential genomic networks regulating these biomarkers. These results, highlighting plausible biological pathways connecting miRNAs with biomarkers and outcomes, may inform future studies seeking to delineate genomic pathways underlying NSTE-ACS outcomes.
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Affiliation(s)
| | - Megan L Neely
- Duke Clinical Research Institute, Durham, North Carolina
| | | | - Simon G Gregory
- Duke Molecular Physiology Institute, Durham, North Carolina.,Department of Neurology, Duke University School of Medicine, Durham, North Carolina
| | - Matthew T Roe
- Duke Clinical Research Institute, Durham, North Carolina.,Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - E Magnus Ohman
- Duke Clinical Research Institute, Durham, North Carolina.,Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Keith A A Fox
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Harvey D White
- Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
| | - Paul W Armstrong
- Canadian VIGOUR Centre and Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Lenden M Bowsman
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
| | - Joseph V Haas
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
| | - Kevin L Duffin
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
| | - Mark Y Chan
- Division of Cardiology, Department of Medicine, National University of Singapore, Singapore
| | - Svati H Shah
- Duke Molecular Physiology Institute, Durham, North Carolina.,Duke Clinical Research Institute, Durham, North Carolina.,Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
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30
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Vos PD, Leedman PJ, Filipovska A, Rackham O. Modulation of miRNA function by natural and synthetic RNA-binding proteins in cancer. Cell Mol Life Sci 2019; 76:3745-3752. [PMID: 31165201 PMCID: PMC11105495 DOI: 10.1007/s00018-019-03163-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/02/2019] [Accepted: 05/28/2019] [Indexed: 02/06/2023]
Abstract
RNA-binding proteins (RBPs) and microRNAs (miRNAs) are the most important regulators of mRNA stability and translation in eukaryotic cells; however, the complex interplay between these systems is only now coming to light. RBPs and miRNAs regulate a unique set of targets in either a positive or negative manner and their regulation is mainly opposed to each other on overlapping targets. In some cases, the levels of RBPs or miRNAs regulate the cellular levels of one another and decreased levels of either results in changes in translation of their targets. There is growing evidence that these regulatory circuits are crucial in the development and progression of cancer; however, the rules underlying synergism and antagonism between miRNAs and RNA-binding proteins remain unclear. Synthetic biology seeks to develop artificial systems to better understand their natural counterparts and to develop new, useful technologies for manipulation of gene expression at the RNA level. The recent development of artificial RNA-binding proteins promises to enable a much greater understanding of the importance of the functional interactions between RNA-binding proteins and miRNAs, as well as enabling their manipulation for therapeutic purposes.
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Affiliation(s)
- Pascal D Vos
- Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, 6009, Australia
- Centre for Medical Research, The University of Western Australia, Nedlands, WA, 6009, Australia
- School of Molecular and Chemical Sciences, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Peter J Leedman
- Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, 6009, Australia
- Centre for Medical Research, The University of Western Australia, Nedlands, WA, 6009, Australia
- Medical School, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Aleksandra Filipovska
- Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, 6009, Australia
- Centre for Medical Research, The University of Western Australia, Nedlands, WA, 6009, Australia
- School of Molecular and Chemical Sciences, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Oliver Rackham
- Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, 6009, Australia.
- School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, WA, 6102, Australia.
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, 6102, Australia.
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31
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Zhang L, Song Y, Chen L, Li D, Feng H, Lu Z, Fan T, Chen Z, Livingston MJ, Geng Q. MiR-20a-containing exosomes from umbilical cord mesenchymal stem cells alleviates liver ischemia/reperfusion injury. J Cell Physiol 2019; 235:3698-3710. [PMID: 31566731 DOI: 10.1002/jcp.29264] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 09/03/2019] [Indexed: 12/11/2022]
Abstract
Mesenchymal stem cells (MSCs) have been proved to exert considerable therapeutic effects on ischemia-reperfusion (I/R)-induced injury, but the underlying mechanism remains unknown. In this study, we aimed to explore the potential molecular mechanism underlying the therapeutic effect of MSCs-derived exosome reinforced with miR-20a in reversing liver I/R injury. Quantitative real-time polymerase chain reaction, Western blot, and IHC were carried out to compare the differential expressions of miR-20a, Beclin-I, FAS, Caspase-3, mTOR and P62 in IR rats and normal rats. TUNEL was performed to assess IR-induced apoptosis in IR rats, and luciferase assay was used to confirm the inhibitory effect of miR-20a on Beclin-I and FAS expression. Among the 12 candidate microRNAs (miRNAs), miR-486, miR-25, miR-24, miR-20a,miR-466 and miR-433-3p were significantly downregulated in I/R. In particular, miR-20a, a miRNA highly expressed in umbilical cord-derived mesenchymal stem cells, was proved to bind to the 3' UTR of Beclin-I and FAS to exert an inhibitory effect on their expressions. Since Beclin-I and FAS were aberrantly upregulated in IR, exosomes separated from UC-MSCs showed therapeutic efficacy in reversing I/R induced apoptosis. In addition, exosomes reinforced with miR-20a and separated from UC-MSCs almost fully alleviated I/R injury. Furthermore, our results showed that miR-20a could alleviate the abnormal expression of genes related to apoptosis and autophagy, such as active Caspase-3, mTOR, P62, and LC3II. This study presented detailed evidence to clarify the mechanism underlying the therapeutic efficacy of UC-MSCs in the treatment of I/R injury.
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Affiliation(s)
- Lin Zhang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yaolin Song
- Department of Thoracic Surgery, Ezhou Central Hospital, Ezhou, Hubei, China
| | - Lei Chen
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Donghang Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Haohao Feng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zilong Lu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Tao Fan
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zubin Chen
- Department of Hepatological Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Man J Livingston
- Department of Cellular Biology and Anatomy, Augusta University, Augusta, Georgia
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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32
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Xiong P, Schneider RF, Hulsey CD, Meyer A, Franchini P. Conservation and novelty in the microRNA genomic landscape of hyperdiverse cichlid fishes. Sci Rep 2019; 9:13848. [PMID: 31554838 PMCID: PMC6761260 DOI: 10.1038/s41598-019-50124-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 09/05/2019] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs (miRNAs) play crucial roles in the post-transcriptional control of messenger RNA (mRNA). These miRNA-mRNA regulatory networks are present in nearly all organisms and contribute to development, phenotypic divergence, and speciation. To examine the miRNA landscape of cichlid fishes, one of the most species-rich families of vertebrates, we profiled the expression of both miRNA and mRNA in a diverse set of cichlid lineages. Among these, we found that conserved miRNAs differ from recently arisen miRNAs (i.e. lineage specific) in average expression levels, number of target sites, sequence variability, and physical clustering patterns in the genome. Furthermore, conserved miRNA target sites tend to be enriched at the 5' end of protein-coding gene 3' UTRs. Consistent with the presumed regulatory role of miRNAs, we detected more negative correlations between the expression of miRNA-mRNA functional pairs than in random pairings. Finally, we provide evidence that novel miRNA targets sites are enriched in genes involved in protein synthesis pathways. Our results show how conserved and evolutionarily novel miRNAs differ in their contribution to the genomic landscape and highlight their particular evolutionary roles in the adaptive diversification of cichlids.
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Affiliation(s)
- Peiwen Xiong
- Chair in Zoology and Evolutionary Biology, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
| | - Ralf F Schneider
- Chair in Zoology and Evolutionary Biology, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
- Marine Ecology, Helmholtz-Zentrum für Ozeanforschung Kiel (GEOMAR), 24105 Kiel, Germany
| | - C Darrin Hulsey
- Chair in Zoology and Evolutionary Biology, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
| | - Axel Meyer
- Chair in Zoology and Evolutionary Biology, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
| | - Paolo Franchini
- Chair in Zoology and Evolutionary Biology, Department of Biology, University of Konstanz, 78457, Konstanz, Germany.
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33
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Nothnick WB, Swan K, Flyckt R, Falcone T, Graham A. Human endometriotic lesion expression of the miR-144-3p/miR-451a cluster, its correlation with markers of cell survival and origin of lesion content. Sci Rep 2019; 9:8823. [PMID: 31217548 PMCID: PMC6584560 DOI: 10.1038/s41598-019-45243-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 06/04/2019] [Indexed: 01/02/2023] Open
Abstract
Endometriosis is an inflammatory condition in which endometrial tissue grows in ectopic locations. Survival and growth of these ectopic lesions is associated with pain and infertility. MicroRNAs (miRNAs) have been postulated to play a role in the pathophysiology of the disease and we have previously demonstrated expression of miR-451 in human endometriotic lesion tissue. Here we report elevated expression of the miR-144-3p/miR-451a cluster in human endometriotic lesion tissue. Use of an endometriotic epithelial cell line (12Z) in which the miRNA processing enzyme, DROSHA, was knocked down resulted in an enrichment in the primary (pri) form of miR-144-3p but not that of pri-miR-451a. Using an experimental mouse model of endometriosis in which ectopic endometriotic lesions were deficient for both of these miRNAs revealed that miR-451a, but not miR-144-3p may be derived from exogenous sources such as the circulation/erythrocytes. Together, these data suggest that the miR-144-3p/miR-451a cluster is expressed in human endometriotic lesion tissue, the level of expression correlates with survival status of the lesion tissue and that miR-451a, but not miR-144-3p may be derived from exogenous sources such as erythrocytes.
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Affiliation(s)
- Warren B Nothnick
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
- Center for Reproductive Sciences, Institute of Reproductive and Perinatal Research, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
| | - Kimberly Swan
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Rebecca Flyckt
- Department of Obstetrics, Gynecology and Women's Health Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA
| | - Tommaso Falcone
- Department of Obstetrics, Gynecology and Women's Health Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA
| | - Amanda Graham
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
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34
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McAnena P, Tanriverdi K, Curran C, Gilligan K, Freedman JE, Brown JAL, Kerin MJ. Circulating microRNAs miR-331 and miR-195 differentiate local luminal a from metastatic breast cancer. BMC Cancer 2019; 19:436. [PMID: 31077182 PMCID: PMC6511137 DOI: 10.1186/s12885-019-5636-y] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 04/23/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Breast cancer is the leading cause of cancer related death in women, with metastasis the principle cause of mortality. New non-invasive prognostic markers are needed for the early detection of metastasis, facilitating treatment decision optimisation. MicroRNA (miRNA) are small, non-coding RNAs regulating gene expression and involved in many cellular processes, including metastasis. As biomarkers, circulating miRNAs (in blood) hold great promise for informing diagnosis or monitoring treatment responses. METHODS Plasma extracted RNA from age matched local Luminal A (n = 4) or metastatic disease (n = 4) were profiled using Next Generation Sequencing. Selected differentially expressed miRNA were validated on a whole blood extracted miRNA cohort [distant metastatic disease (n = 22), local disease (n = 31), healthy controls (n = 21)]. Area Under the Curve (AUC) in Receiver Operating Characteristic (ROC) analyses was performed. RESULTS Of 4 miRNA targets tested (miR-181a, miR-329, miR-331, miR-195), mir-331 was significantly over-expressed in patients with metastatic disease, compared to patients with local disease (p < 0.001) or healthy controls (p < 0.001). miR-195 was significantly under-expressed in patients with metastatic disease, compared to patients with local disease (p < 0.001) or healthy controls (p = 0.043). In combination, miR-331 and miR-195 produced an AUC of 0.902, distinguishing metastatic from local breast cancer. CONCLUSIONS We identified and validated two circulating miRNAs differentiating local Luminal A breast cancers from metastatic breast cancers. Further investigation will reveal the molecular role of these miRNAs in metastasis, and determine if they are subtype specific. This work demonstrates the ability of circulating miRNA to identify metastatic disease, and potentially inform diagnosis or treatment effectiveness.
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Affiliation(s)
- Peter McAnena
- Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, Ireland
| | - Kahraman Tanriverdi
- UMass Memorial Heart & Vascular Center, University of Massachusetts Medical School, The Albert Sherman Center, 7th Floor West, AS7-1051, 368 Plantation St, Worcester, MA, 01605-4319, USA
| | - Catherine Curran
- Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, Ireland
| | - K Gilligan
- Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, Ireland
| | - Jane E Freedman
- UMass Memorial Heart & Vascular Center, University of Massachusetts Medical School, The Albert Sherman Center, 7th Floor West, AS7-1051, 368 Plantation St, Worcester, MA, 01605-4319, USA
| | - James A L Brown
- Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, Ireland.
| | - Michael J Kerin
- Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, Ireland.
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Abstract
PURPOSE OF REVIEW The review describes studies investigating the role of microRNAs in the signaling pathway of the mineralocorticoid hormone, aldosterone. RECENT FINDINGS Emerging evidence indicates that aldosterone alters the expression of microRNAs in target tissues thereby modulating the expression of key regulatory proteins. SUMMARY The mineralocorticoid hormone aldosterone is released by the adrenal glands in a homeostatic mechanism to regulate blood volume. The long-term renal action of aldosterone is to increase the retrieval of sodium from filtered plasma to restore blood pressure. Emerging evidence indicates aldosterone may alter noncoding RNAs (ncRNAs) to integrate this hormonal response in target tissue. Expression of the best characterized small ncRNAs, microRNAs, is regulated by aldosterone stimulation. MicroRNAs modulate protein expression at all steps in the renin-angiotensin-aldosterone-signaling (RAAS) system. In addition to acting as a rheostat to fine-tune protein levels in aldosterone-responsive cells, there is evidence that microRNAs down-regulate components of the signaling cascade as a feedback mechanism. The role of microRNAs is, therefore, as signal integrator, and damper in aldosterone signaling, which has implications in understating the RAAS system from both a physiological and pathophysiological perspective. Recent evidence for microRNA's role in RAAS signaling will be discussed.
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Chen C, Liu Q, Hua H, Wang X, Wang P, Cui Z, Qian T. Novel microRNA, miR-sc6, modulates Schwann cell phenotype via targeting ErbB4. Exp Ther Med 2019; 17:4116-4122. [PMID: 30988788 PMCID: PMC6447931 DOI: 10.3892/etm.2019.7426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 02/21/2019] [Indexed: 11/26/2022] Open
Abstract
MicroRNAs (miRNAs) are non-coding RNAs that regulate various tissues and organs, including the nervous system. Peripheral nerve injury is a common pathology of the nervous system and leads to differential expressions of a variety of miRNAs. Previously, a group of novel miRNAs have been identified in rat proximal nerve segments after sciatic nerve transection. However, the biological functions of these novel miRNAs remain undetermined. The aim of the current study was therefore to identify the function of a novel miRNA, miR-sc6, following nerve injury. Its target genes and effects on phenotypic modulation of Schwann cells were determined using a miR-sc6 mimic transfection. These observations contribute to the understanding of miRNA involvement in peripheral nerve injury and the cognition of regulatory mechanisms in peripheral nerve regeneration.
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Affiliation(s)
- Chu Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P.R. China.,Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Qianyan Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Hao Hua
- Department of Medicine, Xinglin College, Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xinghui Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Pan Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Zhiming Cui
- Department of Spine Surgery, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Tianmei Qian
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P.R. China
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Guo C, Dong G, Liang X, Dong Z. Epigenetic regulation in AKI and kidney repair: mechanisms and therapeutic implications. Nat Rev Nephrol 2019; 15:220-239. [PMID: 30651611 PMCID: PMC7866490 DOI: 10.1038/s41581-018-0103-6] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Acute kidney injury (AKI) is a major public health concern associated with high morbidity and mortality. Despite decades of research, the pathogenesis of AKI remains incompletely understood and effective therapies are lacking. An increasing body of evidence suggests a role for epigenetic regulation in the process of AKI and kidney repair, involving remarkable changes in histone modifications, DNA methylation and the expression of various non-coding RNAs. For instance, increases in levels of histone acetylation seem to protect kidneys from AKI and promote kidney repair. AKI is also associated with changes in genome-wide and gene-specific DNA methylation; however, the role and regulation of DNA methylation in kidney injury and repair remains largely elusive. MicroRNAs have been studied quite extensively in AKI, and a plethora of specific microRNAs have been implicated in the pathogenesis of AKI. Emerging research suggests potential for microRNAs as novel diagnostic biomarkers of AKI. Further investigation into these epigenetic mechanisms will not only generate novel insights into the mechanisms of AKI and kidney repair but also might lead to new strategies for the diagnosis and therapy of this disease.
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Affiliation(s)
- Chunyuan Guo
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Guie Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA
| | - Xinling Liang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Geriatrics Institute, Guangzhou, China
| | - Zheng Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA.
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38
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Cheng Z, Xing D. Ginsenoside Rg3 inhibits growth and epithelial-mesenchymal transition of human oral squamous carcinoma cells by down-regulating miR-221. Eur J Pharmacol 2019; 853:353-363. [PMID: 30928631 DOI: 10.1016/j.ejphar.2019.03.040] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 03/19/2019] [Accepted: 03/22/2019] [Indexed: 12/21/2022]
Abstract
Ginsenoside Rg3, isolated from the roots of Panax ginseng, has been found to exert anti-cancer activity on multiple human cancers. However, there is no any literature available about the effect of Rg3 on oral squamous cell carcinoma (OSCC). This study investigated the possible anti-cancer effects of Rg3 on OSCC, as well as the possible molecular mechanisms. In vitro, cell viability and proliferation were respectively detected by CCK-8 assay and BrdU assay. Cell apoptosis was detected by Annexin V-FITC/PI assay. Cell transfection was used to change the expression of miR-221 and TIMP3. qRT-PCR and western blotting were performed to measure the expression of molecules involving in cell apoptosis, epithelial-mesenchymal transition (EMT) process, PI3K/AKT pathway and MAPK/ERK pathway. In vivo, OSCC orthotopic murine model was established and tumor volumes were measured. We found that Rg3 treatment inhibited viability, proliferation and EMT process of human OSCC SCC-9 and HSC-5 cells, but promoted cell apoptosis. miR-221 was highly expressed in OSCC tissues and cells. Rg3 reduced the expression of miR-221 in OSCC cells. Up-regulation of miR-221 abrogated the effects of Rg3 on SCC-9 and HSC-5 cell viability, proliferation, apoptosis and EMT process. TIMP3 was lowly expressed in OSCC tissues and cells, which was a direct target gene of miR-221. Rg3 inactivated PI3K/AKT and MAPK/ERK pathways in SCC-9 cells by up-regulating TIMP3. In vivo, Rg3 reduced the tumor volume of OSCC orthotopic murine model. In conclusion, Rg3 exerted anti-cancer effects on OSCC might be via down-regulating miR-221, up-regulating TIMP3, and then inactivating PI3K/AKT and MAPK/ERK pathways.
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Affiliation(s)
- Zhou Cheng
- Department of Stomatology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, China.
| | - Dayuan Xing
- Department of Stomatology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, China
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Characterization of Alzheimer's Disease Micro-RNA Profile in Exosome-Enriched CSF Samples. Methods Mol Biol 2019; 2044:343-352. [PMID: 31432424 DOI: 10.1007/978-1-4939-9706-0_22] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Micro-RNAs (miRNAs) are small endogenous noncoding ribonucleic acids that modulate gene expression at a post-transcriptional level. miRNAs have been postulated as potential biomarkers and therapeutic targets in a wide list of human diseases including cancer, autoimmune, cardiovascular, and neurodegenerative diseases. miRNAs are secreted by the cells into exosomes. These are small cell-derived membrane vesicles that can be isolated from many body fluids including urine, saliva, blood, and cerebrospinal fluid (CSF). Exosomes contain a variety of proteins and noncoding RNAs and seem to play an important role in cell-cell communication and the regulation of immune response and other body functions. In this chapter, we will discuss the sequential procedure to characterize the miRNA profile in exosome-enriched CSF samples.
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40
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Rennie W, Kanoria S, Liu C, Carmack CS, Lu J, Ding Y. Sfold Tools for MicroRNA Target Prediction. Methods Mol Biol 2019; 1970:31-42. [PMID: 30963486 DOI: 10.1007/978-1-4939-9207-2_3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Computational prediction of miRNA binding sites on target mRNAs facilitates experimental investigation of miRNA functions. In this chapter, we describe STarMir and STarMirDB, two application modules of the Sfold RNA package. STarMir is a Web server for performing miRNA binding site predictions for mRNA and target sequences submitted by users. STarMirDB is a database of precomputed transcriptome-scale predictions. Both STarMir and STarMirDB provide comprehensive sequence, thermodynamic, and target structure features, a logistic probability as a measure of confidence for each predicted site, and a publication-quality diagram of the predicted miRNA-target hybrid. In addition, STarMir now offers a new quantitative score to address combined regulatory effects of multiple seed and seedless sites. This score provides a quantitative measure of the overall regulatory effects of both seed and seedless sites on the target. STarMir and STarMirDB are freely available to all through the Sfold Web application server at http://sfold.wadsworth.org .
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Affiliation(s)
- William Rennie
- New York State Department of Health, Wadsworth Center, Center for Medical Science, Albany, NY, USA
| | - Shaveta Kanoria
- New York State Department of Health, Wadsworth Center, Center for Medical Science, Albany, NY, USA
| | - Chaochun Liu
- New York State Department of Health, Wadsworth Center, Center for Medical Science, Albany, NY, USA
| | - C Steven Carmack
- New York State Department of Health, Wadsworth Center, Center for Medical Science, Albany, NY, USA
| | - Jun Lu
- Department of Genetics, Yale Stem Cell Center, Yale University, New Haven, CT, USA
| | - Ye Ding
- New York State Department of Health, Wadsworth Center, Center for Medical Science, Albany, NY, USA.
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Yang S, Guo J, Zhou L, Xing H, Wang X, Dong C. miR-148b-3p, miR-337-5p and miR-423-5p expression in alveolar ridge atrophy and their roles in the proliferation and apoptosis of OMMSCs. Exp Ther Med 2018; 16:5334-5342. [PMID: 30542492 DOI: 10.3892/etm.2018.6850] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Accepted: 07/20/2018] [Indexed: 01/03/2023] Open
Abstract
MicroRNAs (miRNAs/miRs) have key roles in various physiological and pathological processes by regulating the expression of specific genes. The identification of miRNAs involved in bone metabolism may provide insight into the expression of genes associated with the development of alveolar ridge atrophy. In the present study, the miRNA expression profiles in alveolar ridge atrophy and normal tissue samples were investigated by miRNA microarray analysis. Among the 52 differentially expressed miRNAs identified, the expression levels of 20 selected miRNAs in the alveolar ridge atrophy and normal tissue samples were verified by reverse transcription-quantitative polymerase chain reaction. The results indicated that the expression levels of 11 miRNAs were significantly different between alveolar ridge atrophy and normal tissue samples; however, only three of them (miR-148b-3p, miR-337-5p and miR-423-5p) were previously reported to be involved in bone metabolism. In vitro, miR-148b-3p, miR-337-5p and miR-423-5p mimics promoted the proliferation and inhibited apoptosis of bone marrow mesenchymal stem cells from orofacial bone (OMMSCs), while antisense inhibitors of these miRNAs had the opposite effect. In conclusion, the present study indicated that these miRNAs are involved in the pathogenesis of alveolar ridge atrophy. miR-148b-3p, miR-337-5p and miR-423-5p promote the proliferation of OMMSCs and inhibit their apoptosis. The present results provide a novel perspective for understanding the pathogenesis of alveolar ridge atrophy.
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Affiliation(s)
- Sefei Yang
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Jun Guo
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, P.R. China.,Department of Orthodontics, Hospital of Stomatology, Nankai University, Tianjin 300041, P.R. China
| | - Lei Zhou
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Helin Xing
- Department of Prosthodontics, School of Stomatology, Capital Medical University, Beijing 100050, P.R. China
| | - Xianli Wang
- Department of Prosthodontics, Anyang Sixth People's Hospital, Anyang, Henan 455000, P.R. China
| | - Chaofang Dong
- Lab for Corrosion Control and Research Development, School of Mathematics and Physics, University of Science and Technology Beijing, Beijing 100853, P.R. China
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42
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Abstract
The mineralocorticoid hormone aldosterone is released by the adrenal glands in a homeostatic mechanism to regulate blood volume. Several cues elicit aldosterone release, and the long-term action of the hormone is to restore blood pressure and/or increase the retrieval of sodium from filtered plasma in the kidney. While the signaling cascade that results in aldosterone release is well studied, the impact of this hormone on tissues and cells in various organ systems is pleotropic. Emerging evidence indicates aldosterone may alter non-coding RNAs (ncRNAs) to integrate the hormonal response, and these ncRNAs may contribute to the heterogeneity of signaling outcomes in aldosterone target tissues. The best studied of the ncRNAs in aldosterone action are the small ncRNAs, microRNAs. MicroRNA expression is regulated by aldosterone stimulation, and microRNAs are able to modulate protein expression at all steps in the renin-angiotensin-aldosterone-signaling system. The discovery and synthesis of microRNAs will be briefly covered followed by a discussion of the reciprocal role of aldosterone/microRNA regulation, including misregulation of microRNA signaling in aldosterone-linked disease states.
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43
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Yao ZS, Li C, Liang D, Jiang XB, Tang JJ, Ye LQ, Yuan K, Ren H, Yang ZD, Jin DX, Zhang SC, Ding JY, Tang YC, Xu JX, Chen K, Xie WX, Guo DQ, Cui JC. Diagnostic and prognostic implications of serum miR-101 in osteosarcoma. Cancer Biomark 2018; 22:127-133. [PMID: 29630525 PMCID: PMC6004928 DOI: 10.3233/cbm-171103] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Blood-circulating microRNAs (miRNAs) have been reported to be used as potential biomarkers in various cancers. MiR-101 has been found to act as a tumor suppressor in many tumor types, but little is known for osteosarcoma. The purpose of this study was to investigate miR-101 expression in osteosarcoma patients and assess its correlation with clinical features and prognosis. Serum samples from 152 osteosarcoma patients and 70 healthy controls were detected using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The data showed that miR-101 expression levels were remarkably underexpressed in serum samples from osteosarcoma patients compared to controls, and the post-treatment serum miR-101 expression was significantly higher than that in the pre-treatment expression. Low serum miR-101 expression was positively associated with advanced clinical stage and distant metastasis. Receiver operating characteristic (ROC) curve analysis showed that serum miR-101 could serve as a useful marker for osteosarcoma diagnosis, with a high sensitivity and specificity. Moreover, patients with high miR-101 expression had longer overall survival and recurrence free survival than those with low miR-101 expression. In addition, both univariate and multivariate analyses showed that serum miR-101 downregulation was associated with shorter overall survival and recurrence free survival. Our present results implicated serum miR-101 might be a useful biomarker for the clinical diagnosis and prognosis of osteosarcoma.
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Affiliation(s)
- Z-S Yao
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - C Li
- Departments of Clinical Laboratory, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - D Liang
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - X-B Jiang
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - J-J Tang
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - L-Q Ye
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - K Yuan
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - H Ren
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Z-D Yang
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - D-X Jin
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - S-C Zhang
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - J-Y Ding
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Y-C Tang
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - J-X Xu
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - K Chen
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - W-X Xie
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - D-Q Guo
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - J-C Cui
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
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Corrà F, Agnoletto C, Minotti L, Baldassari F, Volinia S. The Network of Non-coding RNAs in Cancer Drug Resistance. Front Oncol 2018; 8:327. [PMID: 30211115 PMCID: PMC6123370 DOI: 10.3389/fonc.2018.00327] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 07/31/2018] [Indexed: 12/12/2022] Open
Abstract
Non-coding RNAs (ncRNAs) have been implicated in most cellular functions. The disruption of their function through somatic mutations, genomic imprinting, transcriptional and post-transcriptional regulation, plays an ever-increasing role in cancer development. ncRNAs, including notorious microRNAs, have been thus proposed to function as tumor suppressors or oncogenes, often in a context-dependent fashion. In parallel, ncRNAs with altered expression in cancer have been reported to exert a key role in determining drug sensitivity or restoring drug responsiveness in resistant cells. Acquisition of resistance to anti-cancer drugs is a major hindrance to effective chemotherapy and is one of the most important causes of relapse and mortality in cancer patients. For these reasons, non-coding RNAs have become recent focuses as prognostic agents and modifiers of chemo-sensitivity. This review starts with a brief outline of the role of most studied non-coding RNAs in cancer and then highlights the modulation of cancer drug resistance via known ncRNAs based mechanisms. We identified from literature 388 ncRNA-drugs interactions and analyzed them using an unsupervised approach. Essentially, we performed a network analysis of the non-coding RNAs with direct relations with cancer drugs. Within such a machine-learning framework we detected the most representative ncRNAs-drug associations and groups. We finally discussed the higher integration of the drug-ncRNA clusters with the goal of disentangling effectors from downstream effects and further clarify the involvement of ncRNAs in the cellular mechanisms underlying resistance to cancer treatments.
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Affiliation(s)
- Fabio Corrà
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Chiara Agnoletto
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Linda Minotti
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Federica Baldassari
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Stefano Volinia
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
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Genetic Variants in pre-miR-146a, pre-miR-499, pre-miR-125a, pre-miR-605, and pri-miR-182 Are Associated with Breast Cancer Susceptibility in a South American Population. Genes (Basel) 2018; 9:genes9090427. [PMID: 30135399 PMCID: PMC6162394 DOI: 10.3390/genes9090427] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 08/13/2018] [Accepted: 08/17/2018] [Indexed: 12/17/2022] Open
Abstract
Breast cancer (BC) is one of the most frequent tumors affecting women worldwide. microRNAs (miRNAs) single-nucleotide polymorphisms (SNPs) likely contribute to BC susceptibility. We evaluated the association of five SNPs with BC risk in non-carriers of the BRCA1/2-mutation from a South American population. The SNPs were genotyped in 440 Chilean BRCA1/2-negative BC cases and 1048 controls. Our data do not support an association between rs2910164:G>C or rs3746444:A>G and BC risk. The rs12975333:G>T is monomorphic in the Chilean population. The pre-miR-605 rs2043556-C allele was associated with a decreased risk of BC, both in patients with a strong family history of BC and in early-onset non-familial BC (Odds ratio (OR) = 0.5 [95% confidence interval (CI) 0.4⁻0.9] p = 0.006 and OR = 0.6 [95% CI 0.5⁻0.9] p = 0.02, respectively). The rs4541843-T allele is associated with increased risk of familial BC. This is the first association study on rs4541843 and BC risk. Previously, we showed that the TOX3-rs3803662:C>T was significantly associated with increased risk of familial BC. Given that TOX3 mRNA is a target of miR-182, and that both the TOX3 rs3803662-T and pri-miR-182 rs4541843-T alleles are associated with increased BC risk, we evaluated their combined effect. Risk of familial BC increased in a dose-dependent manner with the number of risk alleles (p-trend = 0.0005), indicating an additive effect.
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Lapshina AM, Khandaeva PM, Belaya ZE, Rozhinskaya LY, Melnichenko GA. [Role of microRNA in oncogenesis of pituitary tumors and their practical significance]. TERAPEVT ARKH 2018. [PMID: 28635944 DOI: 10.17116/terarkh2016888115-120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Microribonucleic acids (miRNAs) are a class of noncoding RNAs that regulate posttranscriptional gene expression. These molecules are regulators of cell proliferation, metabolism, apoptosis, and differentiation. MiRNAs are not degraded by RNAases and their concentrations can be measured in different body fluids, including serum. The expression of miRNAs varies in intact tissues and tumors, including pituitary adenomas. Pituitary tumors are encountered in 22.5% of the population and, in a number of cases, may be asymptomatic, but in case of invasion or/and hormone overproduction, their clinical presentation is severe with multiple symptoms leading to disability and even death. The mechanisms for the development and progression of pituitary tumors and the markers for remission and recurrence have not been adequately investigated. This literature review discusses the biological significance of miRNAs in pituitary tumors and the potential value of circulating miRNAs as biomarkers.
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Affiliation(s)
- A M Lapshina
- Endocrine Research Center, Ministry of Health of Russia, Moscow, Russia
| | - P M Khandaeva
- Endocrine Research Center, Ministry of Health of Russia, Moscow, Russia
| | - Zh E Belaya
- Endocrine Research Center, Ministry of Health of Russia, Moscow, Russia
| | - L Ya Rozhinskaya
- Endocrine Research Center, Ministry of Health of Russia, Moscow, Russia
| | - G A Melnichenko
- Endocrine Research Center, Ministry of Health of Russia, Moscow, Russia
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De Felice B, Manfellotto F, Fiorentino G, Annunziata A, Biffali E, Pannone R, Federico A. Wide-Ranging Analysis of MicroRNA Profiles in Sporadic Amyotrophic Lateral Sclerosis Using Next-Generation Sequencing. Front Genet 2018; 9:310. [PMID: 30154826 PMCID: PMC6102490 DOI: 10.3389/fgene.2018.00310] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 07/23/2018] [Indexed: 12/11/2022] Open
Abstract
MicroRNA (miRNA) has emerged as an important regulator of gene expression in neurodegenerative disease as amyotrophic lateral sclerosis (ALS). In the nervous system, dysregulation in miRNA-related pathways is subordinated to neuronal damage and cell death, which contributes to the expansion of neurodegenerative disorders, such as ALS. In the present research, we aimed to profile dysregulation of miRNAs in ALS blood and neuromuscular junction as well as healthy blood control by next-generation sequencing (NGS). The expression of three upregulated miRNAs, as miR-338-3p, miR-223-3p, and miR-326, in the ALS samples compared to healthy controls, has been validated by qRT-PCR in a cohort of 45 samples collected previously. Bioinformatics tools were used to perform ALS miRNAs target analysis and to predict novel miRNAs secondary structure. The analysis of the NGS data identified 696 and 49 novel miRNAs which were differentially expressed in ALS tissues. In particular, in neuromuscular junction the differential expression of miR-338-3p, which we previously found upregulated in different types of ASL tissues, miR-223-3p, and miR-326 was elevated compared to normal control. ALS miRNAs gene target were significantly involved in neuronal related pathway as BDFN1 and HIF-1genes. This study presents the direct experimental evidence that, overall, miR-338-3p is highly expressed in ALS tissues including neuromuscular junction characterizing ALS from normal tissues. Beside, our analysis identified, for the first time, novel miRNAs highly expressed in ALS tissues. In conclusion, the results indicate that miRNAs has an important role in the diagnosis and treatment of ALS.
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Affiliation(s)
- Bruna De Felice
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Francesco Manfellotto
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | | | - Anna Annunziata
- Division of Physiopathology, Monaldi Hospital, Naples, Italy
| | | | | | - Antonio Federico
- Institute of Genetics and Biophysics "Adriano Buzzati Traverso", National Research Council, Naples, Italy
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Wang Y, Kong D. MicroRNA-136 promotes lipopolysaccharide-induced ATDC5 cell injury and inflammatory cytokine expression by targeting myeloid cell leukemia 1. J Cell Biochem 2018; 119:9316-9326. [PMID: 30074264 DOI: 10.1002/jcb.27208] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 05/24/2018] [Indexed: 12/21/2022]
Abstract
Osteoarthritis is the most frequent chronic bone and joint diseases in older populations all over the world. Lipopolysaccharide (LPS)-induced murine chondrogenic ATDC5 cell model has been widely used for testing new osteoarthritis therapeutic targets. This study aimed to explore the effects of microRNA-136 (miR-136) on LPS-induced ATDC5 cell injury and inflammatory cytokine expression, as well as underlying potential mechanism. We found that LPS remarkably inhibited ATDC5 cell viability, induced ATDC5 cell apoptosis, and upregulated the expression of inflammatory cytokines, including interleukin 1β (IL-1β), IL-6, IL-8, and tumor necrosis factor α (TNF-α; P < .01 or < .001). Moreover, LPS obviously upregulated the expression of miR-136 in ATDC5 cells (P < .05). Overexpression of miR-136 markedly exacerbated the LPS-induced ATDC5 cell viability inhibition, cell apoptosis enhancement, and inflammatory cytokine expression (P < .05), and suppression of miR-136 had opposite effects (P < .05). Myeloid cell leukemia 1 (Mcl-1) was a direct target gene of miR-136, which participated in the effect of miR-136 on LPS-induced ATDC5 cell inflammatory injury. Overexpression of Mcl-1 alleviated the LPS-induced inactivation of Wnt/β-catenin and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways, while suppression of Mcl-1 had opposite effects. To conclude, this study verified that miR-136 promoted LPS-induced ATDC5 cell injury and inflammatory cytokine expression by targeting Mcl-1, and Mcl-1 was involved in the regulatory effects of LPS on Wnt/β-catenin and JAK/STAT signaling pathways in ATDC5 cells.
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Affiliation(s)
- Yang Wang
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Daliang Kong
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
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Wu Q, Chen Z, Zhang G, Zhou W, Peng Y, Liu R, Chen C, Feng J. EZH2 induces the expression of miR-1301 as a negative feedback control mechanism in triple negative breast cancer. Acta Biochim Biophys Sin (Shanghai) 2018; 50:693-700. [PMID: 29790898 DOI: 10.1093/abbs/gmy050] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 04/17/2018] [Indexed: 12/25/2022] Open
Abstract
Breast cancer is one of the most common malignancies in women. ERα, PR, and HER2 triple negative breast cancer (TNBC) is the current research focus because of the lack of effective targeted therapies. In our study, lentivirus systems were used to overexpress EZH2 and miR-1301 in TNBC cell lines. Western blot analysis and RT-qPCR were used to detect the protein and microRNA levels. The TCGA and Kaplan Meier plotter databases were used to analyze the EZH2 and miR-1301 expression levels in breast cancer. The effect of miR-1301 overexpression on cell proliferation, migration and colony formation were determined by using the sulforhodamine B (SRB) assay, wound healing assay and colony formation assay, respectively. Furthermore, an xenograft mouse model was used to investigate the function of miR-1301 overexpression in vivo. Finally, dual luciferase reporter assay was used to verify the binding site of EZH2 and miR-1301. We found that EZH2 induced the expression of miR-1301 in two TNBC cell lines, HCC1937 and HCC1806. Overexpression of miR-1301 suppressed TNBC cell proliferation, migration and colony formation, as well as the xenograft tumor growth in immunodeficient mice. Interestingly, miR-1301 inhibited the expression of EZH2 by binding to the 3'-UTR of EZH2 gene. These data suggest that EZH2 induces the expression of miR-1301 as a negative feedback control mechanism in TNBC.
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Affiliation(s)
- Qiuju Wu
- Fengxian District Center Hospital Graduate Student Training Base, Jinzhou Medical University, Shanghai, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
- Department of Laboratory Medicine, Fengxian District Center Hospital, Shanghai, China
| | - Zekun Chen
- Department of Laboratory Medicine, Huizhou No. 3 People's Hospital, Affiliated hospital of Guangzhou Medical University, Huizhou, China
| | - Guihua Zhang
- Department of Laboratory Medicine, Huizhou No. 3 People's Hospital, Affiliated hospital of Guangzhou Medical University, Huizhou, China
| | - Wenhui Zhou
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - You Peng
- Department of Laboratory Medicine, Fengxian District Center Hospital, Shanghai, China
| | - Rong Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Jing Feng
- Department of Laboratory Medicine, Fengxian District Center Hospital, Shanghai, China
- Shanghai University of Medicine & Health Sciences Affiliated Six People's Hospital South Campus, Shanghai, China
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