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1
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Capasso G, Mouawad N, Castronuovo M, Ruggeri E, Visentin A, Trentin L, Frezzato F. Focal adhesion kinase as a new player in the biology of onco-hematological diseases: the starting evidence. Front Oncol 2024; 14:1446723. [PMID: 39281374 PMCID: PMC11392731 DOI: 10.3389/fonc.2024.1446723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 07/31/2024] [Indexed: 09/18/2024] Open
Abstract
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase mainly found in the focal adhesion regions of the plasma membrane and it has a crucial role in migration and the remodeling of cellular morphology. FAK is also linked to several aspects of cancer biology, from cytokine production to angiogenesis, drug resistance, invasion, and metastasis, as well as epithelial-to-mesenchymal transition. The gene locus of FAK is frequently amplified in several human tumors, thus causing FAK overexpression in several cancers. Furthermore, FAK can influence extracellular matrix production and exosome secretion through cancer-associated fibroblasts, thus it has an important role in tumor microenvironment regulation. Although the role of FAK in solid tumors is well known, its importance in onco-hematological diseases remains poorly explored. This review collects studies related to FAK significance in onco-hematological diseases and their microenvironments. Overall, the importance of FAK in blood tumors is increasingly evident, but further research is required to confirm it as a new therapeutic target in hematological contexts.
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Affiliation(s)
- Guido Capasso
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Nayla Mouawad
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Maria Castronuovo
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Edoardo Ruggeri
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Andrea Visentin
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Livio Trentin
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Federica Frezzato
- Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
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2
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Wang FX, Shi ZA, Mu G. Regulation of immune cells by miR-451 and its potential as a biomarker in immune-related disorders: a mini review. Front Immunol 2024; 15:1421473. [PMID: 39076992 PMCID: PMC11284029 DOI: 10.3389/fimmu.2024.1421473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 07/01/2024] [Indexed: 07/31/2024] Open
Abstract
In 2005, Altuvia and colleagues were the first to identify the gene that encodes miR-451 in the human pituitary gland, located in chromosome region 17q11.2. Subsequent studies have confirmed that miR-451 regulates various immune cells, including T cells, B cells, microglia, macrophages, and neutrophils, thereby influencing disease progression. The range of immune-related diseases affected encompasses various cancers, lymphoblastic leukemia, and injuries to the lungs and spinal cord, among others. Moreover, miR-451 is produced by immune cells and can regulate both their own functions and those of other immune cells, thus creating a regulatory feedback loop. This article aims to comprehensively review the interactions between miR-451 and immune cells, clarify the regulatory roles of miR-451 within the immune system, and assess its potential as both a therapeutic target and a biomarker for immune-related diseases.
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Affiliation(s)
- Fei-xiang Wang
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan, China
| | - Zu-an Shi
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan, China
| | - Guo Mu
- Department of Anesthesiology, Zigong Fourth People’s Hospital, Zigong, Sichuan, China
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3
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Jeong HR, Hwang IT. MicroRNAs as novel biomarkers for the diagnosis and treatment of pediatric diseases. Clin Exp Pediatr 2024; 67:119-125. [PMID: 37232075 PMCID: PMC10915459 DOI: 10.3345/cep.2023.00171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 04/22/2023] [Accepted: 04/24/2023] [Indexed: 05/27/2023] Open
Abstract
MicroRNAs (miRNAs) are highly conserved noncoding RNAs that regulate gene expression by silencing or degrading messenger RNAs. Many of the approximately 2,500 miRNAs discovered in humans are known to regulate vital biological processes, including cell differentiation, proliferation, apoptosis, and embryonic tissue development. Aberrant miRNA expression may have pathological and malignant consequences. Therefore, miRNAs have emerged as novel diagnostic markers and potential therapeutic targets for various diseases. Children undergo various stages of growth, development, and maturation between birth and adulthood. It is important to study the role of miRNA expression in normal growth and disease development during these developmental stages. In this mini-review, we discuss the role of miRNAs as diagnostic and prognostic biomarkers in various pediatric diseases.
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Affiliation(s)
- Hwal Rim Jeong
- Department of Pediatrics, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Il Tae Hwang
- Department of Pediatrics, Hallym University Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
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4
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Huang W, Paul D, Calin GA, Bayraktar R. miR-142: A Master Regulator in Hematological Malignancies and Therapeutic Opportunities. Cells 2023; 13:84. [PMID: 38201290 PMCID: PMC10778542 DOI: 10.3390/cells13010084] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/29/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
MicroRNAs (miRNAs) are a type of non-coding RNA whose dysregulation is frequently associated with the onset and progression of human cancers. miR-142, an ultra-conserved miRNA with both active -3p and -5p mature strands and wide-ranging physiological targets, has been the subject of countless studies over the years. Due to its preferential expression in hematopoietic cells, miR-142 has been found to be associated with numerous types of lymphomas and leukemias. This review elucidates the multifaceted role of miR-142 in human physiology, its influence on hematopoiesis and hematopoietic cells, and its intriguing involvement in exosome-mediated miR-142 transport. Moreover, we offer a comprehensive exploration of the genetic and molecular landscape of the miR-142 genomic locus, highlighting its mutations and dysregulation within hematological malignancies. Finally, we discuss potential avenues for harnessing the therapeutic potential of miR-142 in the context of hematological malignancies.
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Affiliation(s)
- Wilson Huang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (W.H.); (G.A.C.)
| | - Doru Paul
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA;
| | - George A. Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (W.H.); (G.A.C.)
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Recep Bayraktar
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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5
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MiRNAs in Hematopoiesis and Acute Lymphoblastic Leukemia. Int J Mol Sci 2023; 24:ijms24065436. [PMID: 36982511 PMCID: PMC10049736 DOI: 10.3390/ijms24065436] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/03/2023] [Accepted: 02/04/2023] [Indexed: 03/14/2023] Open
Abstract
Acute lymphoblastic leukemia (ALL) is the most common kind of pediatric cancer. Although the cure rates in ALL have significantly increased in developed countries, still 15–20% of patients relapse, with even higher rates in developing countries. The role of non-coding RNA genes as microRNAs (miRNAs) has gained interest from researchers in regard to improving our knowledge of the molecular mechanisms underlying ALL development, as well as identifying biomarkers with clinical relevance. Despite the wide heterogeneity reveled in miRNA studies in ALL, consistent findings give us confidence that miRNAs could be useful to discriminate between leukemia linages, immunophenotypes, molecular groups, high-risk-for-relapse groups, and poor/good responders to chemotherapy. For instance, miR-125b has been associated with prognosis and chemoresistance in ALL, miR-21 has an oncogenic role in lymphoid malignancies, and the miR-181 family can act either as a oncomiR or tumor suppressor in several hematological malignancies. However, few of these studies have explored the molecular interplay between miRNAs and their targeted genes. This review aims to state the different ways in which miRNAs could be involved in ALL and their clinical implications.
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6
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MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools. Cancers (Basel) 2022; 14:cancers14163976. [PMID: 36010971 PMCID: PMC9406077 DOI: 10.3390/cancers14163976] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/14/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary MicroRNAs (miRNAs) have been under the spotlight for the last three decades. These non-coding RNAs seem to be dynamic regulators of mRNA stability and translation, in addition to interfering with transcription. Circulating miRNAs play a critical role in cell-to-cell interplay; therefore, they can serve as disease biomarkers. Meta-analysis of published data revealed that the CC genotype of rs4938723 in pri-miR-34b/c and the TT genotype of rs543412 in miR-100 confer protection against acute lymphoblastic leukemia (ALL) in children. Reanalysis of small RNA-seq data with novel tools identified significantly overexpressed members of the miR-128, miR-181, miR-130 and miR-17 families and significantly lower expression of miR-30, miR-24-2 and miR143~145 clusters, miR-574 and miR-618 in pediatric T-ALL cases compared with controls. Inconsistencies in methodology and study designs in most published material preclude reproducibility, and further cohort studies need to be conducted in order to empower novel tools, such as ALLSorts and RNAseqCNV. Abstract MicroRNAs (miRNAs) have been implicated in childhood acute lymphoblastic leukemia (ALL) pathogenesis. We performed a systematic review and meta-analysis of miRNA single-nucleotide polymorphisms (SNPs) in childhood ALL compared with healthy children, which revealed (i) that the CC genotype of rs4938723 in pri-miR-34b/c and the TT genotype of rs543412 in miR-100 confer protection against ALL occurrence in children; (ii) no significant association between rs2910164 genotypes in miR-146a and childhood ALL; and (iii) SNPs in DROSHA, miR-449b, miR-938, miR-3117 and miR-3689d-2 genes seem to be associated with susceptibility to B-ALL in childhood. A review of published literature on differential expression of miRNAs in children with ALL compared with controls revealed a significant upregulation of the miR-128 family, miR-130b, miR-155, miR-181 family, miR-210, miR-222, miR-363 and miR-708, along with significant downregulation of miR-143 and miR-148a, seem to have a definite role in childhood ALL development. MicroRNA signatures among childhood ALL subtypes, along with differential miRNA expression patterns between B-ALL and T-ALL cases, were scrutinized. With respect to T-ALL pediatric cases, we reanalyzed RNA-seq datasets with a robust and sensitive pipeline and confirmed the significant differential expression of hsa-miR-16-5p, hsa-miR-19b-3p, hsa-miR-92a-2-5p, hsa-miR-128-3p (ranked first), hsa-miR-130b-3p and -5p, hsa-miR-181a-5p, -2-3p and -3p, hsa-miR-181b-5p and -3p, hsa-miR-145-5p and hsa-miR-574-3p, as described in the literature, along with novel identified miRNAs.
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7
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Marley AR, Ryder JR, Turcotte LM, Spector LG. Maternal obesity and acute lymphoblastic leukemia risk in offspring: A summary of trends, epidemiological evidence, and possible biological mechanisms. Leuk Res 2022; 121:106924. [PMID: 35939888 DOI: 10.1016/j.leukres.2022.106924] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/13/2022] [Accepted: 08/01/2022] [Indexed: 10/16/2022]
Abstract
Acute lymphoblastic leukemia, a heterogenous malignancy characterized by uncontrolled proliferation of lymphoid progenitors and generally initiated in utero, is the most common pediatric cancer. Although incidence of ALL has been steadily increasing in recent decades, no clear reason for this trend has been identified. Rising concurrently with ALL incidence, increasing maternal obesity rates may be partially contributing to increasing ALL prevelance. Epidemiological studies, including a recent meta-analysis, have found an association between maternal obesity and leukemogenesis in offspring, although mechanisms underlying this association remain unknown. Therefore, the purpose of this review is to propose possible mechanisms connecting maternal obesity to ALL risk in offspring, including changes to fetal/neonatal epigenetics, altered insulin-like growth factor profiles and insulin resistance, modified adipokine production and secretion, changes to immune cell populations, and impacts on birthweight and childhood obesity/adiposity. We describe how each proposed mechanism is biologically plausible due to their connection with maternal obesity, presence in neonatal and/or fetal tissue, observation in pediatric ALL patients at diagnosis, and association with leukemogenesis, A description of ALL and maternal obesity trends, a summary of epidemiological evidence, a discussion of the pathway from intrauterine environment to subsequent malignancy, and propositions for future directions are also presented.
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Affiliation(s)
- Andrew R Marley
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, 420 Delaware St SE MMC 715, Minneapolis, MN 55455, USA.
| | - Justin R Ryder
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, 420 Delaware St SE MMC 715, Minneapolis, MN 55455, USA; Center for Pediatric Obesity Medicine, Department of Pediatrics, University of Minnesota, 2450 Riverside Ave S AO-102, Minneapolis, MN 55454, USA
| | - Lucie M Turcotte
- Division of Hematology/Oncology, Department of Pediatrics, University of Minnesota, 420 Delaware St SE MMC 484, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, 425 East River Parkway, Minneapolis, MN 55455, USA
| | - Logan G Spector
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, 420 Delaware St SE MMC 715, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, 425 East River Parkway, Minneapolis, MN 55455, USA
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8
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Soofiyani SR, Hosseini K, Soleimanian A, Abkhooei L, Hoseini AM, Tarhriz V, Ghasemnejad T. An Overview on the Role of miR-451 in Lung Cancer: Diagnosis, Therapy, and Prognosis. Microrna 2021; 10:181-190. [PMID: 34514995 DOI: 10.2174/2211536610666210910130828] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/15/2021] [Accepted: 08/03/2021] [Indexed: 11/22/2022]
Abstract
MicroRNAs (miRNAs) are highly conserved non-coding RNAs involved in many physiological processes such as cell proliferation, inhibition, development of apoptosis, differentiation, suppresses tumorigenicity, and regulating cell growth. The description of the alterations of miRNA expression patterns in cancers will be helpful to recognize biomarkers for early detection and possible therapeutic intervention in the treatment of cancers. Recent studies have shown that miR-451 is broadly dysregulated in lung cancer and is a crucial agent in lung tumor progression. This review summarizes recent advances of the potential role of miR-451 in lung cancer diagnosis, prognosis, and treatment and provides an insight into the potential use of miR-451 for the development of advanced therapeutic methods in lung cancer.
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Affiliation(s)
- Saiedeh Razi Soofiyani
- Clinical Research Development Unit of Sina Educational, Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz. Iran
| | - Kamram Hosseini
- Student research committee, Shiraz University of Medical Sciences, Shiraz. Iran
| | - Alireza Soleimanian
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz. Iran
| | - Liela Abkhooei
- Department of Medical Biotechnology, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad. Iran
| | - Akbar Mohammad Hoseini
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine and Tabriz Blood Transfusion Center, Tabriz. Iran
| | - Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz. Iran
| | - Tohid Ghasemnejad
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz. Iran
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9
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Gutierrez-Camino A, Garcia-Obregon S, Lopez-Lopez E, Astigarraga I, Garcia-Orad A. miRNA deregulation in childhood acute lymphoblastic leukemia: a systematic review. Epigenomics 2019; 12:69-80. [PMID: 31833405 DOI: 10.2217/epi-2019-0154] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Despite remarkable improvements in survival of childhood acute lymphoblastic leukemia (ALL), nonresponding or relapsing patients still represent one of the most frequent causes of death by disease in children. Accurate patient risk stratification based on genetic markers could increases survival rates. miRNAs can represent novel candidates with diagnostic, predictive and prognostic potential; however, many groups investigated their involvement with contradictory results. Aim: To clarify the role of miRNAs as biomarkers through a systematic review. Results: From a revision of 45 manuscripts, we found that miR-128 and miR-181 overexpression could represent markers for ALL diagnosis and underexpression of miR-708 and miR-99a could be markers for bad prognosis. Conclusion: These signatures could refine classification and risk stratification of patients and improve ALL outcome.
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Affiliation(s)
- Angela Gutierrez-Camino
- Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country, UPV/EHU, Leioa, 48940, Spain.,BioCruces Bizkaia Health Research Institute, Pediatric Oncology Group, Barakaldo, 48903, Spain.,Division of Hematology-Oncology, Research Center, Sainte-Justine University Health Center, Montreal, QC H3T 1C5, Canada
| | - Susana Garcia-Obregon
- BioCruces Bizkaia Health Research Institute, Pediatric Oncology Group, Barakaldo, 48903, Spain
| | - Elixabet Lopez-Lopez
- Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country, UPV/EHU, Leioa, 48940, Spain.,BioCruces Bizkaia Health Research Institute, Pediatric Oncology Group, Barakaldo, 48903, Spain
| | - Itziar Astigarraga
- BioCruces Bizkaia Health Research Institute, Pediatric Oncology Group, Barakaldo, 48903, Spain.,Department of Pediatrics, University Hospital Cruces, Barakaldo, 48903, Spain.,Department of Pediatrics, University of the Basque Country, UPV/EHU, Leioa, 48940, Spain
| | - Africa Garcia-Orad
- Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country, UPV/EHU, Leioa, 48940, Spain.,BioCruces Bizkaia Health Research Institute, Pediatric Oncology Group, Barakaldo, 48903, Spain
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10
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Rzepiel A, Kutszegi N, Gézsi A, Sági JC, Egyed B, Péter G, Butz H, Nyírő G, Müller J, Kovács GT, Szalai C, Semsei ÁF, Erdélyi DJ. Circulating microRNAs as minimal residual disease biomarkers in childhood acute lymphoblastic leukemia. J Transl Med 2019; 17:372. [PMID: 31727091 PMCID: PMC6854698 DOI: 10.1186/s12967-019-2114-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 10/26/2019] [Indexed: 12/21/2022] Open
Abstract
Background Treatment stratification based on bone marrow minimal residual disease (MRD) at set time points has resulted in considerably improved survival in pediatric acute lymphoblastic leukemia (ALL). Treatment response is assessed using bone marrow samples. MicroRNAs (miRs) easily traffic among fluid spaces and are more stable than most other RNA classes. We examined the role of circulating miRs as putative less invasive MRD biomarkers. Methods In an exploratory experiment, expression of 46 preselected miRs was studied in platelet-free blood plasma samples of 15 de novo, 5 relapsed ALL patients and 10 controls by Custom TaqMan Array Advanced MicroRNA Card. Based on their high expression in ALL compared to controls, and on the reduction observed along the induction therapy, four miRs were selected for further analyses: miR-128-3p, -181a-5p, -181b-5p and 222-3p. Their expression was measured by qPCR at 4 time points in 27 de novo ALL patients treated in the ALL IC-BFM 2009 study. Results The expression of all 4 miRs significantly decreased over the first week of therapy (miR-128-3p: log2 fold change − 2.86; adjusted p 3.6 × 10−7; miR-181b-5p: log2 fold change − 1.75; adjusted p 1.48 × 10−2; miR-181a-5p: log2 fold change -1.33; adjusted p 3.12 × 10−2; miR-222-3p: log2 fold change − 1.25; adjusted p 1.66 × 10−2). However, no significant further reduction in miR expression was found after the 8th day of therapy. Measured drop in expression of 2 miRs at day 8 strongly correlated with day 15 bone marrow flow cytometry MRD results (miR-128-3p: Pearson’s r = 0.88, adjusted p = 2.71 × 10−4; miR-222-3p: r = 0.81, adjusted p = 2.99 × 10−3). Conclusion In conclusion, these circulating miRs might act as biomarkers of residual leukemia. MiR-128-3p and miR-222-3p in blood predict day 15 flow cytometry MRD results 7 days earlier. Although, their sensitivity falls behind that of bone marrow flow cytometry MRD at day 15.
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Affiliation(s)
- Andrea Rzepiel
- 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - Nóra Kutszegi
- 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary.,Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
| | - András Gézsi
- MTA-SE Immune-Proteogenomics Extracellular Vesicle Research Group, Budapest, Hungary.,Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary
| | - Judit C Sági
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Bálint Egyed
- 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary.,Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
| | | | - Henriett Butz
- Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary
| | - Gábor Nyírő
- MTA-SE Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
| | - Judit Müller
- 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - Gábor T Kovács
- 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - Csaba Szalai
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary.,Heim Pál Children's Hospital, Budapest, Hungary
| | - Ágnes F Semsei
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Dániel J Erdélyi
- 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary.
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11
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Khordadmehr M, Jigari-Asl F, Ezzati H, Shahbazi R, Sadreddini S, Safaei S, Baradaran B. A comprehensive review on miR-451: A promising cancer biomarker with therapeutic potential. J Cell Physiol 2019; 234:21716-21731. [PMID: 31140618 DOI: 10.1002/jcp.28888] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 05/07/2019] [Accepted: 05/09/2019] [Indexed: 12/16/2022]
Abstract
MicroRNAs (miRNAs) are proposed as a family of short noncoding molecules able to manage and control the expression of the gene targets at the posttranscriptional level. They contribute in several fundamental physiological mechanisms as well as a verity of human and animal diseases such as cancer progression. Among these tiny RNAs, miR-451 placed on chromosome 17 at 17q11.2 presents an essential role in many biological processes in health condition and also in pathogenesis of different diseases. Besides, it has been recently considered as a valuable biomarker for cancer detection, prognosis and treatment. Therefore, this review will provide the critical functions of miR-451 on biological mechanisms including cell cycle and proliferation, cell survival and apoptosis, differentiation and development as well as disease initiation and progression such as tumor formation, migration, invasion, and metastasis.
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Affiliation(s)
- Monireh Khordadmehr
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Farinaz Jigari-Asl
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Hamed Ezzati
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Roya Shahbazi
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Sanam Sadreddini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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12
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13
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Rashed WM, Hammad AM, Saad AM, Shohdy KS. MicroRNA as a diagnostic biomarker in childhood acute lymphoblastic leukemia; systematic review, meta-analysis and recommendations. Crit Rev Oncol Hematol 2019; 136:70-78. [PMID: 30878131 DOI: 10.1016/j.critrevonc.2019.02.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 02/17/2019] [Accepted: 02/21/2019] [Indexed: 12/11/2022] Open
Abstract
Several studies detected abnormal mi-RNAs expression levels in childhood Acute Lymphoblastic Leukemia (ALL) with potential diagnostic value. We conducted a systematic search on certain microRNAs in childhood ALL. We included 17 studies with a total of 928 ALL children and 307 controls. Ten studies provided miRNAs expression levels and seven provided frequency data. Sensitivity and specificity of a single miRNA ranged from 46.55% to 100% and from 71.8% to 100%, respectively. The highest diagnostic odds ratio (DOR) was for the diagnostic panel (miR-128a and miR-223) reaching 546 [95% CI: 73.768-4041.282]. Also, miR-128a, miR-128b, miR-223, let-7b, miR-155 and miR-24 can be used as diagnostic discriminatory biomarkers between ALL and AML. Further large cohort studies are needed to confirm our results.
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Affiliation(s)
- Wafaa M Rashed
- Research Department, Children's Cancer Hospital 57357 (CCHE-57357), Egypt.
| | - Ali M Hammad
- Kasr Alainy School of Medicine, Cairo University, Egypt
| | - Anas M Saad
- Faculty of Medicine, Ain Shams University, Egypt
| | - Kyrillus S Shohdy
- Clinical Oncology Department, Kasr Alainy School of Medicine, Cairo University, Egypt
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14
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Valiollahi E, Ribera JM, Genescà E, Behravan J. Genome-wide identification of microRNA signatures associated with stem/progenitor cells in Philadelphia chromosome-positive acute lymphoblastic leukemia. Mol Biol Rep 2019; 46:1295-1306. [PMID: 30712246 DOI: 10.1007/s11033-019-04600-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 01/15/2019] [Indexed: 12/19/2022]
Abstract
Acute lymphoblastic leukemia (ALL) is a malignant transformation with uncontrolled proliferation of lymphoid precursor cells within bone marrow including a dismal prognosis after relapse. Survival of a population of quiescent leukemia stem cells (LSCs, also termed leukemia-initiating cells (LICs)) after treatment is one of the relapse reasons in Ph+ ALL patient. MicroRNAs (miRNAs) are known as highly conserved 19-24 nucleotides non-protein-coding small RNAs that regulate the expression of human genes. miRNAs are often involved in the tuning of hematopoiesis. Therefore, the deregulation of miRNA expression and function in hematopoietic cells can cause cancer and promote its progression. This is the first comprehensive analysis of miRNA expression differences between CD34+CD38- LSCs and CD34+CD38+ leukemic progenitors (LPs) from the same Ph+ B-ALL bone marrow samples using high-throughput sequencing technologies. We identified multiple differentially expressed miRNAs including hsa-miR-3143, hsa-miR-6503-3p, hsa-miR-744-3p, hsa-miR-1226-3p, hsa-miR-10a-5p, hsa-miR-4658 and hsa-miR-493-3p related to LSC and LP populations which have regulatory functions in stem-cell associated biological processes. The deregulation of these miRNAs could affect leukemogenesis, clonogenic and stemness capacities in these subpopulations of Ph+ B-ALL. Therefore, identification of these LSC associated miRNAs may improve the diagnosis and management of B-ALL. These findings may also lead to future strategies to eliminate the presence of resistant LSCs, either by induction of apoptosis or by sensitizing these cells to chemotherapy.
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Affiliation(s)
- Ehsan Valiollahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Josep Maria Ribera
- Josep Carreras Research Institute (IJC), ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Eulàlia Genescà
- Josep Carreras Research Institute (IJC), ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
| | - Javad Behravan
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- School of Pharmacy, University of Waterloo, 200 University Ave, Waterloo, N2L 3G1, Canada.
- Theraphage Inc, Waterloo, ON, Canada.
- Mediphage Bioceuticals, Inc, 661 University Avenue, Suite 1300, MaRS Centre, West Tower, Toronto, M5G0B7, Canada.
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15
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Wei B, Kong W, Mou X, Wang S. Comprehensive analysis of tumor immune infiltration associated with endogenous competitive RNA networks in lung adenocarcinoma. Pathol Res Pract 2019; 215:159-170. [DOI: 10.1016/j.prp.2018.10.032] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 10/13/2018] [Accepted: 10/26/2018] [Indexed: 12/29/2022]
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16
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Carvalho de Oliveira J, Molinari Roberto G, Baroni M, Bezerra Salomão K, Alejandra Pezuk J, Sol Brassesco M. MiRNA Dysregulation in Childhood Hematological Cancer. Int J Mol Sci 2018; 19:ijms19092688. [PMID: 30201877 PMCID: PMC6165337 DOI: 10.3390/ijms19092688] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/03/2018] [Accepted: 09/08/2018] [Indexed: 12/14/2022] Open
Abstract
For decades, cancer biology focused largely on the protein-encoding genes that have clear roles in tumor development or progression: cell-cycle control, apoptotic evasion, genome instability, drug resistance, or signaling pathways that stimulate growth, angiogenesis, or metastasis. MicroRNAs (miRNAs), however, represent one of the more abundant classes of cell modulators in multicellular organisms and largely contribute to regulating gene expression. Many of the ~2500 miRNAs discovered to date in humans regulate vital biological processes, and their aberrant expression results in pathological and malignant outcomes. In this review, we highlight what has been learned about the roles of miRNAs in some of the most common human pediatric leukemias and lymphomas, along with their value as diagnostic/prognostic factors.
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Affiliation(s)
| | - Gabriela Molinari Roberto
- Department of Pediatrics, Ribeirão Preto School of Medicine, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
| | - Mirella Baroni
- Department of Pediatrics, Ribeirão Preto School of Medicine, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
| | - Karina Bezerra Salomão
- Department of Pediatrics, Ribeirão Preto School of Medicine, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
| | - Julia Alejandra Pezuk
- Programa de Pós-graduação em Farmácia, Anhanguera University of São Paulo, UNIAN/SP, 05145-200 São Paulo, Brazil.
| | - María Sol Brassesco
- Departamento de Biologia, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, 14040-901 Ribeirão Preto, Brazil.
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17
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Memari F, Joneidi Z, Taheri B, Aval SF, Roointan A, Zarghami N. Epigenetics and Epi-miRNAs: Potential markers/therapeutics in leukemia. Biomed Pharmacother 2018; 106:1668-1677. [PMID: 30170355 DOI: 10.1016/j.biopha.2018.07.133] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 07/04/2018] [Accepted: 07/24/2018] [Indexed: 12/12/2022] Open
Abstract
Epigenetic variations can play remarkable roles in different normal and abnormal situations. Such variations have been shown to have a direct role in the pathogenesis of various diseases either through inhibition of tumor suppressor genes or increasing the expression of oncogenes. Enzymes involving in epigenetic machinery are the main actors in tuning the epigenetic-based controls on gene expressions. Aberrant expression of these enzymes can trigger a big chaos in the cellular gene expression networks and finally lead to cancer progression. This situation has been shown in different types of leukemia, where high or low levels of an epigenetic enzyme are partly or highly responsible for involvement or progression of a disease. DNA hypermethylation, different histone modifications, and aberrant miRNA expressions are three main epigenetic variations, which have been shown to play a role in leukemia progression. Epigenetic based treatments now are considered as novel and effective therapies in order to decrease the abnormal epigenetic modifications in patient cells. Different epigenetic-based approaches have been developed and tested to inhibit or reverse the unusual expression of epigenetic agents in leukemia. The reciprocal behavior of miRNAs in the regulation of epigenetic modifiers, while being regulated by them, unlocks a new opportunity in order to design some epigenetic-based miRNAs able to silence or sensitize these effectors in leukemia.
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Affiliation(s)
- Fatemeh Memari
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zeinab Joneidi
- Department of Genetics and Molecular Medicine, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Behnaz Taheri
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sedigheh Fekri Aval
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Roointan
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nosratollah Zarghami
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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18
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Rajasinghe LD, Pindiprolu RH, Gupta SV. Delta-tocotrienol inhibits non-small-cell lung cancer cell invasion via the inhibition of NF-κB, uPA activator, and MMP-9. Onco Targets Ther 2018; 11:4301-4314. [PMID: 30100736 PMCID: PMC6065470 DOI: 10.2147/ott.s160163] [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] [Indexed: 12/17/2022] Open
Abstract
Background Delta-tocotrienol (δT), an isomer of vitamin E, exhibits anticancer properties in different cancer types including non-small-cell lung cancer (NSCLC). Yet, anti-invasive effects of δT and its underlying cellular mechanism in NSCLC have not been fully explored. Matrix metalloproteinase 9 (MMP-9)-based cell migration and invasion are critical cellular mechanisms in cancer development. The current evidence indicates that MMP-9 is upregulated in most patients, and the inhibition of MMPs is involved in decreasing invasion and metastasis in NSCLC. Therefore, its suppression is a promising strategy for attenuating cell invasion and metastasis processes in NSCLC. Purpose The aim of this study was to evaluate the possibility of MMP-9 inhibition as the underlying mechanism behind the antimetastatic properties of δT on NSCLC cells. Methods The effects of δT on cell proliferation, migration, invasion, adhesion, and aggregation capabilities were investigated using different cell-based assays. An inhibitory effect of MMP-9 enzyme activity with δT was also identified using gel zymography. Using real-time PCR and Western blot analysis, a number of cellular proteins, regulatory genes, and miRNA involved in the Notch-1 and urokinase-type plasminogen activator (uPA)-mediated MMP-9 pathways were examined. Results The study found that δT inhibited cell proliferation, cell migration, invasion, aggregation, and adhesion in a concentration-dependent manner and reduced MMP-9 activities. Real-time PCR and Western blot analysis data revealed that δT increased miR-451 expressions and downregulated Notch-1-mediated nuclear factor-κB (NF-κB), which led to the repressed expression of MMP-9 and uPA proteins. Conclusion δT attenuated tumor invasion and metastasis by the repression of MMP-9/uPA via downregulation of Notch-1 and NF-κB pathways and upregulation of miR-451. The data suggest that δT may have potential therapeutic benefit against NSCLC metastasis.
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Affiliation(s)
| | - Rohini H Pindiprolu
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI, USA,
| | - Smiti Vaid Gupta
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI, USA,
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19
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Ramos KN, Ramos IN, Zeng Y, Ramos KS. Genetics and epigenetics of pediatric leukemia in the era of precision medicine. F1000Res 2018; 7. [PMID: 30079227 PMCID: PMC6053694 DOI: 10.12688/f1000research.14634.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/11/2018] [Indexed: 01/06/2023] Open
Abstract
Pediatric leukemia represents a heterogeneous group of diseases characterized by germline and somatic mutations that manifest within the context of disturbances in the epigenetic machinery and genetic regulation. Advances in genomic medicine have allowed finer resolution of genetic and epigenetic strategies that can be effectively used to risk-stratify patients and identify novel targets for therapy. This review discusses the genetic and epigenetic mechanisms of leukemogenesis, particularly as it relates to acute lymphocytic leukemias, the mechanisms of epigenetic control of leukemogenesis, namely DNA methylation, histone modifications, microRNAs, and LINE-1 retroelements, and highlights opportunities for precision medicine therapeutics in further guiding disease management. Future efforts to broaden the integration of advances in genomic and epigenomic science into the practice of pediatric oncology will not only identify novel therapeutic strategies to improve clinical outcomes but also improve the quality of life for this unique patient population. Recent findings in precision therapeutics of acute lymphocytic leukemias over the past three years, along with some provocative areas of epigenetics research, are reviewed here.
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Affiliation(s)
- Kristie N Ramos
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Arizona College of Medicine-Tucson, Tucson, USA
| | - Irma N Ramos
- Department of Promotion Health Sciences, University of Arizona Mel and Enid Zucherman College of Public Health, Tucson, USA
| | - Yi Zeng
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Arizona College of Medicine-Tucson, Tucson, USA.,University of Arizona Cancer Center, Tucson, USA
| | - Kenneth S Ramos
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Arizona College of Medicine-Tucson, Tucson, USA.,University of Arizona Cancer Center, Tucson, USA.,Department of Medicine, Division of Clinical Support and Data Analytics, University of Arizona College of Medicine-Phoenix, Phoenix, USA
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20
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Navarrete-Meneses MDP, Pérez-Vera P. Alteraciones epigenéticas en leucemia linfoblástica aguda. BOLETIN MEDICO DEL HOSPITAL INFANTIL DE MEXICO 2017; 74:243-264. [DOI: 10.1016/j.bmhimx.2017.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 02/04/2017] [Accepted: 02/08/2017] [Indexed: 12/22/2022] Open
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21
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22
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Organista-Nava J, Gómez-Gómez Y, Illades-Aguiar B, Leyva-Vázquez MA. Regulation of the miRNA expression by TEL/AML1, BCR/ABL, MLL/AF4 and TCF3/PBX1 oncoproteins in acute lymphoblastic leukemia (Review). Oncol Rep 2016; 36:1226-32. [PMID: 27431573 DOI: 10.3892/or.2016.4948] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Accepted: 03/28/2016] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that play important regulatory roles by targeting mRNAs for cleavage or translational repression. miRNAs act in diverse biological processes including development, cell growth, apoptosis, and hematopoiesis. The miRNA expression is associated with specific cytogenetic changes and can also be used to discriminate between the different subtypes of leukemia in acute lymphoblastic leukemia with common translocations, it is shown that the miRNAs have the potential to be used for clinical diagnosis and prognosis. We reviewed the roles of miRNA here with emphasis on their function in human leukemia and the mechanisms of the TEL/AML1, BCR/ABL, MLL/AF4 and TCF3/PBX1 oncoproteins on miRNAs expression in acute lymphoblastic leukemia.
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Affiliation(s)
- Jorge Organista-Nava
- Institute of Cellular Physiology, National Autonomous University of Mexico (UNAM), University City, D.F., Mexico
| | - Yazmín Gómez-Gómez
- Institute of Cellular Physiology, National Autonomous University of Mexico (UNAM), University City, D.F., Mexico
| | - Berenice Illades-Aguiar
- Laboratory of Molecular Biomedicine, School of Chemical-Biological Sciences, Guerrero State University, Chilpancingo, Guerrero, Mexico
| | - Marco Antonio Leyva-Vázquez
- Laboratory of Molecular Biomedicine, School of Chemical-Biological Sciences, Guerrero State University, Chilpancingo, Guerrero, Mexico
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23
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Mutalib NSA, Yusof AM, Mokhtar NM, Harun R, Muhammad R, Jamal R. MicroRNAs and Lymph Node Metastasis in Papillary Thyroid Cancers. Asian Pac J Cancer Prev 2016; 17:25-35. [DOI: 10.7314/apjcp.2016.17.1.25] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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24
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Candia J, Cherukuri S, Guo Y, Doshi KA, Banavar JR, Civin CI, Losert W. Uncovering low-dimensional, miR-based signatures of acute myeloid and lymphoblastic leukemias with a machine-learning-driven network approach. CONVERGENT SCIENCE PHYSICAL ONCOLOGY 2015; 1. [PMID: 27274862 DOI: 10.1088/2057-1739/1/2/025002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Complex phenotypic differences among different acute leukemias cannot be fully captured by analyzing the expression levels of one single molecule, such as a miR, at a time, but requires systematic analysis of large sets of miRs. While a popular approach for analysis of such datasets is principal component analysis (PCA), this method is not designed to optimally discriminate different phenotypes. Moreover, PCA and other low-dimensional representation methods yield linear or non-linear combinations of all measured miRs. Global human miR expression was measured in AML, B-ALL, and TALL cell lines and patient RNA samples. By systematically applying support vector machines to all measured miRs taken in dyad and triad groups, we built miR networks using cell line data and validated our findings with primary patient samples. All the coordinately transcribed members of the miR-23a cluster (which includes also miR-24 and miR-27a), known to function as tumor suppressors of acute leukemias, appeared in the AML, B-ALL and T-ALL centric networks. Subsequent qRT-PCR analysis showed that the most connected miR in the B-ALL-centric network, miR-708, is highly and specifically expressed in B-ALLs, suggesting that miR-708 might serve as a biomarker for B-ALL. This approach is systematic, quantitative, scalable, and unbiased. Rather than a single signature, our approach yields a network of signatures reflecting the redundant nature of biological signaling pathways. The network representation allows for visual analysis of all signatures by an expert and for future integration of additional information. Furthermore, each signature involves only small sets of miRs, such as dyads and triads, which are well suited for in depth validation through laboratory experiments. In particular, loss-and gain-of-function assays designed to drive changes in leukemia cell survival, proliferation and differentiation will benefit from the identification of multi-miR signatures that characterize leukemia subtypes and their normal counterpart cells of origin.
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Affiliation(s)
- Julián Candia
- Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, MD 20892, USA; Department of Physics, University of Maryland, College Park, MD 20742, USA; Center for Stem Cell Biology & Regenerative Medicine, Departments of Pediatrics and Physiology, University of Maryland School of Medicine, Baltimore MD 21201, USA
| | - Srujana Cherukuri
- Center for Stem Cell Biology & Regenerative Medicine, Departments of Pediatrics and Physiology, University of Maryland School of Medicine, Baltimore MD 21201, USA; Noble Life Sciences, 22 Firstfield Rd, Gaithersburg, MD 20878, USA
| | - Yin Guo
- Center for Stem Cell Biology & Regenerative Medicine, Departments of Pediatrics and Physiology, University of Maryland School of Medicine, Baltimore MD 21201, USA
| | - Kshama A Doshi
- Center for Stem Cell Biology & Regenerative Medicine, Departments of Pediatrics and Physiology, University of Maryland School of Medicine, Baltimore MD 21201, USA
| | - Jayanth R Banavar
- Department of Physics, University of Maryland, College Park, MD 20742, USA
| | - Curt I Civin
- Center for Stem Cell Biology & Regenerative Medicine, Departments of Pediatrics and Physiology, University of Maryland School of Medicine, Baltimore MD 21201, USA
| | - Wolfgang Losert
- Department of Physics, University of Maryland, College Park, MD 20742, USA
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25
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Avigad S, Verly IRN, Lebel A, Kordi O, Shichrur K, Ohali A, Hameiri-Grossman M, Kaspers GJL, Cloos J, Fronkova E, Trka J, Luria D, Kodman Y, Mirsky H, Gaash D, Jeison M, Avrahami G, Elitzur S, Gilad G, Stark B, Yaniv I. miR expression profiling at diagnosis predicts relapse in pediatric precursor B-cell acute lymphoblastic leukemia. Genes Chromosomes Cancer 2015; 55:328-39. [PMID: 26684414 DOI: 10.1002/gcc.22334] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Revised: 10/28/2015] [Accepted: 10/29/2015] [Indexed: 11/11/2022] Open
Abstract
Our aim was to identify miRNAs that can predict risk of relapse in pediatric patients with acute lymphoblastic leukemia (ALL). Following high-throughput miRNA expression analysis (48 samples), five miRs were selected for further confirmation performed by real time quantitative PCR on a cohort of precursor B-cell ALL patients (n = 138). The results were correlated with clinical parameters and outcome. Low expression of miR-151-5p, and miR-451, and high expression of miR-1290 or a combination of all three predicted inferior relapse free survival (P = 0.007, 0.042, 0.025, and <0.0001, respectively). Cox regression analysis identified aberrant expression of the three miRs as an independent prognostic marker with a 10.5-fold increased risk of relapse (P = 0.041) in PCR-MRD non-high risk patients. Furthermore, following exclusion of patients harboring IKZF1 deletion, the aberrant expression of all three miRs could identify patients with a 24.5-fold increased risk to relapse (P < 0.0001). The prognostic relevance of the three miRNAs was evaluated in a non-BFM treated precursor B-cell ALL cohort (n = 33). A significant correlation between an aberrant expression of at least one of the three miRs and poor outcome was maintained (P < 0.0001). Our results identify an expression profile of miR-151-5p, miR-451, and miR-1290 as a novel biomarker for outcome in pediatric precursor B-cell ALL patients, regardless of treatment protocol. The use of these markers may lead to improved risk stratification at diagnosis and allow early therapeutic interventions in an attempt to improve survival of high risk patients.
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Affiliation(s)
- Smadar Avigad
- Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel.,Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Iedan R N Verly
- Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel.,Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, the Netherlands
| | - Asaf Lebel
- Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel.,Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Oshrit Kordi
- Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel.,Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Keren Shichrur
- Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel.,Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Anat Ohali
- Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel.,Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michal Hameiri-Grossman
- Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel.,Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gertjan J L Kaspers
- Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, the Netherlands
| | - Jacqueline Cloos
- Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, the Netherlands
| | - Eva Fronkova
- Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University Prague, Czech Republic
| | - Jan Trka
- Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University Prague, Czech Republic
| | - Drorit Luria
- Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yona Kodman
- Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Hadar Mirsky
- Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel.,Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dafna Gaash
- Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel.,Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Marta Jeison
- Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Galia Avrahami
- Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sarah Elitzur
- Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gil Gilad
- Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Batia Stark
- Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Isaac Yaniv
- Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel.,Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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26
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Luan C, Yang Z, Chen B. The functional role of microRNA in acute lymphoblastic leukemia: relevance for diagnosis, differential diagnosis, prognosis, and therapy. Onco Targets Ther 2015; 8:2903-14. [PMID: 26508875 PMCID: PMC4610789 DOI: 10.2147/ott.s92470] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs), a new class of noncoding RNAs, which can hybridize to target messenger RNAs and regulate their expression posttranscriptionally, express differentially in distinct stages of lymphopoiesis and influence the direction of lymphoid precursor maturation. Hence, there is aberrant expression of miRNAs involved in malignant lymphopoiesis, and these aberrations can be used as signatures of acute lymphoblastic leukemia (ALL) with different subtypes. In addition, changes in the expression of several miRNAs may have functional relevance with leukemogenesis or drug resistance. As a result, the reversal of the expression of these miRNAs may alleviate the disease to some extent and improve clinical outcomes. However, among the studies of miRNAs, there are still some problems that need to be solved to understand the function of miRNAs in ALL more thoroughly.
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Affiliation(s)
- Chengxin Luan
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Zixue Yang
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, People's Republic of China
| | - Baoan Chen
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
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27
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Huang YK, Yu JC. Circulating microRNAs and long non-coding RNAs in gastric cancer diagnosis: An update and review. World J Gastroenterol 2015; 21:9863-9886. [PMID: 26379393 PMCID: PMC4566381 DOI: 10.3748/wjg.v21.i34.9863] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 05/15/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the fourth most common cancer and the third leading cause of cancer mortality worldwide. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most popular non-coding RNAs in cancer research. To date, the roles of miRNAs and lncRNAs have been extensively studied in GC, suggesting that miRNAs and lncRNAs represent a vital component of tumor biology. Furthermore, circulating miRNAs and lncRNAs are found to be dysregulated in patients with GC compared with healthy individuals. Circulating miRNAs and lncRNAs may function as promising biomarkers to improve the early detection of GC. Multiple possibilities for miRNA secretion have been elucidated, including active secretion by microvesicles, exosomes, apoptotic bodies, high-density lipoproteins and protein complexes as well as passive leakage from cells. However, the mechanism underlying lncRNA secretion and the functions of circulating miRNAs and lncRNAs have not been fully illuminated. Concurrently, to standardize results of global investigations of circulating miRNAs and lncRNAs biomarker studies, several recommendations for pre-analytic considerations are put forward. In this review, we summarize the known circulating miRNAs and lncRNAs for GC diagnosis. The possible mechanism of miRNA and lncRNA secretion as well as methodologies for identification of circulating miRNAs and lncRNAs are also discussed. The topics covered here highlight new insights into GC diagnosis and screening.
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Vrijens K, Bollati V, Nawrot TS. MicroRNAs as potential signatures of environmental exposure or effect: a systematic review. ENVIRONMENTAL HEALTH PERSPECTIVES 2015; 123:399-411. [PMID: 25616258 PMCID: PMC4421768 DOI: 10.1289/ehp.1408459] [Citation(s) in RCA: 237] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Accepted: 01/14/2015] [Indexed: 05/19/2023]
Abstract
BACKGROUND The exposome encompasses all life-course environmental exposures from the prenatal period onward that influence health. MicroRNAs (miRNAs) are interesting entities within this concept as markers and causation of disease. MicroRNAs are short oligonucleotide sequences that can interact with several mRNA targets. OBJECTIVES We reviewed the current state of the field on the potential of using miRNAs as biomarkers for environmental exposure. We investigated miRNA signatures in response to all types of environmental exposure to which a human can be exposed, including cigarette smoke, air pollution, nanoparticles, and diverse chemicals; and we examined the health conditions for which the identified miRNAs have been reported (i.e., cardiovascular disease, cancer, and diabetes). METHODS We searched the PubMed and ScienceDirect databases to identify relevant studies. RESULTS For all exposures incorporated in this review, 27 miRNAs were differentially expressed in at least two independent studies. miRNAs that had expression alterations associated with smoking observed in multiple studies are miR-21, miR-34b, miR-125b, miR-146a, miR-223, and miR-340; and those miRNAs that were observed in multiple air pollution studies are miR-9, miR-10b, miR-21, miR-128, miR-143, miR-155, miR-222, miR-223, and miR-338. We found little overlap among in vitro, in vivo, and human studies between miRNAs and exposure. Here, we report on disease associations for those miRNAs identified in multiple studies on exposure. CONCLUSIONS miRNA changes may be sensitive indicators of the effects of acute and chronic environmental exposure. Therefore, miRNAs are valuable novel biomarkers for exposure. Further studies should elucidate the role of the mediation effect of miRNA between exposures and effect through all stages of life to provide a more accurate assessment of the consequences of miRNA changes.
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Affiliation(s)
- Karen Vrijens
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
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Lakshmanan A, Wojcicka A, Kotlarek M, Zhang X, Jazdzewski K, Jhiang SM. microRNA-339-5p modulates Na+/I- symporter-mediated radioiodide uptake. Endocr Relat Cancer 2015; 22:11-21. [PMID: 25404690 PMCID: PMC4298451 DOI: 10.1530/erc-14-0439] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Na(+)/I(-) symporter (NIS)-mediated radioiodide uptake (RAIU) serves as the basis for targeted ablation of thyroid cancer remnants. However, many patients with thyroid cancer have reduced NIS expression/function and hence do not benefit from radioiodine therapy. microRNA (miR) has emerged as a promising therapeutic target in many diseases; yet, the role of miRs in NIS-mediated RAIU has not been investigated. In silico analysis was used to identify miRs that may bind to the 3'UTR of human NIS (hNIS). The top candidate miR-339-5p directly bound to the 3'UTR of hNIS. miR-339-5p overexpression decreased NIS-mediated RAIU in HEK293 cells expressing exogenous hNIS, decreased the levels of NIS mRNA, and RAIU in transretinoic acid/hydrocortisone (tRA/H)-treated MCF-7 human breast cancer cells as well as thyrotropin-stimulated PCCl3 rat thyroid cells. Nanostring nCounter rat miR expression assay was conducted to identify miRs deregulated by TGFβ, Akti-1/2, or 17-AAG known to modulate RAIU in PCCl3 cells. Among 38 miRs identified, 18 were conserved in humans. One of the 18 miRs, miR-195, was predicted to bind to the 3'UTR of hNIS and its overexpression decreased RAIU in tRA/H-treated MCF-7 cells. miR-339-5p was modestly increased in most papillary thyroid carcinomas (PTCs), yet miR-195 was significantly decreased in PTCs. Interestingly, the expression profiles of 18 miRs could be used to distinguish most PTCs from nonmalignant thyroid tissues. This is the first report, to our knowledge, demonstrating that hNIS-mediated RAIU can be modulated by miRs, and that the same miRs may also play roles in the development or maintenance of thyroid malignancy. Accordingly, miRs may serve as emerging targets to halt the progression of thyroid cancer and to enhance the efficacy of radioiodine therapy.
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Affiliation(s)
- Aparna Lakshmanan
- Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA
| | - Anna Wojcicka
- Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA
| | - Marta Kotlarek
- Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA
| | - Xiaoli Zhang
- Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA
| | - Krystian Jazdzewski
- Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA
| | - Sissy M Jhiang
- Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA
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Tan YS, Kim M, Kingsbury TJ, Civin CI, Cheng WC. Regulation of RAB5C is important for the growth inhibitory effects of MiR-509 in human precursor-B acute lymphoblastic leukemia. PLoS One 2014; 9:e111777. [PMID: 25368993 PMCID: PMC4219775 DOI: 10.1371/journal.pone.0111777] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 10/03/2014] [Indexed: 11/25/2022] Open
Abstract
MicroRNAs (miRs) regulate essentially all cellular processes, but few miRs are known to inhibit growth of precursor-B acute lymphoblastic leukemias (B-ALLs). We identified miR-509 via a human genome-wide gain-of-function screen for miRs that inhibit growth of the NALM6 human B-ALL cell line. MiR-509-mediated inhibition of NALM6 growth was confirmed by 3 independent assays. Enforced miR-509 expression inhibited 2 of 2 additional B-ALL cell lines tested, but not 3 non-B-ALL leukemia cell lines. MiR-509-transduced NALM6 cells had reduced numbers of actively proliferating cells and increased numbers of cells undergoing apoptosis. Using miR target prediction algorithms and a filtering strategy, RAB5C was predicted as a potentially relevant target of miR-509. Enforced miR-509 expression in NALM6 cells reduced RAB5C mRNA and protein levels, and RAB5C was demonstrated to be a direct target of miR-509. Knockdown of RAB5C in NALM6 cells recapitulated the growth inhibitory effects of miR-509. Co-expression of the RAB5C open reading frame without its 3' untranslated region (3'UTR) blocked the growth-inhibitory effect mediated by miR-509. These findings establish RAB5C as a target of miR-509 and an important regulator of B-ALL cell growth with potential as a therapeutic target.
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Affiliation(s)
- Yee Sun Tan
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - MinJung Kim
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Tami J. Kingsbury
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
- Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Curt I. Civin
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
- Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Wen-Chih Cheng
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
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31
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Venturelli S, Sinnberg TW, Berger A, Noor S, Levesque MP, Böcker A, Niessner H, Lauer UM, Bitzer M, Garbe C, Busch C. Epigenetic impacts of ascorbate on human metastatic melanoma cells. Front Oncol 2014; 4:227. [PMID: 25202679 PMCID: PMC4142417 DOI: 10.3389/fonc.2014.00227] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 08/06/2014] [Indexed: 01/01/2023] Open
Abstract
In recent years, increasing evidence has emerged demonstrating that high-dose ascorbate bears cytotoxic effects on cancer cells in vitro and in vivo, making ascorbate a pro-oxidative drug that catalyzes hydrogen peroxide production in tissues instead of acting as a radical scavenger. This anticancer effect of ascorbate is hypoxia-inducible factor-1α- and O2-dependent. However, whether the intracellular mechanisms governing this effect are modulated by epigenetic phenomena remains unknown. We treated human melanoma cells with physiological (200 μM) or pharmacological (8 mM) ascorbate for 1 h to record the impact on DNA methyltransferase (DNMT)-activity, histone deacetylases (HDACs), and microRNA (miRNA) expression after 12 h. The results were analyzed with the MIRUMIR online tool that estimates the power of miRNA to serve as potential biomarkers to predict survival of cancer patients. FACS cell-cycle analyses showed that 8 mM ascorbate shifted BLM melanoma cells toward the sub-G1 fraction starting at 12 h after an initial primary G2/M arrest, indicative for secondary apoptosis induction. In pharmacological doses, ascorbate inhibited the DNMT activity in nuclear extracts of MeWo and BLM melanoma cells, but did not inhibit human HDAC enzymes of classes I, II, and IV. The expression of 151 miRNAs was altered 12 h after ascorbate treatment of BLM cells in physiological or pharmacological doses. Pharmacological doses up-regulated 32 miRNAs (≥4-fold) mainly involved in tumor suppression and drug resistance in our preliminary miRNA screening array. The most prominently up-regulated miRNAs correlated with a significantly increased overall survival of breast cancer or nasopharyngeal carcinoma patients of the MIRUMIR database with high expression of the respective miRNA. Our results suggest a possible epigenetic signature of pharmacological doses of ascorbate in human melanoma cells and support further pre-clinical and possibly even clinical evaluation of ascorbate for melanoma therapy.
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Affiliation(s)
- Sascha Venturelli
- Department of Internal Medicine I, Medical University Hospital , Tuebingen , Germany
| | - Tobias W Sinnberg
- Division of Dermatologic Oncology, Department of Dermatology and Allergology, University of Tuebingen , Tuebingen , Germany
| | - Alexander Berger
- Department of Internal Medicine I, Medical University Hospital , Tuebingen , Germany
| | - Seema Noor
- Division of Dermatologic Oncology, Department of Dermatology and Allergology, University of Tuebingen , Tuebingen , Germany
| | | | | | - Heike Niessner
- Division of Dermatologic Oncology, Department of Dermatology and Allergology, University of Tuebingen , Tuebingen , Germany
| | - Ulrich M Lauer
- Department of Internal Medicine I, Medical University Hospital , Tuebingen , Germany
| | - Michael Bitzer
- Department of Internal Medicine I, Medical University Hospital , Tuebingen , Germany
| | - Claus Garbe
- Division of Dermatologic Oncology, Department of Dermatology and Allergology, University of Tuebingen , Tuebingen , Germany
| | - Christian Busch
- Division of Dermatologic Oncology, Department of Dermatology and Allergology, University of Tuebingen , Tuebingen , Germany
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Veerappa AM, N MM, Vishweswaraiah S, Lingaiah K, Suresh RV, Nachappa SA, Prashali N, Yadav SN, Srikanta MA, Manjegowda DS, Seshachalam KB, Ramachandra NB. Copy number variations burden on miRNA genes reveals layers of complexities involved in the regulation of pathways and phenotypic expression. PLoS One 2014; 9:e90391. [PMID: 24587348 PMCID: PMC3938728 DOI: 10.1371/journal.pone.0090391] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 01/28/2014] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs are involved in post-transcriptional down-regulation of gene expression. Variations in miRNA genes can severely affect downstream-regulated genes and their pathways. However, population-specific burden of CNVs on miRNA genes and the complexities created towards the phenotype is not known. From a total of 44109 CNVs investigated from 1715 individuals across 12 populations using high-throughput arrays, 4007 miRNA-CNVs (∼ 9%) consisting 6542 (∼ 5%) miRNA genes with a total of 333 (∼ 5%) singleton miRNA genes were identified. We found miRNA-CNVs across the genomes of individuals showing multiple hits in many targets, co-regulated under the same pathway. This study proposes four mechanisms unraveling the many complexities in miRNA genes, targets and co-regulated miRNA genes towards establishment of phenotypic diversity.
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Affiliation(s)
- Avinash M. Veerappa
- Genetics and Genomics Lab, Department of Studies in Zoology, University of Mysore, Manasagangotri, Mysore, Karnataka, India
| | - Megha Murthy N
- Genetics and Genomics Lab, Department of Studies in Zoology, University of Mysore, Manasagangotri, Mysore, Karnataka, India
| | - Sangeetha Vishweswaraiah
- Genetics and Genomics Lab, Department of Studies in Zoology, University of Mysore, Manasagangotri, Mysore, Karnataka, India
| | - Kusuma Lingaiah
- Genetics and Genomics Lab, Department of Studies in Zoology, University of Mysore, Manasagangotri, Mysore, Karnataka, India
| | - Raviraj V. Suresh
- Genetics and Genomics Lab, Department of Studies in Zoology, University of Mysore, Manasagangotri, Mysore, Karnataka, India
| | - Somanna Ajjamada Nachappa
- Genetics and Genomics Lab, Department of Studies in Zoology, University of Mysore, Manasagangotri, Mysore, Karnataka, India
| | - Nelchi Prashali
- Genetics and Genomics Lab, Department of Studies in Zoology, University of Mysore, Manasagangotri, Mysore, Karnataka, India
| | - Sangeetha Nuggehalli Yadav
- Genetics and Genomics Lab, Department of Studies in Zoology, University of Mysore, Manasagangotri, Mysore, Karnataka, India
| | - Manjula Arsikere Srikanta
- Genetics and Genomics Lab, Department of Studies in Zoology, University of Mysore, Manasagangotri, Mysore, Karnataka, India
| | - Dinesh S. Manjegowda
- Department of Anatomy, Yenepoya Medical College, Yenepoya University, Mangalore, Karnataka, India
- Nitte University Centre for Science Education & Research, K S Hegde Medical Academy, Nitte University, Deralakatte, Mangalore, Karnataka, India
| | | | - Nallur B. Ramachandra
- Genetics and Genomics Lab, Department of Studies in Zoology, University of Mysore, Manasagangotri, Mysore, Karnataka, India
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Burke MJ, Bhatla T. Epigenetic modifications in pediatric acute lymphoblastic leukemia. Front Pediatr 2014; 2:42. [PMID: 24860797 PMCID: PMC4030177 DOI: 10.3389/fped.2014.00042] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 04/29/2014] [Indexed: 12/22/2022] Open
Abstract
Aberrant epigenetic modifications are well-recognized drivers for oncogenesis. Pediatric acute lymphoblastic leukemia (ALL) is no exception and serves as a model toward the significant impact these heritable alterations can have in leukemogenesis. In this brief review, we will focus on the main aspects of epigenetics, which control leukemogenesis in pediatric ALL, mainly DNA methylation, histone modification, and microRNA alterations. As we continue to gain better understanding of the driving mechanisms for pediatric ALL at both diagnosis and relapse, therapeutic interventions directed toward these pathways and mechanisms can be harnessed and introduced into clinical trials for pediatric ALL.
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Affiliation(s)
- Michael J Burke
- Division of Pediatric Hematology-Oncology, Medical College of Wisconsin , Milwaukee, WI , USA
| | - Teena Bhatla
- Division of Pediatric Hematology-Oncology, New York University Langone Medical Center , New York, NY , USA
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Long JM, Ray B, Lahiri DK. MicroRNA-339-5p down-regulates protein expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects. J Biol Chem 2013; 289:5184-98. [PMID: 24352696 DOI: 10.1074/jbc.m113.518241] [Citation(s) in RCA: 150] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Alzheimer disease (AD) results, in part, from the excess accumulation of the amyloid-β (Aβ) peptide as neuritic plaques in the brain. The short Aβ peptide is derived from the large transmembrane Aβ precursor protein (APP). The rate-limiting step in the production of Aβ from APP is mediated by the β-site APP-cleaving enzyme 1 (BACE1). Dysregulation of BACE1 levels leading to excess Aβ deposition is implicated in sporadic AD. Thus, elucidating the full complement of regulatory pathways that control BACE1 expression is key to identifying novel drug targets central to the Aβ-generating process. MicroRNAs (miRNAs) are expected to participate in this molecular network. Here, we identified a known miRNA, miR-339-5p, as a key contributor to this regulatory network. Two distinct miR-339-5p target sites were predicted in the BACE1 3'-UTR by in silico analyses. Co-transfection of miR-339-5p with a BACE1 3'-UTR reporter construct resulted in significant reduction in reporter expression. Mutation of both target sites eliminated this effect. Delivery of the miR-339-5p mimic also significantly inhibited expression of BACE1 protein in human glioblastoma cells and human primary brain cultures. Delivery of target protectors designed against the miR-339-5p BACE1 3'-UTR target sites in primary human brain cultures significantly elevated BACE1 expression. Finally, miR-339-5p levels were found to be significantly reduced in brain specimens isolated from AD patients as compared with age-matched controls. Therefore, miR-339-5p regulates BACE1 expression in human brain cells and is most likely dysregulated in at least a subset of AD patients making this miRNA a novel drug target.
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Affiliation(s)
- Justin M Long
- From the Laboratory of Molecular Neurogenetics, Institute of Psychiatric Research, Departments of Psychiatry and
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35
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Atarod S, Dickinson AM. MicroRNAs: The Missing Link in the Biology of Graft-Versus-Host Disease? Front Immunol 2013; 4:420. [PMID: 24348483 PMCID: PMC3845018 DOI: 10.3389/fimmu.2013.00420] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 11/18/2013] [Indexed: 01/22/2023] Open
Abstract
Graft-versus-host disease (GVHD) is still the major complication of allogeneic hematopoietic stem cell transplantation. Despite extensive studies in understanding the pathophysiology of GVHD, its pathogenesis remains unclear. Recently, important functions of microRNAs have been demonstrated in various autoimmune diseases and cancers such as psoriasis and lymphoma. This review highlights the need to investigate the role of microRNAs in GVHD and hypothesizes that microRNAs may be one of the missing links in our understanding of GVHD, with the potential for novel therapeutics.
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Affiliation(s)
- Sadaf Atarod
- Haematological Sciences, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne , UK
| | - Anne Mary Dickinson
- Haematological Sciences, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne , UK
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Li X, Li D, Zhuang Y, Shi Q, Wei W, Ju X. Overexpression of miR-708 and its targets in the childhood common precursor B-cell ALL. Pediatr Blood Cancer 2013; 60:2060-7. [PMID: 23970374 DOI: 10.1002/pbc.24583] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 04/07/2013] [Indexed: 01/08/2023]
Abstract
BACKGROUND The critical function of microRNAs in the pathogenesis and prognosis of hematopoietic cancer has become increasingly apparent. However, only a few miRNAs have been reported to be altered in acute lymphocytic leukemia (ALL). PROCEDURES To uncover aberrantly expressed miRNAs in pediatric B-cell ALL, our study employed genome-wide miRNA microarray analysis and stem-loop real-time quantitative polymerase chain reaction (qRT-PCR) to examine common precursor B-cell ALL samples. The target genes of miRNA-708 were then identified and verified by bioinformatics, dual-luciferase reporter assay, qRT-PCR, and Western blot. RESULTS Significant upregulation of miR-708, miR-210, and miR-181b, and downregulation of miR-345 and miR-27a were observed in common precursor B-cell ALL (common-ALL) samples (P < 0.05). In addition, elevated expression of miR-708 and miR-181b were found in high-risk common-ALL compared to standard and intermediate ones. miR-708 inhibited luciferase reporter activity by binding to the 3'-untranslated regions (3'-UTRs) of CNTFR, NNAT, and GNG12 mRNA in HEK-293 cell line and suppressed the protein levels of CNTFR, NNAT, and GNG12 in Jurkat cells. In addition, mRNA levels of CNTFR and NNAT, but not of GNG12, were found to be downregulated in high risk common-ALL samples. Mutational analysis revealed that miR-708 binds to the 394-400 bp sequence region of the 3'-UTR of CNTFR mRNA. CONCLUSION The expression level of miR-708 reflects differences among the clinical types of common-ALL, and CNTFR, NNAT, and GNG12 were identified as targets of miR-708.
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Affiliation(s)
- Xue Li
- Department of Pediatrics, Cryomedicine Laboratory, Qilu Hospital, Shandong University, Shandong, PR China
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MicroRNA-142-3p inhibits cell proliferation in human acute lymphoblastic leukemia by targeting the MLL-AF4 oncogene. Mol Biol Rep 2013; 40:6811-9. [PMID: 24057258 DOI: 10.1007/s11033-013-2798-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 09/14/2013] [Indexed: 12/21/2022]
Abstract
The mixed-lineage leukemia (MLL)-AF4 fusion protein encoded by the chromosomal translocation t(4;11) predicts a poorer prognosis in acute lymphoblastic leukemia (ALL) than in other MLL-associated leukemias. However, the detailed mechanism underlying regulation of MLL-AF4 expression remains largely unknown. In this study, we showed that microRNA (miR)-142-3p was significantly downregulated in ALL patients expressing MLL-AF4. Upregulation of miR-142-3p decreased MLL-AF4 expression in the RS4;11 leukemic cell line, which suggests that MLL-AF4 is a direct target of miR-142-3p. Ectopic expression of miR-142-3p remarkably suppressed cell proliferation and induced apoptosis in RS4;11 cells expressing the MLL-AF4 fusion protein. We also found that exogenous expression of miR-142-3p strongly reduced the expression of MLL-AF4 target genes such as homeobox A (HOXA)9, HOXA7, and HOXA10 in RS4;11 cells. Taken together, our results indicate that miR-142-3p functions as a growth suppressor in MLL-AF4(+) ALL, and its suppressive effects are mediated primarily through repression of MLL-AF4 expression.
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Lagrange B, Martin RZ, Droin N, Aucagne R, Paggetti J, Largeot A, Itzykson R, Solary E, Delva L, Bastie JN. A role for miR-142-3p in colony-stimulating factor 1-induced monocyte differentiation into macrophages. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2013; 1833:1936-46. [DOI: 10.1016/j.bbamcr.2013.04.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Revised: 04/01/2013] [Accepted: 04/09/2013] [Indexed: 01/24/2023]
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Khan SY, Tariq MA, Perrott JP, Brumbaugh CD, Kim HJ, Shabbir MI, Ramesh GT, Pourmand N. Distinctive microRNA expression signatures in proton-irradiated mice. Mol Cell Biochem 2013; 382:225-35. [PMID: 23817773 DOI: 10.1007/s11010-013-1738-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 06/14/2013] [Indexed: 12/13/2022]
Abstract
Proton particles comprise the most abundant ionizing radiation (IR) in outer space. These high energy particles are known to cause frequent double- and single-stranded DNA lesions that can lead to cancer and tumor formation. Understanding the mechanism of cellular response to proton-derived IR is vital for determining health risks to astronauts during space missions. Our understanding of the consequences of these high energy charged particles on microRNA (miRNA) regulation is still in infancy. miRNAs are non-coding, single-stranded RNAs of ~22 nucleotides that constitute a novel class of gene regulators. They regulate diverse biological processes, and each miRNA can control hundreds of gene targets. To investigate the effect of proton radiation on these master regulators, we examined the miRNA expression in selected mice organs that had been exposed to whole-body proton irradiation (2 Gy), and compared this to control mice (0 Gy exposure). RNA was isolated from three tissues (testis, brain, and liver) from treated and control mice and subjected to high-throughput small RNA sequencing. Bioinformatics analysis of small RNA sequencing data revealed dysregulation of (p < 0.05; 20 up- and 10 down-regulated) 14 mouse testis, 8 liver, and 8 brain miRNAs. The statistically significant and unique miRNA expression pattern found among three different proton-treated mouse tissues indicates a tissue-specific response to proton radiation. In addition to known miRNAs, sequencing revealed differential expression of 11 miRNAs in proton-irradiated mice that have not been previously reported in association with radiation exposure and cancer. The dysregulation of miRNAs on exposure to proton radiation suggest a possible mechanism of proton particles involvement in the onset of cell tumorgenesis. In summary, we have established that specific miRNAs are vulnerable to proton radiation, that such differential expression profile may depend upon the tissue, and that there are more miRNAs affected by proton radiation than have been previously observed.
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Affiliation(s)
- Shahid Yar Khan
- Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, 95064, USA
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Pan X, Wang R, Wang ZX. The potential role of miR-451 in cancer diagnosis, prognosis, and therapy. Mol Cancer Ther 2013; 12:1153-62. [PMID: 23814177 DOI: 10.1158/1535-7163.mct-12-0802] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
MicroRNAs (miRNA) are small noncoding RNAs that converge to maintain an intrinsic balance of various processes, including cell proliferation, differentiation, and apoptosis. Recent research efforts have been devoted to translating these basic discoveries into applications that could improve the early diagnosis and therapeutic outcome of patients with cancer. Early studies have shown that miRNA-451 (miR-451) is widely dysregulated in human cancers and plays a critical role in tumorigenesis and tumor progression. In this review, we summarize the potential use of miR-451 for cancer diagnosis, prognosis, and treatment. In addition, we discuss the possible mechanisms of miR-451 dysregulation and future challenges in development of miR-451 as a noninvasive biomarker and a potential therapeutic target in human cancers.
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Affiliation(s)
- Xuan Pan
- Department of Medical Oncology, Nanjing Medical University Affiliated Cancer Hospital of Jiangsu Province, Cancer Institution of Jiangsu Province, Nanjing 210009, Jiangsu, PR China.
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Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson AG, Hoadley K, Triche TJ, Laird PW, Baty JD, Fulton LL, Fulton R, Heath SE, Kalicki-Veizer J, Kandoth C, Klco JM, Koboldt DC, Kanchi KL, Kulkarni S, Lamprecht TL, Larson DE, Lin L, Lu C, McLellan MD, McMichael JF, Payton J, Schmidt H, Spencer DH, Tomasson MH, Wallis JW, Wartman LD, Watson MA, Welch J, Wendl MC, Ally A, Balasundaram M, Birol I, Butterfield Y, Chiu R, Chu A, Chuah E, Chun HJ, Corbett R, Dhalla N, Guin R, He A, Hirst C, Hirst M, Holt RA, Jones S, Karsan A, Lee D, Li HI, Marra MA, Mayo M, Moore RA, Mungall K, Parker J, Pleasance E, Plettner P, Schein J, Stoll D, Swanson L, Tam A, Thiessen N, Varhol R, Wye N, Zhao Y, Gabriel S, Getz G, Sougnez C, Zou L, Leiserson MDM, Vandin F, Wu HT, Applebaum F, Baylin SB, Akbani R, Broom BM, Chen K, Motter TC, Nguyen K, Weinstein JN, Zhang N, Ferguson ML, Adams C, Black A, Bowen J, Gastier-Foster J, Grossman T, Lichtenberg T, Wise L, Davidsen T, Demchok JA, Shaw KRM, Sheth M, Sofia HJ, Yang L, Downing JR, Eley G. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368:2059-74. [PMID: 23634996 PMCID: PMC3767041 DOI: 10.1056/nejmoa1301689] [Citation(s) in RCA: 3889] [Impact Index Per Article: 324.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. RESULTS AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. CONCLUSIONS We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.).
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de Oliveira JC, Brassesco MS, Scrideli CA, Tone LG, Narendran A. MicroRNA expression and activity in pediatric acute lymphoblastic leukemia (ALL). Pediatr Blood Cancer 2012; 59:599-604. [PMID: 22492670 DOI: 10.1002/pbc.24167] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2011] [Accepted: 03/19/2012] [Indexed: 12/26/2022]
Abstract
Acute lymphoblastic leukemia (ALL) is the most common type of pediatric neoplasia. Highly heterogeneous, ALL includes several genetic subtypes with varying clinical outcome. Although, some features are well established as prognostic predictors, the details of the molecular mechanisms underlying different phenotypes are only beginning to emerge. Recently, microRNAs (miRNAs) have been shown to influence a range of physiological processes and, consequently, alterations in their expression and functions have been associated with the development of many cancers, including leukemia. This article aims to review the current state of knowledge of the role of miRNAs on the biology of childhood ALL, also including relevant findings from the adult leukemia literature.
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Affiliation(s)
- Jaqueline C de Oliveira
- Department of Genetics, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
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Chatterton Z, Morenos L, Saffery R, Craig JM, Ashley D, Wong NC. DNA methylation and miRNA expression profiling in childhood B-cell acute lymphoblastic leukemia. Epigenomics 2012; 2:697-708. [PMID: 22122053 DOI: 10.2217/epi.10.39] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Acute lymphoblastic leukemia (ALL) is the most common cancer in children in the modern world. Recent efforts in characterizing the genetic contribution to this disease through uncovering gene mutations, deletions and structural variation by genome-scale methods have only accounted for a modest proportion of children with ALL. This suggests that either further genetic contributions to ALL have yet to be characterized or other factors, such as epigenetic aberrations are involved. A number of DNA methylation and miRNA profiling studies have investigated the role of both in childhood ALL. Here, we review these profiling efforts, summarize their major findings and speculate as to what the future may hold.
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Affiliation(s)
- Zac Chatterton
- Developmental Epigenetics, Early Development & Disease Theme, Murdoch Children's Research Institute, Melbourne, Australia
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de Oliveira JC, Scrideli CA, Brassesco MS, Morales AG, Pezuk JA, Queiroz RDP, Yunes JA, Brandalise SR, Tone LG. Differential miRNA expression in childhood acute lymphoblastic leukemia and association with clinical and biological features. Leuk Res 2011; 36:293-8. [PMID: 22099053 DOI: 10.1016/j.leukres.2011.10.005] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2011] [Revised: 08/27/2011] [Accepted: 10/07/2011] [Indexed: 01/02/2023]
Abstract
The present study aimed to analyze the expression profile of the microRNAs previously described as associated with childhood ALL, miR-92a, miR-100, miR-125a-5p, miR-128a, miR-181b, miR-196b and let-7e, and their association with biological/prognostic features in 128 consecutive samples of childhood acute lymphoblastic leukemia (ALL) by quantitative real-time PCR. A significant association was observed between higher expression levels of miR-196b and T-ALL, miR-100 and patients with low white blood cell count at diagnosis and t(12;21) positive ALL. These findings suggest a potential activity of these microRNAs in pediatric ALL biology.
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Cytokines and microRNA in pediatric B-acute lymphoblastic leukemia. Cytokine Growth Factor Rev 2011; 22:149-56. [DOI: 10.1016/j.cytogfr.2011.05.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Revised: 05/13/2011] [Accepted: 05/24/2011] [Indexed: 01/05/2023]
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Marcinkowska M, Szymanski M, Krzyzosiak WJ, Kozlowski P. Copy number variation of microRNA genes in the human genome. BMC Genomics 2011; 12:183. [PMID: 21486463 PMCID: PMC3087710 DOI: 10.1186/1471-2164-12-183] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2010] [Accepted: 04/12/2011] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are important genetic elements that regulate the expression of thousands of human genes. Polymorphisms affecting miRNA biogenesis, dosage and target recognition may represent potentially functional variants. The functional consequences of single nucleotide polymorphisms (SNPs) within critical miRNA sequences and outside of miRNA genes were previously demonstrated using both experimental and computational methods. However, little is known about how copy number variations (CNVs) affect miRNA genes. RESULTS In this study, we analyzed the co-localization of all miRNA loci with known CNV regions. Using bioinformatic tools we identified and validated 209 copy number variable miRNA genes (CNV-miRNAs) in CNV regions deposited in Database of Genomic Variations (DGV) and 11 CNV-miRNAs in two sets of CNVs defined as highly polymorphic. We propose potential mechanisms of CNV-mediated variation of functional copies of miRNAs (dosage) for different types of CNVs overlapping miRNA genes. We also showed that, consistent with their essential biological functions, miRNA loci are underrepresented in highly polymorphic and well-validated CNV regions. CONCLUSION We postulate that CNV-miRNAs are potential functional variants and should be considered high priority candidate variants in genotype-phenotype association studies.
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Wang R, Wang ZX, Yang JS, Pan X, De W, Chen LB. MicroRNA-451 functions as a tumor suppressor in human non-small cell lung cancer by targeting ras-related protein 14 (RAB14). Oncogene 2011; 30:2644-58. [PMID: 21358675 DOI: 10.1038/onc.2010.642] [Citation(s) in RCA: 249] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Accumulating evidence suggests that microRNAs (miRNAs) are important gene regulators, which can have critical roles in diverse biological processes including tumorigenesis. In this study, we analyzed the miRNA expression profiles in non-small cell lung carcinoma (NSCLC) by use of a miRNA microarray platform and identified 40 differentially expressed miRNAs. We showed that miRNA (miR)-451 was the most downregulated in NSCLC tissues. The expression level of miR-451 was found to be significantly correlated with tumor differentiation, pathological stage and lymph-node metastasis. Moreover, low miR-451 expression level was also correlated with shorter overall survival of NSCLC patients (P<0.001). Ectopic miR-451 expression significantly suppressed the in vitro proliferation and colony formation of NSCLC cells and the development of tumors in nude mice by enhancing apoptosis, which might be associated with inactivation of Akt signaling pathway. Interestingly, ectopic miR-451 expression could significantly inhibit RAB14 protein expression and decrease a luciferase-reporter activity containing the RAB14 3'-untranslated region (UTR). In addition,, RNA interference silencing of RAB14 gene could recapitulate the tumor suppressor function of miR-451, whereas restoration of RAB14 expression could partially attenuate the tumor suppressor function of miR-451 in NSCLC cells. Furthermore, we also showed that strong positive immunoreactivity of RAB14 protein was significantly associated with downregulation of miR-451 (P=0.01). These findings suggest that miR-451 regulates survival of NSCLC cells partially through the downregulation of RAB14. Therefore, targeting with the miR-451/RAB14 interaction might serve as a novel therapeutic application to treat NSCLC patients.
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Affiliation(s)
- R Wang
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
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Borze I, Guled M, Musse S, Raunio A, Elonen E, Saarinen-Pihkala U, Karjalainen-Lindsberg ML, Lahti L, Knuutila S. MicroRNA microarrays on archive bone marrow core biopsies of leukemias—Method validation. Leuk Res 2011; 35:188-95. [DOI: 10.1016/j.leukres.2010.08.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2010] [Revised: 08/12/2010] [Accepted: 08/12/2010] [Indexed: 01/25/2023]
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Li Z, Branham WS, Dial SL, Wang Y, Guo L, Shi L, Chen T. Genomic analysis of microRNA time-course expression in liver of mice treated with genotoxic carcinogen N-ethyl-N-nitrosourea. BMC Genomics 2010; 11:609. [PMID: 21029445 PMCID: PMC3091750 DOI: 10.1186/1471-2164-11-609] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2010] [Accepted: 10/28/2010] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Dysregulated expression of microRNAs (miRNAs) has been previously observed in human cancer tissues and shown promise in defining tumor status. However, there is little information as to if or when expression changes of miRNAs occur in normal tissues after carcinogen exposure. RESULTS To explore the possible time-course changes of miRNA expression induced by a carcinogen, we treated mice with one dose of 120 mg/kg N-ethyl-N-nitrosourea (ENU), a model genotoxic carcinogen, and vehicle control. The miRNA expression profiles were assessed in the mouse livers in a time-course design. miRNAs were isolated from the livers at days 1, 3, 7, 15, 30 and 120 after the treatment and their expression was determined using a miRNA PCR Array. Principal component analysis of the miRNA expression profiles showed that miRNA expression at post-treatment days (PTDs) 7 and 15 were different from those at the other time points and the control. The number of differentially expressed miRNAs (DEMs) changed over time (3, 5, 14, 32, 5 and 5 at PTDs 1, 3, 7, 15, 30 and 120, respectively). The magnitude of the expression change varied with time with the highest changes at PTDs 7 or 15 for most of the DEMs. In silico functional analysis of the DEMs at PTDs 7 and 15 indicated that the major functions of these ENU-induced DEMs were associated with DNA damage, DNA repair, apoptosis and other processes related to carcinogenesis. CONCLUSION Our results showed that many miRNAs changed their expression to respond the exposure of the genotoxic carcinogen ENU and the number and magnitude of the changes were highest at PTDs 7 to 15. Thus, one to two weeks after the exposure is the best time for miRNA expression sampling.
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Affiliation(s)
- Zhiguang Li
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079, USA
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