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Rashwan HH, Taher AM, Hassan HA, Awaji AA, Kiriacos CJ, Assal RA, Youness RA. Harnessing the supremacy of MEG3 LncRNA to defeat gastrointestinal malignancies. Pathol Res Pract 2024; 256:155223. [PMID: 38452587 DOI: 10.1016/j.prp.2024.155223] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 03/09/2024]
Abstract
Evidence suggests that long non-coding RNAs (lncRNAs) play a pivotal role in the carcinogenesis and progression of various human malignancies including gastrointestinal malignancies. This comprehensive review reports the functions and mechanisms of the lncRNA maternally expressed gene 3 (MEG3) involved in gastrointestinal malignancies. It summarizes its roles in mediating the regulation of cellular proliferation, apoptosis, migration, invasiveness, epithelial-to-mesenchymal transition, and drug resistance in several gastrointestinal cancers such as colorectal cancer, gall bladder cancer, pancreatic cancer, gastric cancer, esophageal cancer, cholangiocarcinoma, gastrointestinal stromal tumors and most importantly, hepatocellular carcinoma. In addition, the authors briefly highlight its implicated mechanistic role and interactions with different non-coding RNAs and oncogenic signaling cascades. This review presents the rationale for developing non coding RNA-based anticancer therapy via harnessing the power of MEG3 in gastrointestinal malignancies.
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Affiliation(s)
- H H Rashwan
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt; Bioinformatics Group, Center for Informatics Science (CIS), School of Information Technology and Computer Science (ITCS), Nile University, 12677, Giza, Egypt
| | - A M Taher
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt
| | - H A Hassan
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt
| | - A A Awaji
- Department of Biology, Faculty of Science, University College of Taymaa, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - C J Kiriacos
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt
| | - R A Assal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - R A Youness
- Molecular Genetics and Biochemistry Department, Molecular Genetics Research Team (MGRT), Faculty of Biotechnology, German International University (GIU), Cairo 11835, Egypt.
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Lee BB, Kim D, Kim Y, Han J, Shim YM, Kim DH. Metformin regulates expression of DNA methyltransferases through the miR-148/-152 family in non-small lung cancer cells. Clin Epigenetics 2023; 15:48. [PMID: 36959680 PMCID: PMC10037810 DOI: 10.1186/s13148-023-01466-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 03/15/2023] [Indexed: 03/25/2023] Open
Abstract
BACKGROUND To understand the molecular mechanisms involved in regulation of DNA methyltransferases (DNMTs) by metformin in non-small cell lung cancer (NSCLC) cells. METHODS Expression levels of DNMTs in response to metformin were analyzed in NSCLC cells. MicroRNAs regulating expression of DNMTs at the post-transcriptional level were searched using miRNA-target databases (miRDB and miRTarBase), TCGA RNASeqV2 lung cancer data, and miRNA-seq. RESULTS Metformin dose-dependently downregulated expression of DNMT1 and DNMT3a at the post-transcriptional level and expression of DNMT3b at the transcriptional level in A549 lung cancer cells. Activity of DNMTs was reduced by about 2.6-fold in A549 cells treated with 10 mM metformin for 72 h. miR-148/-152 family members (miR-148a, miR-148b, and miR-152) targeting the 3'UTR of DNMTs were associated with post-transcriptional regulation of DNMTs by metformin. Metformin upregulated expression of miR-148a, miR-148b, and miR-152 in A549 and H1650 cells. Transfection with an miR-148b plasmid or a mimic suppressed expression of DNMT1 and DNMT3b in A549 cells. Transfection with the miR-148a mimic in A549 and H1650 cells decreased the luciferase activity of DNMT1 3'UTR. A combination of metformin and cisplatin synergistically increased expression levels of miR-148/-152 family members but decreased expression of DNMTs in A549 cells. Low expression of miR-148b was associated with poor overall survival (HR = 2.56, 95% CI 1.09-6.47; P = 0.04) but not with recurrence-free survival. CONCLUSIONS The present study suggests that metformin inhibits expression of DNMTs by upregulating miR-148/-152 family members in NSCLC cells.
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Affiliation(s)
- Bo Bin Lee
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea
| | - Dongho Kim
- Yonsei New I1 Han Institute for Integrative Lung Cancer Research, Yonsei University College of Medicine, Seoul, 03772, Korea
| | - Yujin Kim
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea
| | - Joungho Han
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
| | - Young Mog Shim
- Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
| | - Duk-Hwan Kim
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Korea.
- Samsung Comprehensive Cancer CenterResearch Institute for Future Medicine S139-7, #50 Ilwon-dong, Gangnam-gu, Seoul, 06351, Korea.
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Sun G, Qi M, Kim AS, Lizhar EM, Sun OW, Al-Abdullah IH, Riggs AD. Reassessing the Abundance of miRNAs in the Human Pancreas and Rodent Cell Lines and Its Implication. Noncoding RNA 2023; 9:ncrna9020020. [PMID: 36960965 PMCID: PMC10037588 DOI: 10.3390/ncrna9020020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/24/2023] [Accepted: 03/13/2023] [Indexed: 03/22/2023] Open
Abstract
miRNAs are critical for pancreas development and function. However, we found that there are discrepancies regarding pancreatic miRNA abundance in published datasets. To obtain a more relevant profile that is closer to the true profile, we profiled small RNAs from human islets cells, acini, and four rodent pancreatic cell lines routinely used in diabetes and pancreatic research using a bias reduction protocol for small RNA sequencing. In contrast to the previous notion that miR-375-3p is the most abundant pancreatic miRNA, we found that miR-148a-3p and miR-7-5p were also abundant in islets. In silico studies using predicted and validated targets of these three miRNAs revealed that they may work cooperatively in endocrine and exocrine cells. Our results also suggest, compared to the most-studied miR-375, that both miR-148a-3p and miR-7-5p may play more critical roles in the human pancreas. Moreover, according to in silico-predicted targets, we found that miR-375-3p had a much broader target spectrum by targeting the coding sequence and the 5' untranslated region, rather than the conventional 3' untranslated region, suggesting additional unexplored roles of miR-375-3p beyond the pancreas. Our study provides a valuable new resource for studying miRNAs in pancreata.
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Affiliation(s)
- Guihua Sun
- Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
- Department of Neurodegenerative Diseases, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Meirigeng Qi
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Alexis S Kim
- Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Elizabeth M Lizhar
- Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Olivia W Sun
- Department of Diabetes & Cancer Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Ismail H Al-Abdullah
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Arthur D Riggs
- Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
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Sibuh BZ, Quazi S, Panday H, Parashar R, Jha NK, Mathur R, Jha SK, Taneja P, Jha AK. The Emerging Role of Epigenetics in Metabolism and Endocrinology. BIOLOGY 2023; 12:256. [PMID: 36829533 PMCID: PMC9953656 DOI: 10.3390/biology12020256] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/25/2023] [Accepted: 01/31/2023] [Indexed: 02/10/2023]
Abstract
Each cell in a multicellular organism has its own phenotype despite sharing the same genome. Epigenetics is a somatic, heritable pattern of gene expression or cellular phenotype mediated by structural changes in chromatin that occur without altering the DNA sequence. Epigenetic modification is an important factor in determining the level and timing of gene expression in response to endogenous and exogenous stimuli. There is also growing evidence concerning the interaction between epigenetics and metabolism. Accordingly, several enzymes that consume vital metabolites as substrates or cofactors are used during the catalysis of epigenetic modification. Therefore, altered metabolism might lead to diseases and pathogenesis, including endocrine disorders and cancer. In addition, it has been demonstrated that epigenetic modification influences the endocrine system and immune response-related pathways. In this regard, epigenetic modification may impact the levels of hormones that are important in regulating growth, development, reproduction, energy balance, and metabolism. Altering the function of the endocrine system has negative health consequences. Furthermore, endocrine disruptors (EDC) have a significant impact on the endocrine system, causing the abnormal functioning of hormones and their receptors, resulting in various diseases and disorders. Overall, this review focuses on the impact of epigenetics on the endocrine system and its interaction with metabolism.
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Affiliation(s)
- Belay Zeleke Sibuh
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Knowledge Park III, Greater Noida 201310, India
| | - Sameer Quazi
- GenLab Biosolutions Private Limited, Bangalore 560043, India
- Department of Biomedical Sciences, School of Life Sciences, Anglia Ruskin University, Cambridge CB1 1PT, UK
- Clinical Bioinformatics, School of Health Sciences, The University of Manchester, Manchester M13 9P, UK
- SCAMT Institute, ITMO University, St. Petersburg 197101, Russia
| | - Hrithika Panday
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Knowledge Park III, Greater Noida 201310, India
| | - Ritika Parashar
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Knowledge Park III, Greater Noida 201310, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Knowledge Park III, Greater Noida 201310, India
- School of Bioengineering & Biosciences, Lovely Professional University, Phagwara 144411, India
| | - Runjhun Mathur
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Knowledge Park III, Greater Noida 201310, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Knowledge Park III, Greater Noida 201310, India
- Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun 248007, India
- Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali 140413, India
| | - Pankaj Taneja
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Knowledge Park III, Greater Noida 201310, India
| | - Abhimanyu Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Knowledge Park III, Greater Noida 201310, India
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MicroRNA and mRNA Expression Changes in Glioblastoma Cells Cultivated under Conditions of Neurosphere Formation. Curr Issues Mol Biol 2022; 44:5294-5311. [PMID: 36354672 PMCID: PMC9688839 DOI: 10.3390/cimb44110360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 10/21/2022] [Accepted: 10/27/2022] [Indexed: 11/29/2022] Open
Abstract
Glioblastoma multiforme (GBM) is one of the most highly metastatic cancers. The study of the pathogenesis of GBM, as well as the development of targeted oncolytic drugs, require the use of actual cell models, in particular, the use of 3D cultures or neurospheres (NS). During the formation of NS, the adaptive molecular landscape of the transcriptome, which includes various regulatory RNAs, changes. The aim of this study was to reveal changes in the expression of microRNAs (miRNAs) and their target mRNAs in GBM cells under conditions of NS formation. Neurospheres were obtained from both immortalized U87 MG and patient-derived BR3 GBM cell cultures. Next generation sequencing analysis of small and long RNAs of adherent and NS cultures of GBM cells was carried out. It was found that the formation of NS proceeds with an increase in the level of seven and a decrease in the level of 11 miRNAs common to U87 MG and BR3, as well as an increase in the level of 38 and a decrease in the level of 12 mRNA/lncRNA. Upregulation of miRNAs hsa-miR: -139-5p; -148a-3p; -192-5p; -218-5p; -34a-5p; and -381-3p are accompanied by decreased levels of their target mRNAs: RTN4, FLNA, SH3BP4, DNPEP, ETS2, MICALL1, and GREM1. Downregulation of hsa-miR: -130b-5p, -25-5p, -335-3p and -339-5p occurs with increased levels of mRNA-targets BDKRB2, SPRY4, ERRFI1 and TGM2. The involvement of SPRY4, ERRFI1, and MICALL1 mRNAs in the regulation of EGFR/FGFR signaling highlights the role of hsa-miR: -130b-5p, -25-5p, -335-3p, and -34a-5p not only in the formation of NS, but also in the regulation of malignant growth and invasion of GBM. Our data provide the basis for the development of new approaches to the diagnosis and treatment of GBM.
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Zamberlan M, Boeckx A, Muller F, Vinelli F, Ek O, Vianello C, Coart E, Shibata K, Christian A, Grespi F, Giacomello M, Struman I, Scorrano L, Herkenne S. Inhibition of the mitochondrial protein Opa1 curtails breast cancer growth. J Exp Clin Cancer Res 2022; 41:95. [PMID: 35279198 PMCID: PMC8917763 DOI: 10.1186/s13046-022-02304-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 02/26/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Mitochondrial fusion and fission proteins have been nominated as druggable targets in cancer. Whether their inhibition is efficacious in triple negative breast cancer (TNBC) that almost invariably develops chemoresistance is unknown. METHODS We used a combination of bioinformatics analyses of cancer genomic databases, genetic and pharmacological Optic Atrophy 1 (OPA1) inhibition, mitochondrial function and morphology measurements, micro-RNA (miRNA) profiling and formal epistatic analyses to address the role of OPA1 in TNBC proliferation, migration, and invasion in vitro and in vivo. RESULTS We identified a signature of OPA1 upregulation in breast cancer that correlates with worse prognosis. Accordingly, OPA1 inhibition could reduce breast cancer cells proliferation, migration, and invasion in vitro and in vivo. Mechanistically, while OPA1 silencing did not reduce mitochondrial respiration, it increased levels of miRNAs of the 148/152 family known to inhibit tumor growth and invasiveness. Indeed, these miRNAs were epistatic to OPA1 in the regulation of TNBC cells growth and invasiveness. CONCLUSIONS Our data show that targeted inhibition of the mitochondrial fusion protein OPA1 curtails TNBC growth and nominate OPA1 as a druggable target in TNBC.
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Affiliation(s)
- Margherita Zamberlan
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
- Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy
| | - Amandine Boeckx
- Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
| | - Florian Muller
- Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
| | - Federica Vinelli
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
- Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy
| | - Olivier Ek
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
| | - Caterina Vianello
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
| | - Emeline Coart
- Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
| | - Keitaro Shibata
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
- Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy
| | - Aurélie Christian
- Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
| | - Francesca Grespi
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
- Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy
| | - Marta Giacomello
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
| | - Ingrid Struman
- Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
| | - Luca Scorrano
- Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy.
- Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy.
| | - Stéphanie Herkenne
- Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium.
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Choi JM, Kim SG. Effect of Helicobacter pylori Eradication on Epigenetic Changes in Gastric Cancer-related Genes. THE KOREAN JOURNAL OF HELICOBACTER AND UPPER GASTROINTESTINAL RESEARCH 2021. [DOI: 10.7704/kjhugr.2021.0042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
It is known that gastric carcinogenesis results from the progressive changes from chronic gastritis to gastric atrophy, intestinal metaplasia, dysplasia, and invasive carcinoma. Several genetic and epigenetic alterations are involved in this process, and Helicobacter pylori (H. pylori) infection is believed to induce the initiation and progression of these steps. From an epigenetic point of view, H. pylori induces hypermethylation of genes involved in the development of gastric cancer and regulates the expression of various microRNAs (miRNAs). These H. pylori-related epigenetic changes are accumulated not only at the site of neoplasm but also in the adjacent non-cancerous gastric mucosa. Thereby, a state vulnerable to gastric cancer known as an epigenetic field defect is formed. H. pylori eradication can have an effective chemopreventive effect in gastric carcinogenesis. However, the molecular biological changes that occur in the stomach environment during H. pylori eradication have not yet been established. Several studies have reported that H. pylori eradication can restore infection-related changes, especially epigenetic alterations in gastric cancer-related genes, but some studies have shown otherwise. Simply put, it appears that the recovery of methylated gastric cancer-related genes and miRNAs during H. pylori eradication may vary among genes and may also differ depending on the histological subtype of the gastric mucosa. In this review, we will discuss the potential mechanism of gastric cancer prevention by H. pylori eradication, mainly from an epigenetic perspective.
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Yadav P, Bandyopadhayaya S, Ford BM, Mandal C. Interplay between DNA Methyltransferase 1 and microRNAs During Tumorigenesis. Curr Drug Targets 2021; 22:1129-1148. [PMID: 33494674 DOI: 10.2174/1389450122666210120141546] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/16/2020] [Accepted: 10/18/2020] [Indexed: 01/18/2023]
Abstract
Cancer is a genetic disease resulting from genomic changes; however, epigenetic alterations act synergistically with these changes during tumorigenesis and cancer progression. Epigenetic variations are gaining more attention as an important regulator in tumor progression, metastasis and therapy resistance. Aberrant DNA methylation at CpG islands is a central event in epigeneticmediated gene silencing of various tumor suppressor genes. DNA methyltransferase 1 (DNMT1) predominately methylates at CpG islands on hemimethylated DNA substrates in proliferation of cells. DNMT1 has been shown to be overexpressed in various cancer types and exhibits tumor-promoting potential. The major drawbacks to DNMT1-targeted cancer therapy are the adverse effects arising from nucleoside and non-nucleoside based DNMT1 inhibitors. This paper focuses on the regulation of DNMT1 by various microRNAs (miRNAs), which may be assigned as future DNMT1 modulators, and highlights how DNMT1 regulates various miRNAs involved in tumor suppression. Importantly, the role of reciprocal inhibition between DNMT1 and certain miRNAs in tumorigenic potential is approached in this review. Hence, this review seeks to project an efficient and strategic approach using certain miRNAs in conjunction with conventional DNMT1 inhibitors as a novel cancer therapy. It has also been pinpointed to select miRNA candidates associated with DNMT1 regulation that may not only serve as potential biomarkers for cancer diagnosis and prognosis, but may also predict the existence of aberrant methylation activity in cancer cells.
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Affiliation(s)
- Pooja Yadav
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh- 305817, Ajmer, Rajasthan, India
| | - Shreetama Bandyopadhayaya
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh- 305817, Ajmer, Rajasthan, India
| | - Bridget M Ford
- Department of Biology, University of the Incarnate Word, San Antonio, TX 78209, United States
| | - Chandi Mandal
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh- 305817, Ajmer, Rajasthan, India
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Zhang HQ, Wang JY, Li ZF, Cui L, Huang SS, Zhu LB, Sun Y, Yang R, Fan HH, Zhang X, Zhu JH. DNA Methyltransferase 1 Is Dysregulated in Parkinson's Disease via Mediation of miR-17. Mol Neurobiol 2021; 58:2620-2633. [PMID: 33483902 DOI: 10.1007/s12035-021-02298-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 01/14/2021] [Indexed: 12/12/2022]
Abstract
Aberrant DNA methylation is closely associated with the pathogenesis of Parkinson's disease (PD). DNA methyltransferases (DNMTs) are the enzymes for establishment and maintenance of DNA methylation patterns. It has not been clearly defined how DNMTs respond in PD and what mechanisms are associated. Models of PD were established by treatment of five different neurotoxins in cells and intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Plasma samples of PD patients were also used. Western blot, real-time PCR, immunostaining, and/or luciferase reporter were employed. DNA methylation was analyzed by the bisulfite sequencing analysis. Protein expression of DNMT1, but not of DNMT3A and DNMT3B, was reduced in the cellular and mouse models of PD. Paradoxically, mRNA levels of DNMT1 were increased in these models. After ruling out the possibility of protein degradation, we screened a set of miRNAs that potentially targeted DNMT1 3'-UTR by luciferase reporters and expression abundancies. miR-17 was identified for further investigation with miR-19a of low expression as a parallel comparison. Although exogenous transfection of either miR-17 or miR-19a mimics could inhibit DNMT1 expression, results of miRNA inhibitors showed that miR-17, but not miR-19a, endogenously regulated DNMT1 and the subsequent DNA methylation. Furthermore, levels of miR-17 were elevated in the neurotoxin-induced PD models and the plasma of PD patients. This study demonstrates that the miR-17-mediated DNMT1 downregulation underlies the aberrant DNA methylation in PD. Our results provide a link bridging environmental insults and epigenetic changes and implicate miR-17 in therapeutical modulation of DNA methylation in PD.
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Affiliation(s)
- Hong-Qiu Zhang
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Jian-Yong Wang
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Zhao-Feng Li
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Lei Cui
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Shi-Shi Huang
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Lan-Bing Zhu
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Yue Sun
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Rui Yang
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Nelson Institute of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10010, USA
| | - Hui-Hui Fan
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Xiong Zhang
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
| | - Jian-Hong Zhu
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
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Bure IV, Nemtsova MV. Methylation and Noncoding RNAs in Gastric Cancer: Everything Is Connected. Int J Mol Sci 2021; 22:ijms22115683. [PMID: 34073603 PMCID: PMC8199097 DOI: 10.3390/ijms22115683] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 05/19/2021] [Accepted: 05/25/2021] [Indexed: 12/18/2022] Open
Abstract
Despite recent progress, gastric cancer remains one of the most common cancers and has a high mortality rate worldwide. Aberrant DNA methylation pattern and deregulation of noncoding RNA expression appear in the early stages of gastric cancer. Numerous investigations have confirmed their significant role in gastric cancer tumorigenesis and their high potential as diagnostic and prognostic biomarkers. Currently, it is clear that these epigenetic regulators do not work alone but interact with each other, generating a complex network. The aim of our review was to summarize the current knowledge of this interaction in gastric cancer and estimate its clinical potential for the diagnosis, prognosis, and treatment of the disease.
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Affiliation(s)
- Irina V. Bure
- Laboratory of Medical Genetics, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
- Correspondence: ; Tel.: +49-915-069-2721
| | - Marina V. Nemtsova
- Laboratory of Medical Genetics, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
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Regulatory Mechanisms of Epigenetic miRNA Relationships in Human Cancer and Potential as Therapeutic Targets. Cancers (Basel) 2020; 12:cancers12102922. [PMID: 33050637 PMCID: PMC7600069 DOI: 10.3390/cancers12102922] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 10/03/2020] [Accepted: 10/07/2020] [Indexed: 12/15/2022] Open
Abstract
Simple Summary By the virtue of targeting multiple genes, a microRNA (miRNA) can infer variable consequences on tumorigenesis by appearing as both a tumour suppressor and oncogene. miRNAs can regulate gene expression by modulating genome-wide epigenetic status of genes that are involved in various cancers. These miRNAs perform direct inhibition of key mediators of the epigenetic machinery, such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) genes. Along with miRNAs gene expression, similar to other protein-coding genes, miRNAs are also controlled by epigenetic mechanisms. Overall, this reciprocal interaction between the miRNAs and the epigenetic architecture is significantly implicated in the aberrant expression of miRNAs detected in various human cancers. Comprehensive knowledge of the miRNA-epigenetic dynamics in cancer is essential for the discovery of novel anticancer therapeutics. Abstract Initiation and progression of cancer are under both genetic and epigenetic regulation. Epigenetic modifications including alterations in DNA methylation, RNA and histone modifications can lead to microRNA (miRNA) gene dysregulation and malignant cellular transformation and are hereditary and reversible. miRNAs are small non-coding RNAs which regulate the expression of specific target genes through degradation or inhibition of translation of the target mRNA. miRNAs can target epigenetic modifier enzymes involved in epigenetic modulation, establishing a trilateral regulatory “epi–miR–epi” feedback circuit. The intricate association between miRNAs and the epigenetic architecture is an important feature through which to monitor gene expression profiles in cancer. This review summarises the involvement of epigenetically regulated miRNAs and miRNA-mediated epigenetic modulations in various cancers. In addition, the application of bioinformatics tools to study these networks and the use of therapeutic miRNAs for the treatment of cancer are also reviewed. A comprehensive interpretation of these mechanisms and the interwoven bond between miRNAs and epigenetics is crucial for understanding how the human epigenome is maintained, how aberrant miRNA expression can contribute to tumorigenesis and how knowledge of these factors can be translated into diagnostic and therapeutic tool development.
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12
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Frazier S, McBride MW, Mulvana H, Graham D. From animal models to patients: the role of placental microRNAs, miR-210, miR-126, and miR-148a/152 in preeclampsia. Clin Sci (Lond) 2020; 134:1001-1025. [PMID: 32337535 PMCID: PMC7239341 DOI: 10.1042/cs20200023] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 03/23/2020] [Accepted: 04/14/2020] [Indexed: 12/12/2022]
Abstract
Placental microRNAs (miRNAs) regulate the placental transcriptome and play a pathological role in preeclampsia (PE), a hypertensive disorder of pregnancy. Three PE rodent model studies explored the role of placental miRNAs, miR-210, miR-126, and miR-148/152 respectively, by examining expression of the miRNAs, their inducers, and potential gene targets. This review evaluates the role of miR-210, miR-126, and miR-148/152 in PE by comparing findings from the three rodent model studies with in vitro studies, other animal models, and preeclamptic patients to provide comprehensive insight into genetic components and pathological processes in the placenta contributing to PE. The majority of studies demonstrate miR-210 is upregulated in PE in part driven by HIF-1α and NF-κBp50, stimulated by hypoxia and/or immune-mediated processes. Elevated miR-210 may contribute to PE via inhibiting anti-inflammatory Th2-cytokines. Studies report an up- and downregulation of miR-126, arguably reflecting differences in expression between cell types and its multifunctional capacity. MiR-126 may play a pro-angiogenic role by mediating the PI3K-Akt pathway. Most studies report miR-148/152 family members are upregulated in PE. Evidence suggests they may inhibit DNA methylation of genes involved in metabolic and inflammatory pathways. Given the genetic heterogeneity of PE, it is unlikely that a single placental miRNA is a suitable therapeutic target for all patients. Investigating miRNAs in PE subtypes in patients and animal models may represent a more appropriate approach going forward. Developing methods for targeting placental miRNAs and specific placental cell types remains crucial for research seeking to target placental miRNAs as a novel treatment for PE.
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Affiliation(s)
- Sonya Frazier
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K
| | - Martin W. McBride
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K
| | - Helen Mulvana
- Biomedical Engineering, University of Strathclyde, Glasgow, U.K
| | - Delyth Graham
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K
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13
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MicroRNA-148a/b-3p regulates angiogenesis by targeting neuropilin-1 in endothelial cells. Exp Mol Med 2019; 51:1-11. [PMID: 31723119 PMCID: PMC6853980 DOI: 10.1038/s12276-019-0344-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 09/20/2019] [Accepted: 09/26/2019] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRs) are crucial regulators of vascular endothelial cell (EC) functions, including migration, proliferation, and survival. However, the role of most miRs in ECs remains unknown. Using RNA sequencing analysis, we found that miR-148a/b-3p expression was significantly downregulated during the differentiation of umbilical cord blood mononuclear cells into outgrowing ECs and that decreased miR-148a/b-3p levels were closely related to EC behavior. Overexpression of miR-148a/b-3p in ECs significantly reduced migration, filamentous actin remodeling, and angiogenic sprouting. Intriguingly, the effects of decreased miR-148a/b-3p levels were augmented by treatment with vascular endothelial growth factor (VEGF). Importantly, we found that miR-148a/b-3p directly regulated neuropilin-1 (NRP1) expression by binding to its 3′-untranslated region. In addition, because NRP1 is the coreceptor for VEGF receptor 2 (VEGFR2), overexpression of miR-148a/b-3p inhibited VEGF-induced activation of VEGFR2 and inhibited its downstream pathways, as indicated by changes to phosphorylated focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase. Collectively, our results demonstrate that miR-148a/b-3p is a direct transcriptional regulator of NRP1 that mediates antiangiogenic pathways. These data suggest that miR-148a/b-3p is a therapeutic candidate for overcoming EC dysfunction and angiogenic disorders, including ischemia, retinopathy, and tumor vascularization. A small regulatory RNA molecule helps prevent the development of new blood vessels, a finding that could have implications for the treatment of vascular disease and cancer. Young-Guen Kwon from Yonsei University in Seoul, South Korea, and colleagues cataloged all the microRNAs expressed during the differentiation of umbilical cord blood stem cells into precursors of the cells that line the inside of blood vessels. One microRNA in particular stood out for its association with cellular differentiation. The authors showed that this microRNA, called miR-148a/b-3p, directly binds part of the gene transcript encoding neuropilin-1, thereby blocking the production of this receptor for growth factors involved in new blood vessel formation. Modulating the activity of miR-148a/b-3p could have therapeutic value for disorders marked by aberrant blood vessel growth.
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14
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Tang T, Guo C, Xia T, Zhang R, Zen K, Pan Y, Jin L. LncCCAT1 Promotes Breast Cancer Stem Cell Function through Activating WNT/β-catenin Signaling. Theranostics 2019; 9:7384-7402. [PMID: 31695775 PMCID: PMC6831302 DOI: 10.7150/thno.37892] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 08/05/2019] [Indexed: 02/07/2023] Open
Abstract
Background: Breast cancer stem cells (BCSCs) play an essential role in facilitating breast cancer relapse and metastasis. The underlying mechanism, however, remains incompletely understood. In the current study, we investigated the clinical significance, biological function and mechanism of a long noncoding RNA CCAT1 (LncCCAT1) in BCSCs. Methods: Firstly, lncRNAs expression in poorly differentiated breast cancer tissues and BCSCs were measured by lncRNA microarray and confirmed in breast cancer tissues and cell lines. The functional roles and mechanisms of LncCCAT1 were further investigated by gain and loss of function assays in vitro and in vivo. Results: LncCCAT1 is markedly upregulated in breast cancer tissues BCSCs and is correlated with poor outcomes in breast cancer patients. Overexpression of LncCCAT1 contributes to the proliferation, stemness, migration and invasion capacities of BCSCs. Mechanistic investigation suggests that LncCCAT1 can interact with miR-204/211, miR-148a/152 and Annexin A2(ANXA2), then upregulate T-cell factor 4 (TCF4) or promote translocation of β-catenin to the nucleus where it activates TCF4, leading to the activation of wingless/integrated (Wnt) signaling. Furthermore, TCF4 can also bind to the promoter of LncCCAT1 to promote LncCCAT1 transcription, thus forming a positive feedback regulatory circuit of LncCCAT1-TCF4-LncCCAT1 in BCSCs. Conclusions: LncCCAT1 plays an important role in breast cancer progression and may serve as a novel target for breast cancer diagnosis and therapy.
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Affiliation(s)
- Tingting Tang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University. 24 Tongjiaxiang Avenue, Nanjing, Jiangsu, China
| | - Changying Guo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University. 24 Tongjiaxiang Avenue, Nanjing, Jiangsu, China
| | - Tiansong Xia
- Department of Breast Surgery, Breast Disease Center of Jiangsu Province, First Affiliated Hospital of Nanjing Medical University. 300 Guangzhou Road, Nanjing, Jiangsu province, China
| | - Rui Zhang
- Department of Biochemistry and Molecular Biology and Key Laboratory of Breast Cancer Prevention and Treatment, Ministry of Education, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Ke Zen
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu province, China
| | - Yi Pan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University. 24 Tongjiaxiang Avenue, Nanjing, Jiangsu, China
| | - Liang Jin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University. 24 Tongjiaxiang Avenue, Nanjing, Jiangsu, China
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15
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Shimizu T, Sohn Y, Choi E, Petersen CP, Prasad N, Goldenring JR. Decrease in MiR-148a Expression During Initiation of Chief Cell Transdifferentiation. Cell Mol Gastroenterol Hepatol 2019; 9:61-78. [PMID: 31473306 PMCID: PMC6881610 DOI: 10.1016/j.jcmgh.2019.08.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/19/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023]
Abstract
Gastric chief cells differentiate from mucous neck cells and develop their mature state at the base of oxyntic glands with expression of secretory zymogen granules. After parietal cell loss, chief cells transdifferentiate into mucous cell metaplasia, designated spasmolytic polypeptide-expressing metaplasia (SPEM), which is considered a candidate precursor of gastric cancer. We examined the range of microRNA (miRNA) expression in chief cells and identified miRNAs involved in chief cell transdifferentiation into SPEM. Among them, miR-148a was strongly and specifically expressed in chief cells and significantly decreased during the process of chief cell transdifferentiation. Interestingly, suppression of miR-148a in a conditionally immortalized chief cell line induced up-regulation of CD44 variant 9 (CD44v9), one of the transcripts expressed at an early stage of SPEM development, and DNA methyltransferase 1 (Dnmt1), an established target of miR-148a. Immunostaining analyses showed that Dnmt1 was up-regulated in SPEM cells as well as in chief cells before the emergence of SPEM in mouse models of acute oxyntic atrophy using either DMP-777 or L635. In the cascade of events that leads to transdifferentiation, miR-148a was down-regulated after acute oxyntic atrophy either in xCT knockout mice or after sulfasalazine inhibition of xCT. These findings suggest that the alteration of miR-148a expression is an early event in the process of chief cell transdifferentiation into SPEM.
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Affiliation(s)
- Takahiro Shimizu
- Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoojin Sohn
- Department of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Eunyoung Choi
- Nashville VA Medical Center, Nashville, Tennessee; Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Christine P Petersen
- Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Nripesh Prasad
- HudsonAlpha Institute for Biotechnology, Huntsville, Alabama
| | - James R Goldenring
- Nashville VA Medical Center, Nashville, Tennessee; Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
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Curcuminoid Analogs Differentially Modulate Nuclear Factor Kappa-Light-Chain-Enhancer, P65 Serine276, Mitogen- and Stress-activated Protein Kinase 1 And MicroRNA 148a Status. PROGRESS IN PREVENTIVE MEDICINE 2019. [DOI: 10.1097/pp9.0000000000000024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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17
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MicroRNA Dysregulation in Cutaneous Squamous Cell Carcinoma. Int J Mol Sci 2019; 20:ijms20092181. [PMID: 31052530 PMCID: PMC6540078 DOI: 10.3390/ijms20092181] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 04/15/2019] [Accepted: 04/29/2019] [Indexed: 02/07/2023] Open
Abstract
Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and it can be locally invasive and metastatic to distant sites. MicroRNAs (miRNAs or miRs) are endogenous, small, non-coding RNAs of 19–25 nucleotides in length, that are involved in regulating gene expression at a post-transcriptional level. MicroRNAs have been implicated in diverse biological functions and diseases. In cancer, miRNAs can proceed either as oncogenic miRNAs (onco-miRs) or as tumor suppressor miRNAs (oncosuppressor-miRs), depending on the pathway in which they are involved. Dysregulation of miRNA expression has been shown in most of the tumors evaluated. MiRNA dysregulation is known to be involved in the development of cutaneous squamous cell carcinoma (CSCC). In this review, we focus on the recent evidence about the role of miRNAs in the development of CSCC and in the prognosis of this form of skin cancer.
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18
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Wang XX, Zhang H, Li Y. Preliminary study on the role of miR‑148a and DNMT1 in the pathogenesis of acute myeloid leukemia. Mol Med Rep 2019; 19:2943-2952. [PMID: 30720097 DOI: 10.3892/mmr.2019.9913] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 01/17/2019] [Indexed: 11/06/2022] Open
Abstract
MicroRNA (miR)‑148a is differentially expressed in numerous malignant tumors and it was identified to regulate tumor growth, cell proliferation, apoptosis, angiogenesis and drug resistance via the regulation of the expression levels of its target genes. However, the biological function of miR‑148a in acute myeloid leukemia (AML) and its molecular mechanisms of action remain unclear. In the present study, the expression levels of miR‑148a and DNA methyltransferase 1 (DNMT1) were detected using reverse transcription‑quantitative polymerase chain reaction (PCR) and western blotting. Methylation‑specific PCR was used to detect the methylation levels in the miR‑148a promoter. The effects of miR‑148a on cell proliferation and apoptosis were assessed by Cell Counting kit‑8 or flow cytometry assays, respectively. A dual‑luciferase reporter assay was performed to investigate the association between miR‑148a and DNMT1. Patients with AML exhibited an increased expression level of miR‑148a, whereas the expression level of DNMT1 was identified to be decreased compared with healthy control subjects. In AML cell lines, the methylation state of miR‑148 promoter was significantly increased compared with normal cells. Following knockdown of DNMT1 in U937 cells, the expression level of miR‑148a increased significantly, whereas the methylation level of the miR‑148a promoter decreased. The mRNA and protein expression levels of DNMT1 decreased following transfection with miR‑148a mimics in U937 cells. Conversely, transfection with miR‑148a inhibitor in Kasumi‑1 cells led to an increase in the expression level of DNMT. Dual‑luciferase reporter assays suggested that DNMT1 was one of the direct target genes of miR‑148a. Overexpression of miR‑148a inhibited cell proliferation and promoted apoptosis. Inhibition of DNMT1 led to a decreased methylation level of the 5'‑cytosine‑phosphate‑guanine‑3' islands in the miR‑148a promoter, thus increasing the expression level of miR‑148a. DNMT1 was identified to be a downstream target of miR‑148a, and was negatively regulated by miR‑148a in AML cell lines, suggesting that miR‑148a and DNMT1 form a mutual negative feedback loop.
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Affiliation(s)
- Xiao-Xue Wang
- Department of Hematology, The First Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Heyang Zhang
- Department of Hematology, The First Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yan Li
- Department of Hematology, The First Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
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19
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Ariza-Nieto M, Alley JB, Samy S, Fitzgerald L, Vermeylen F, Shuler ML, Alemán JO. Circulating MIR148A associates with sensitivity to adiponectin levels in human metabolic surgery for weight loss. Endocr Connect 2018; 7:975-982. [PMID: 30300537 PMCID: PMC6176280 DOI: 10.1530/ec-18-0205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE We sought to discover secreted biomarkers to monitor the recovery of physiological adiponectin levels with metabolic surgery, focusing on epigenetic changes that might predict adiponectin function. DESIGN We conducted a prospective observational study of patients undergoing metabolic surgery by Roux-en-Y Gastric Bypass (RYGB) for weight loss in a single center (IRB GHS # 1207-27). METHODS All patients (n = 33; 27 females; 6 males) signed informed consent. Metabolites, adiponectin and MIR148A were measured in fasting plasma. We followed MIQE for transcript profiles. RESULTS Patients lost on average 47 ± 12% excess BMI (%EBMI) after 12 weeks. Adiponectin pre, post or delta (post minus pre) did not correlate with %EBMIL. A decrease in adiponectin following weight loss surgery was observed in a subset of patients, chi-square test of independence rejects the null hypotheses that the liver DNA methyltransferase 1 (DNMT1) and delta adiponectin are independent (chi-square statistics χ2 = 6.9205, P = 0.00852, n = 33), as well as MIR148A and delta adiponectin are independent (chi-square statistics χ2 = 9.6823, P = 0.00186, n = 33). The presence of plasma MIR148A allows identification of patients that appear to be adiponectin insensitive at baseline. CONCLUSION We combined the presence of plasma MIR148A, the concentration of total adiponectin and the expression of DNA methyltransferase 1 (DNMT1) in liver biopsy tissue to identify patients with non-physiological adiponectin. Weight loss and physical activity interventions complemented with the new method presented here could serve to monitor the physiological levels of adiponectin, thought to be important for long-term weight loss maintenance.
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Affiliation(s)
- Magnolia Ariza-Nieto
- Cornell UniversityMeinig School of Biomedical Engineering, Ithaca, New York, USA
- epiWELLLLC, Ithaca, New York, USA
- Correspondence should be addressed to M Ariza-Nieto:
| | - Joshua B Alley
- Donald Guthrie Foundation for Education and ResearchGuthrie Clinic, Sayre, Pennsylvania, USA
| | - Sanjay Samy
- Donald Guthrie Foundation for Education and ResearchGuthrie Clinic, Sayre, Pennsylvania, USA
| | - Laura Fitzgerald
- Donald Guthrie Foundation for Education and ResearchGuthrie Clinic, Sayre, Pennsylvania, USA
| | - Francoise Vermeylen
- Cornell UniversityCornell Statistical Consulting Unit, Ithaca, New York, USA
| | - Michael L Shuler
- Cornell UniversityMeinig School of Biomedical Engineering, Ithaca, New York, USA
| | - José O Alemán
- New York University Langone Medical CenterNew York, New York, USA
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Chu D, Li J, Lin H, Zhang X, Pan H, Liu L, Yu T, Yan M, Yao M. Quantitative proteomic analysis of the miR-148a-associated mechanisms of metastasis in non-small cell lung cancer. Oncol Lett 2018; 15:9941-9952. [PMID: 29928367 PMCID: PMC6004687 DOI: 10.3892/ol.2018.8581] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 10/13/2017] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression and protein synthesis. Our previous study demonstrated that miR-148a suppressed the metastasis of non-small cell lung cancer (NSCLC) in vitro and in vivo. However, the modulatory mechanism of this effect remains unclear. In the present study, quantitative proteomic technology was used to study the protein expression profile of SPC-A-1 cells subsequent to the downregulation of miR-148a expression, in order to elucidate the molecular mechanism of the suppression of NSCLC metastasis by miR-148a. The differentially expressed proteins identified were analyzed using bioinformatics tools, including the Database for Annotation, Visualization and Integrated Discovery and the Search Tool for the Retrieval of Interacting Genes/proteins. In two experiments, 4,048 and 4,083 proteins were identified, and 4,014 and 4,039 proteins were quantified, respectively. In total, 44 proteins were upregulated and 40 proteins were downregulated. This was verified at the protein and mRNA levels by western blotting and reverse transcription-quantitative polymerase chain reaction, respectively. Bioinformatics analysis was used to identify potential interactions and signaling networks for the differentially expressed proteins. This may have provided an appropriate perspective for the comprehensive analysis of the modulatory mechanism underlying the metastasis-suppressive effects of miR-148a in NSCLC. In conclusion, quantitative proteomic technology revealed that miR-148a may regulate a panel of tumor-associated proteins to suppress metastasis in NSCLC.
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Affiliation(s)
- Dandan Chu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
| | - Jing Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
| | - Hechun Lin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
| | - Xiao Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
| | - Hongyu Pan
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
| | - Lei Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
| | - Tao Yu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
| | - Mingxia Yan
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
| | - Ming Yao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China
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21
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Zhang S, Li Z, Zhang L, Xu Z. MEF2‑activated long non‑coding RNA PCGEM1 promotes cell proliferation in hormone‑refractory prostate cancer through downregulation of miR‑148a. Mol Med Rep 2018; 18:202-208. [PMID: 29749452 PMCID: PMC6059670 DOI: 10.3892/mmr.2018.8977] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 01/26/2017] [Indexed: 01/04/2023] Open
Abstract
Prostate cancer gene expression marker 1 (PCGEM1) is a prostate-specific gene overexpressed in prostate cancer cells that promotes cell proliferation. To study the molecular mechanism of PCGEM1 function in hormone-refractory prostate cancer, the interaction between myocyte enhancer factor 2 (MEF2) and PCGEM1 was assessed by a luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. In addition, the underlying mechanism of PCGEM1 regulating expression of microRNA (miR)-148a in PC3 prostate cancer cells was evaluated. Relative expression levels were measured by reverse transcription-quantitative polymerase chain reaction, and early apoptosis was measured by flow cytometry. PCGEM1 was demonstrated to be overexpressed in prostate cancer tissues compared with noncancerous tissues. Expression levels of PCGEM1 in PC3 cancer cells were demonstrated to be regulated by MEF2, as PCGME1 mRNA was increased by MEF2 overexpression but decreased by MEF2 silencing. MEF2 was also demonstrated to enhance the activity of PCGEM1 promoter and thus promote PCGEM1 transcription. In addition, downregulation of PCGEM1 expression in PC3 cells increased expression of miR-148a. By contrast, overexpression of PCGEM1 decreased miR-148a expression. Finally, PCGME1 silencing by small interfering RNA significantly induced early cell apoptosis but this effect was reduced by a miR-148a inhibitor. In conclusion, the present study demonstrated a positive regulatory association between MEF2 and PCGEM1, and a reciprocal negative regulatory association between PCGEM1 and miR-148a that controls cell apoptosis. The present study, therefore, provides new insights into the mechanism of PCGEM1 function in prostate cancer development.
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Affiliation(s)
- Shibao Zhang
- Department of Urology, Ji'nan Central Hospital Affiliated to Shandong University, Ji'nan, Shandong 250013, P.R. China
| | - Zongwu Li
- Department of Urology, Ji'nan Central Hospital Affiliated to Shandong University, Ji'nan, Shandong 250013, P.R. China
| | - Longyang Zhang
- Department of Urology, Ji'nan Central Hospital Affiliated to Shandong University, Ji'nan, Shandong 250013, P.R. China
| | - Zhonghua Xu
- Department of Urology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
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22
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Zhou Z, Lin Z, Pang X, Tariq MA, Ao X, Li P, Wang J. Epigenetic regulation of long non-coding RNAs in gastric cancer. Oncotarget 2018; 9:19443-19458. [PMID: 29721215 PMCID: PMC5922409 DOI: 10.18632/oncotarget.23821] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 10/25/2017] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is one of the most common cancers and is the second leading cause of cancer mortality worldwide. Therefore, it is urgent to explore new molecular biomarkers for early diagnosis, early treatment and prognosis for gastric cancer patients. Recently, increasing evidence has shown that epigenetic changes, such as aberrant DNA methylation, histone modifications, and noncoding RNAs (ncRNAs) expression, play substantial roles in the development and progression of malignancies. Among these changes, long non-coding RNAs (lncRNAs), a novel class of ncRNAs, are emerging as highly versatile actors in a variety of cellular processes by regulating gene expression at the epigenetic level as well as at the transcriptional and post-transcriptional levels. Hundreds of lncRNAs become dysregulated in the various pathological processes of gastric cancer, and multiple lncRNAs have been reported to function as tumor-suppressors or oncogenes, although the underlying mechanisms are still under investigation. Here, we provide an overview of the epigenetic regulation of chromatin and the molecular functions of lncRNAs; we focus on lncRNA-mediated epigenetic regulation of cancer-related gene expression in gastric cancer, as well as discuss the clinical implications of lncRNAs on epigenetic-related cancer treatments, which may contribute helpful approaches for the development of new potential strategies for future diagnosis and therapeutic intervention in human cancers.
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Affiliation(s)
- Zhixia Zhou
- Center for Tumor Molecular Biology, Institute for Translational Medicine, Qingdao University, Qingdao 266021, China
| | - Zhijuan Lin
- Center for Tumor Molecular Biology, Institute for Translational Medicine, Qingdao University, Qingdao 266021, China
| | - Xin Pang
- Center for Tumor Molecular Biology, Institute for Translational Medicine, Qingdao University, Qingdao 266021, China
| | - Muhammad Akram Tariq
- Center for Tumor Molecular Biology, Institute for Translational Medicine, Qingdao University, Qingdao 266021, China
| | - Xiang Ao
- Center for Tumor Molecular Biology, Institute for Translational Medicine, Qingdao University, Qingdao 266021, China
| | - Peifeng Li
- Center for Tumor Molecular Biology, Institute for Translational Medicine, Qingdao University, Qingdao 266021, China
| | - Jianxun Wang
- Center for Tumor Molecular Biology, Institute for Translational Medicine, Qingdao University, Qingdao 266021, China
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23
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Miao C, Zhang J, Zhao K, Liang C, Xu A, Zhu J, Wang Y, Hua Y, Tian Y, Liu S, Zhang C, Qin C, Wang Z. The significance of microRNA-148/152 family as a prognostic factor in multiple human malignancies: a meta-analysis. Oncotarget 2018; 8:43344-43355. [PMID: 28574848 PMCID: PMC5522150 DOI: 10.18632/oncotarget.17949] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 04/07/2017] [Indexed: 01/19/2023] Open
Abstract
Recent studies have demonstrated that microRNA-148/152 family emerges as a attractive biomarker for predicting tumor prognosis and progression. However, outcomes of different studies are controversial. Eligible Literature were searched through online databases: PubMed, EMBASE and Web of Science. A total of 24 eligible studies were ultimately enrolled in this meta-analysis. Results indicated that overexpression of miR-148/152 family was significantly correlated with enhanced overall/cause-specific survival (OS/CSS) (HR=0.63, 95% CI: 0.54-0.74). Stratified analysis indicated that high miR-148a and miR-148b expression predicted favorable OS/CSS (HR=0.76; 95% CI: 0.69-0.90) and (HR=0.49; 95% CI: 0.39-0.61), while miR-152 developed no significant impact (HR=0.40, 95% CI: 0.12-1.29). MiR-148/152 family was distinctly associated with superior OS/CSS in Asian (HR=0.53, 95% CI: 0.44-0.64), but not in Caucasian (HR=0.96, 95% CI: 0.82-1.13). Futhermore, miR-148/152 family expression also predicted longer disease/relapse/progression-free survival (DFS/RFS/PFS) (HR=0.37, 95% CI: 0.16-0.88). A significantly favorable DFS/RFS/PFS was observed in Asian (HR=0.21, 95% CI: 0.06-0.81) than that in Caucasian (HR=0.76, 95% CI: 0.31-1.87). miR-148/152 family overexpression also predicted longer DFS/RFS/PFS in tissues (HR=0.11, 95% CI: 0.01-0.98), but not in plasma/serum (HR=0.67, 95% CI: 0.38-1.18). Our meta-analysis demonstrated that overexpression of miR-148/152 predicted enhanced OS/CSS and DFS/RFS/PFS of cancer patients. MiR-148a/b family may serve as a potential prognostic factor in multiple human malignancies.
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Affiliation(s)
- Chenkui Miao
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jianzhong Zhang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kai Zhao
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chao Liang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Aiming Xu
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jundong Zhu
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuhao Wang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yibo Hua
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ye Tian
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shouyong Liu
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chao Zhang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chao Qin
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zengjun Wang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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24
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Li T, Cox CD, Ozer BH, Nguyen NT, Nguyen HN, Lai TJ, Li S, Liu F, Kornblum HI, Liau LM, Nghiemphu PL, Cloughesy TF, Lai A. D-2-Hydroxyglutarate Is Necessary and Sufficient for Isocitrate Dehydrogenase 1 Mutant-Induced MIR148A Promoter Methylation. Mol Cancer Res 2018; 16:947-960. [PMID: 29545476 DOI: 10.1158/1541-7786.mcr-17-0367] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 01/13/2018] [Accepted: 02/20/2018] [Indexed: 12/14/2022]
Abstract
Mutant isocitrate dehydrogenase (IDH) 1/2 converts α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2-HG), a putative oncometabolite that can inhibit α-KG-dependent enzymes, including ten-eleven translocation methylcytosine dioxygenase (TET) DNA demethylases. We recently established that miRNAs are components of the IDH1 mutant-associated glioma CpG island methylator phenotype (G-CIMP) and specifically identified MIR148A as a tumor-suppressive miRNA within G-CIMP. However, the precise mechanism by which mutant IDH induces hypermethylation of MIR148A and other G-CIMP promoters remains to be elucidated. In this study, we demonstrate that treatment with exogenous D-2-HG induces MIR148A promoter methylation and transcriptional silencing in human embryonic kidney 293T (293T) cells and primary normal human astrocytes. Conversely, we show that the development of MIR148A promoter methylation in mutant IDH1-overexpressing 293T cells is abrogated via treatment with C227, an inhibitor of mutant IDH1 generation of D-2-HG. Using dot blot assays for global assessment of 5-hydroxymethylcytosine (5-hmC), we show that D-2-HG treatment reduces 5-hmC levels, whereas C227 treatment increases 5-hmC levels, strongly suggesting TET inhibition by D-2-HG. Moreover, we show that withdrawal of D-2-HG treatment reverses methylation with an associated increase in MIR148A transcript levels and transient generation of 5-hmC. We also demonstrate that RNA polymerase II binds endogenously to the predicted promoter region of MIR148A, validating the hypothesis that its transcription is driven by an independent promoter.Implications: Establishment of D-2-HG as a necessary and sufficient intermediate by which mutant IDH1 induces CpG island methylation of MIR148A will help with understanding the efficacy of selective mutant IDH1 inhibitors in the clinic. Mol Cancer Res; 16(6); 947-60. ©2018 AACR.
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Affiliation(s)
- Tie Li
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Christopher D Cox
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Byram H Ozer
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Nhung T Nguyen
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - HuyTram N Nguyen
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Thomas J Lai
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Sichen Li
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Fei Liu
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Harley I Kornblum
- Department of Pediatrics, Psychiatry and Biobehavioral Sciences, Pediatric Neurology, Semel Institute for Neuroscience and Human Behavior, Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Linda M Liau
- Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Phioanh L Nghiemphu
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Timothy F Cloughesy
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Albert Lai
- Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
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25
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Kowolik CM, Lin M, Xie J, Overman LE, Horne DA. NT1721, a novel epidithiodiketopiperazine, exhibits potent in vitro and in vivo efficacy against acute myeloid leukemia. Oncotarget 2018; 7:86186-86197. [PMID: 27863389 PMCID: PMC5349906 DOI: 10.18632/oncotarget.13364] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 11/07/2016] [Indexed: 12/24/2022] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive malignancy characterized by heterogeneous genetic and epigenetic changes in hematopoietic progenitors that lead to abnormal self-renewal and proliferation. Despite high initial remission rates, prognosis remains poor for most AML patients, especially for those harboring internal tandem duplication (ITD) mutations in the fms-related tyrosine kinase-3 (FLT3). Here, we report that a novel epidithiodiketopiperazine, NT1721, potently decreased the cell viability of FLT3-ITD+ AML cell lines, displaying IC50 values in the low nanomolar range, while leaving normal CD34+ bone marrow cells largely unaffected. The IC50 values for NT1721 were significantly lower than those for clinically used AML drugs (i.e. cytarabine, sorafenib) in all tested AML cell lines regardless of their FLT3 mutation status. Moreover, combinations of NT1721 with sorafenib or cytarabine showed better antileukemic effects than the single agents in vitro. Combining cytarabine with NT1721 also attenuated the cytarabine-induced FLT3 ligand surge that has been linked to resistance to tyrosine kinase inhibitors. Mechanistically, NT1721 depleted DNA methyltransferase 1 (DNMT1) protein levels, leading to the re-expression of silenced tumor suppressor genes and apoptosis induction. NT1721 concomitantly decreased the expression of EZH2 and BMI1, two genes that are associated with the maintenance of leukemic stem/progenitor cells. In a systemic FLT3-ITD+ AML mouse model, treatment with NT1721 reduced tumor burdens by > 95% compared to the control and significantly increased survival times. Taken together, our results suggest that NT1721 may represent a promising novel agent for the treatment of AML.
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Affiliation(s)
- Claudia M Kowolik
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Min Lin
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Jun Xie
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Larry E Overman
- Department of Chemistry, University of California, Irvine, CA 92697, USA
| | - David A Horne
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA
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26
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Epigenetics and MicroRNAs in Cancer. Int J Mol Sci 2018; 19:ijms19020459. [PMID: 29401683 PMCID: PMC5855681 DOI: 10.3390/ijms19020459] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 01/29/2018] [Accepted: 01/30/2018] [Indexed: 02/08/2023] Open
Abstract
The ability to reprogram the transcriptional circuitry by remodeling the three-dimensional structure of the genome is exploited by cancer cells to promote tumorigenesis. This reprogramming occurs because of hereditable chromatin chemical modifications and the consequent formation of RNA-protein-DNA complexes that represent the principal actors of the epigenetic phenomena. In this regard, the deregulation of a transcribed non-coding RNA may be both cause and consequence of a cancer-related epigenetic alteration. This review summarizes recent findings that implicate microRNAs in the aberrant epigenetic regulation of cancer cells.
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27
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Sharma NK, Varma V, Ma L, Hasstedt SJ, Das SK. Obesity Associated Modulation of miRNA and Co-Regulated Target Transcripts in Human Adipose Tissue of Non-Diabetic Subjects. Microrna 2018; 4:194-204. [PMID: 26527284 PMCID: PMC4740938 DOI: 10.2174/2211536604666151103121817] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2015] [Revised: 10/15/2015] [Accepted: 11/02/2015] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Micro RNAs (miRNAs) are a class of non-coding regulatory RNAs. We performed a transcriptome-wide analysis of subcutaneous adipose tissue and in vitro studies to identify miRNAs and co-regulated target transcripts associated with insulin sensitivity (SI) and obesity in human. METHODS We selected 20 insulin-resistant (IR, SI=2.0±0.7) and 20 insulin-sensitive (IS, SI=7.2±2.3) subjects from a cohort of 117 metabolically characterized non-diabetic Caucasians for comparison. RESULTS After global profiling, 3 miRNAs had marginally different expressions between IR and IS subjects. A total of 14 miRNAs were significantly correlated with %fat mass, body mass index (BMI), or SI. The qRT-PCR validated the correlation of miR-148a-3p with BMI (r=-0.70, P=2.73X10(-6)). MiRNA target filtering analysis identified DNA methyltransferase 1 (DNMT1) as one of the target genes of miR-148a-3p. DNMT1 expression in adipose tissue was positively correlated with BMI (r=0.47, p=8.42X10(-7)) and was inversely correlated with miR-148a-3p (r=-0.34). Differentiation of SGBS preadipocytes showed up-regulation of miR-148a-3p and down-regulation of DNMT1 in differentiated adipocytes. After transfecting miR-148a-3p mimics into HeLa-S3 cells, DNMT1 was down-regulated, while transfection of adipose stem cells with miR-148a-3p inhibitor up-regulated DNMT1. CONCLUSIONS Our results indicate that miR-148a-3pmediated regulation of DNMT1 expression may play a mechanistic role in obesity.
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Affiliation(s)
| | | | | | | | - Swapan K Das
- Section on Endocrinology and Metabolism, Department of Internal Medicine Wake Forest School of Medicine, Medical Center Boulevard, NRC Building#E159 Winston-Salem, North Carolina 27157, USA.
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28
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Friedrich M, Pracht K, Mashreghi MF, Jäck HM, Radbruch A, Seliger B. The role of the miR-148/-152 family in physiology and disease. Eur J Immunol 2017; 47:2026-2038. [DOI: 10.1002/eji.201747132] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 07/30/2017] [Accepted: 09/01/2017] [Indexed: 12/14/2022]
Affiliation(s)
- Michael Friedrich
- Institute of Medical Immunology; Martin-Luther-University Halle-Wittenberg; Halle/Saale Germany
| | - Katharina Pracht
- Division of Molecular Immunology; Nikolaus-Fiebiger Center; Department of Internal Medicine III; University of Erlangen-Nürnberg; Erlangen Germany
| | | | - Hans-Martin Jäck
- Division of Molecular Immunology; Nikolaus-Fiebiger Center; Department of Internal Medicine III; University of Erlangen-Nürnberg; Erlangen Germany
| | | | - Barbara Seliger
- Institute of Medical Immunology; Martin-Luther-University Halle-Wittenberg; Halle/Saale Germany
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29
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Wang P, Li X, Cao L, Huang S, Li H, Zhang Y, Yang T, Jiang J, Shi D. MicroRNA-148a overexpression improves the early development of porcine somatic cell nuclear transfer embryos. PLoS One 2017; 12:e0180535. [PMID: 28665977 PMCID: PMC5493425 DOI: 10.1371/journal.pone.0180535] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 06/02/2017] [Indexed: 12/15/2022] Open
Abstract
Incomplete epigenetic reprogramming of donor cell nuclei is one of the main contributors to the low efficiency of somatic cell nuclear transfer (SCNT). To improve the success of SCNT, somatic cell DNA methylation levels must be reduced to those levels found in totipotent embryonic cells. Recent studies have demonstrated that miR-148a can affect DNA methylation via DNMT1 modulation in various cancers. Therefore, the focus of this study was to examine the influence of miR-148a on DNA methylation in donor cells and in SCNT embryo development. Thus, a stable cell line overexpressing miR-148a was established and used to produce SCNT embryos. Upon examination, DNMT1 was found to be a miR-148a target in porcine fetal fibroblasts (PFF). Furthermore, miR-148a overexpression in PFFs significantly decreased DNMT1 expression and global DNA methylation levels (P < 0.05). Moreover, miRNA-148a expression levels in SCNT embryos were significantly lower at the 2-cell and 4-cell stages when compared to IVF and parthenogenetic embryos. The group overexpressing miRNA-148a also showed a significant increase in blastocyst formation and total cell numbers (P < 0.05). Additionally, miR-148a overexpression altered the immunofluorescence signal of 5-mC and H3K9ac, and enhanced pluripotent gene (Oct4 and Nanog) expression levels during embryo development. These results indicate that miR-148a overexpression enhances the developmental potential of SCNT embryos and modifies epigenetic status.
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Affiliation(s)
- Ping Wang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Xiangping Li
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China
- * E-mail: (XPL); (DSS)
| | - Lihua Cao
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Shihai Huang
- College of Life Science and Technology, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Haiyan Li
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Yan Zhang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Ting Yang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Jianrong Jiang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Deshun Shi
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, China
- * E-mail: (XPL); (DSS)
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30
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Lorenzon L, Cippitelli C, Avantifiori R, Uccini S, French D, Torrisi MR, Ranieri D, Mercantini P, Canu V, Blandino G, Cavallini M. Down-regulated miRs specifically correlate with non-cardial gastric cancers and Lauren's classification system. J Surg Oncol 2017; 116:184-194. [PMID: 28475823 DOI: 10.1002/jso.24648] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 03/22/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVES Gastric cancers are usually characterized using Lauren's classification into intestinal and diffuse types. We previously documented the down-modulation of miR31, miR148a, miR204, and miR375 in gastric cancers. We aimed this manuscript to investigate these miRs with the end-points of diagnosis, Lauren's classification and prognosis. METHODS A total of 117 resected non-cardial adenocarcinomas were evaluated for miRs' expressions. The performance of miRs' expressions for cancer diagnosis was tested using ROC curves. Logistic regression was conducted with the end-point of Lauren's classification. Kaplan-Meier and Cox analyses were performed for OS, DFS, and DSS. miRs' targets were reviewed using PRISMA method and BCL-2 was further investigated in cell lines. RESULTS ROC curves documented that miRs' down-modulation was significant in differentiating cancer versus normal tissues. Diffuse type cancers were associated with female sex, young age, and miR375 higher expression. We confirmed BCL-2 as a miR204 target. However, survival analyses confirmed the pathologic criteria (advanced stages, LNR, and low LNH) as the significant variables correlated to worse prognosis. CONCLUSIONS The down-modulation of miR31, miR148a, miR204, and miR375 is significantly associated with non-cardial gastric cancers and miR375 is specifically linked to Lauren's classification. Nevertheless, standard pathological features display as the independent variables associated with worse prognosis.
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Affiliation(s)
- Laura Lorenzon
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Claudia Cippitelli
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Riccardo Avantifiori
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Stefania Uccini
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Deborah French
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Maria Rosaria Torrisi
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Danilo Ranieri
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Paolo Mercantini
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Valeria Canu
- Italian National Cancer Institute Regina Elena, Translational Oncogenomic Unit, Rome, Italy
| | - Giovanni Blandino
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Marco Cavallini
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
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Wang F, Ma Y, Wang H, Qin H. Reciprocal regulation between microRNAs and epigenetic machinery in colorectal cancer. Oncol Lett 2017; 13:1048-1057. [PMID: 28454212 DOI: 10.3892/ol.2017.5593] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Accepted: 02/24/2016] [Indexed: 12/23/2022] Open
Abstract
Epigenetics encompasses changes in DNA methylation, histone and chromatin structure, and non-coding RNAs, specifically microRNA (miRNA) expression. Recent advances in the rapidly evolving field of colorectal cancer (CRC) epigenetics have revealed a complicated network of reciprocal interconnections between miRNAs and other epigenetic machinery. On the one hand, miRNA expression may be regulated by epigenetic mechanisms including DNA methylation and histone modifications. However, miRNAs may affect the epigenetic machinery by directly targeting its enzymatic components. In this study, we focus on the colorectal miRNA expression profile and further illustrate the reciprocal regulation in CRC, with the aim of offering new insights into the strategies of combatting the disease.
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Affiliation(s)
- Feng Wang
- Department of Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, P.R. China
| | - Yanlei Ma
- Department of Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, P.R. China
| | - Huamin Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Huanlong Qin
- Department of Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, P.R. China
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32
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Azarnezhad A, Mehdipour P. Cancer Genetics at a Glance: The Comprehensive Insights. CANCER GENETICS AND PSYCHOTHERAPY 2017:79-389. [DOI: 10.1007/978-3-319-64550-6_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression mainly at the posttranscriptional level. Similar to protein-coding genes, their expression is also controlled by genetic and epigenetic mechanisms. Disruption of these control processes leads to abnormal expression of miRNAs in cancer. In this chapter, we discuss the supportive links between miRNAs and epigenetics in the context of carcinogenesis. miRNAs can be epigenetically regulated by DNA methylation and/or specific histone modifications. However, they can themselves (epi-miRNAs) repress key enzymes that drive epigenetic remodeling and also bind to complementary sequences in gene promoters, recruiting specific protein complexes that modulate chromatin structure and gene expression. All these issues affect the transcriptional landscape of cells. Most important, in the cancer clinical scenario, knowledge about miRNAs epigenetic dysregulation can not only be beneficial as a prognostic biomarker, but can also help in the design of new therapeutic approaches.
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Affiliation(s)
- Catia Moutinho
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain
| | - Manel Esteller
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain; School of Medicine and Health Sciences, University of Barcelona (UB), Catalonia, Spain.
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Jili S, Eryong L, Lijuan L, Chao Z. RUNX3 inhibits laryngeal squamous cell carcinoma malignancy under the regulation of miR-148a-3p/DNMT1 axis. Cell Biochem Funct 2016; 34:597-605. [PMID: 27859417 DOI: 10.1002/cbf.3233] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 10/07/2016] [Accepted: 10/07/2016] [Indexed: 01/05/2023]
Affiliation(s)
- Su Jili
- Department of Otorhinolaryngology, Head and Neck Surgery; The first Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology; Luoyang 471003 China
| | - Lu Eryong
- Department of Otorhinolaryngology, Head and Neck Surgery; The first Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology; Luoyang 471003 China
| | - Lu Lijuan
- Department of Obstetrics and Gynecology; The first Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology; Luoyang 471003 China
| | - Zhang Chao
- Department of Otorhinolaryngology, Head and Neck Surgery; The first Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology; Luoyang 471003 China
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35
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Li Y, Deng X, Zeng X, Peng X. The Role of Mir-148a in Cancer. J Cancer 2016; 7:1233-41. [PMID: 27390598 PMCID: PMC4934031 DOI: 10.7150/jca.14616] [Citation(s) in RCA: 112] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 05/07/2016] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) are highly conserved noncoding RNAs of about 19-25 nucleotides. Through specifically pairing with complementary sites in 3' untranslated regions (UTRs) of target mRNAs, they mediate post-transcriptional silencing. MicroRNAs have been implicated in many physiological processes including proliferation, differentiation, development, apoptosis, and metabolism. In recent years many studies have revealed that the aberrant expression of miRNA is closely related to oncogenesis and is now an intense field of study. Mir-148a is aberrantly expressed in various cancers and has been identified as an oncogenic or tumor suppressor with crucial roles in the molecular mechanisms of oncogenesis. In this review, we have summarized the role of mir-148a in the oncogenic pathways of gastric, liver, breast and urogenital cancers, and in neurogliocytoma oncogenesis. Studying the functional role of mir-148a is crucial in discovering novel tumor molecular markers and identifying potential therapeutic targets.
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Affiliation(s)
- Yue Li
- 1. Department of Pathology and Pathophysiology, Hunan Normal University Medical School, Changsha 410013, Hunan, China
| | - Xiyun Deng
- 1. Department of Pathology and Pathophysiology, Hunan Normal University Medical School, Changsha 410013, Hunan, China
| | - Xiaomin Zeng
- 2. Department of Statistics and Epidemiology, Public Health School, Central South University, Changsha 410078, Hunan, China
| | - Xiaoning Peng
- 1. Department of Pathology and Pathophysiology, Hunan Normal University Medical School, Changsha 410013, Hunan, China
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Tsai MM, Wang CS, Tsai CY, Huang HW, Chi HC, Lin YH, Lu PH, Lin KH. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer. Int J Mol Sci 2016; 17:945. [PMID: 27322246 PMCID: PMC4926478 DOI: 10.3390/ijms17060945] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 06/01/2016] [Accepted: 06/07/2016] [Indexed: 12/11/2022] Open
Abstract
Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients' survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets.
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Affiliation(s)
- Ming-Ming Tsai
- Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan.
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
| | - Chung-Ying Tsai
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Hsiang-Wei Huang
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Hsiang-Cheng Chi
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Yang-Hsiang Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Pei-Hsuan Lu
- Department of Dermatology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
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37
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Liu B, Song J, Luan J, Sun X, Bai J, Wang H, Li A, Zhang L, Feng X, Du Z. Promoter methylation status of tumor suppressor genes and inhibition of expression of DNA methyltransferase 1 in non-small cell lung cancer. Exp Biol Med (Maywood) 2016; 241:1531-9. [PMID: 27190263 DOI: 10.1177/1535370216645211] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 03/28/2016] [Indexed: 12/15/2022] Open
Abstract
DNA methylation is an epigenetic DNA modification catalyzed by DNA methyltransferase 1 (DNMT1). The purpose of this study was to investigate DNMT1 gene and protein expression and the effects of methylation status on tumor suppressor genes in human non-small cell lung cancer (NSCLC) cell lines grown in vitro and in vivo Human lung adenocarcinoma cell lines, A549 and H838, were grown in vitro and inoculated subcutaneously into nude mice to form tumors and were then treated with the DNA methylation inhibitor, 5-aza-2'-deoxycytidine, with and without treatment with the benzamide histone deacetylase inhibitor, entinostat (MS-275). DNMT1 protein expression was quantified by Western blot. Promoter methylation status of tumor suppressor genes (RASSF1A, ASC, APC, MGMT, CDH13, DAPK, ECAD, P16, and GATA4) was evaluated by methylation-specific polymerase chain reaction. Methylation status of the tumor suppressor genes was regulated by the DNMT1 gene, with the decrease of DNMT1 expression following DNA methylation treatment. Demethylation of tumor suppressor genes (APC, ASC, and RASSF1A) restored tumor growth in nude mice. The results of this study support a role for methylation of DNA as a potential epigenetic clinical biomarker of prognosis or response to therapy and for DNMT1 as a potential therapeutic target in NSCLC.
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Affiliation(s)
- Bangqing Liu
- Thoracic Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, China
| | - Jianfei Song
- Thoracic Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, China
| | - Jiaqiang Luan
- Thoracic Surgery, Henan Provincial Chest Hospital, Zhengzhou, Henan 450000, China
| | - Xiaolin Sun
- Cardiothoracic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - Jian Bai
- Thoracic Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, China
| | - Haiyong Wang
- Cardiothoracic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - Angui Li
- Cardiothoracic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - Lifei Zhang
- Thoracic Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, China
| | - Xiaoyan Feng
- Cardiothoracic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - Zhenzong Du
- Thoracic Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, China
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38
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Bhattacharya S, Chalk AM, Ng AJM, Martin TJ, Zannettino AC, Purton LE, Lu J, Baker EK, Walkley CR. Increased miR-155-5p and reduced miR-148a-3p contribute to the suppression of osteosarcoma cell death. Oncogene 2016; 35:5282-5294. [PMID: 27041566 DOI: 10.1038/onc.2016.68] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 12/16/2015] [Accepted: 01/03/2016] [Indexed: 12/13/2022]
Abstract
Osteosarcoma (OS) is the most common cancer of bone and the 5th leading cause of cancer-related death in young adults. Currently, 5-year survival rates have plateaued at ~70% for patients with localized disease. Those with disseminated disease have an ~20% 5-year survival. An improved understanding of the molecular genetics of OS may yield new approaches to improve outcomes for OS patients. To this end, we applied murine models that replicate human OS to identify and understand dysregulated microRNAs (miRNAs) in OS. miRNA expression patterns were profiled in murine primary osteoblasts, osteoblast cultures and primary OS cell cultures (from primary and paired metastatic locations) isolated from two genetically engineered murine models of OS. The differentially expressed miRNA were further assessed by a cross-species comparison with human osteoblasts and OS cultures. We identified miR-155-5p and miR-148a-3p as deregulated in OS. miR-155-5p suppression or miR-148a-3p overexpression potently reduced proliferation and induced apoptosis in OS cells, yet strikingly, did not impact normal osteoblasts. To define how these miRNAs regulated OS cell fate, we used an integrated computational approach to identify putative candidate targets and then correlated these with the cell biological impact. Although we could not resolve the mechanism through which miR-148a-3p impacts OS, we identified that miR-155-5p overexpression suppressed its target Ripk1 (receptor (TNFRSF)-interacting serine-threonine kinase 1) expression, and miR-155-5p inhibition elevated Ripk1 levels. Ripk1 is directly involved in apoptosis/necroptosis. In OS cells, small interfering RNA against Ripk1 prevented cell death induced by the sequestration of miR-155-5p. Collectively, we show that miR-148a-3p and miR-155-5p are species-conserved deregulated miRNA in OS. Modulation of these miRNAs was specifically toxic to tumor cells but not normal osteoblasts, raising the possibility that these may be tractable targets for miRNA-based therapies for OS.
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Affiliation(s)
- S Bhattacharya
- St Vincent's Institute of Medical Research and Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia
| | - A M Chalk
- St Vincent's Institute of Medical Research and Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia
| | - A J M Ng
- St Vincent's Institute of Medical Research and Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia
| | - T J Martin
- St Vincent's Institute of Medical Research and Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia
| | - A C Zannettino
- Myeloma Research Laboratory, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.,Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - L E Purton
- St Vincent's Institute of Medical Research and Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.,ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
| | - J Lu
- Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT, USA
| | - E K Baker
- St Vincent's Institute of Medical Research and Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia
| | - C R Walkley
- St Vincent's Institute of Medical Research and Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.,ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
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Beeharry MK, Liu WT, Yan M, Zhu ZG. New blood markers detection technology: A leap in the diagnosis of gastric cancer. World J Gastroenterol 2016; 22:1202-1212. [PMID: 26811658 PMCID: PMC4716031 DOI: 10.3748/wjg.v22.i3.1202] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Revised: 09/28/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is still one of the malignant tumors with high morbidity and mortality in the world, with a 5-year survival rate of less than 30%. GC is often either asymptomatic or causes only nonspecific symptoms in its early stages, whereas when the symptoms manifest, the cancer has usually reached an advanced stage, which is one of the main causes of its relatively poor prognosis. Hence, the main focus of GC research has been on discovering new tools and technology to predict, screen and diagnose GC at an early stage which would prompt early treatment. With the tremendous advances in the OMICS technology, serum proteomics has been in the limelight of cancer research over the last few decades and has steered the development of several methods helping to understand the mechanisms underlying gastric carcinogenesis, resulting in the identification of a large number of molecular targets such as circulating tumor cells (CTCs), cell free DNA (cfDNA) and cell tumor DNA (ctDNA) and their sub-molecular components such as miRNA, that show great promise as GC biomarkers. In this review, we are underlying the recent breakthroughs about new blood markers technology for GC while scrutinizing the potential clinical use of CTCs, cfDNA, ctDNA and the role of the methylation of their sub-molecular components in the pathogenesis, diagnosis and management of GC.
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40
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Xie SS, Jin J, Xu X, Zhuo W, Zhou TH. Emerging roles of non-coding RNAs in gastric cancer: Pathogenesis and clinical implications. World J Gastroenterol 2016; 22:1213-1223. [PMID: 26811659 PMCID: PMC4716032 DOI: 10.3748/wjg.v22.i3.1213] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 08/17/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is a leading cause of cancer-related deaths. However, the mechanisms underlying gastric carcinogenesis remain largely unclear. The association of non-coding RNAs (ncRNAs) with cancer has been widely studied during the past decade. In general, ncRNAs have been classified as small ncRNAs, including microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). Emerging evidence shows that miRNAs and lncRNAs play key roles in the formation and progression of many cancers. In this review, we focus on the regulation of miRNAs and lncRNAs in gastric cancer. miRNAs and lncRNAs appear to be involved in gastric tumor growth, invasion, and metastasis and in establishment of the gastric tumor microenvironment through various mechanisms. Furthermore, we also discuss the possibilities of establishing miRNAs and lncRNAs as potential biomarkers and therapeutic targets for gastric cancer. Taken together, we summarize the emerging roles of ncRNAs in gastric cancer development and their possible clinical significance.
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41
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Zhao Y, Lu G, Ke X, Lu X, Wang X, Li H, Ren M, He S. miR-488 acts as a tumor suppressor gene in gastric cancer. Tumour Biol 2016. [PMID: 26738864 DOI: 10.1007/s13277-015-4645-y.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that modulate development, cell proliferation, and apoptosis. The deregulated expression of microRNAs is found in carcinogenesis including gastric cancer (GC). In this study, we showed that the expression levels of miR-488 were downregulated in GC tissues compared to in non-tumor tissues. In addition, the expression of miR-488 was also lower in GC cell lines in contrast with the gastric epithelial cell line (GES). In addition, the expression level of miR-488 was negatively correlated with the TNM stage in GC patients, and lower miR-488 expression was found in tumors with advanced TNM stage. The ectopic expression of miR-488 suppressed the GC cell proliferation, cell cycle, colony information, and migration. PAX6 was identified as a direct target gene of miR-488 in HGC-27. Moreover, we found that the expression level of PAX6 was upregulated in the GC tissues compared with the non-tumor tissues. The PAX6 expression level was correlated with the cancer TNM stage, and higher PAX6 expression was found in tumors with advanced TNM stage. Furthermore, there was an inverse correlation between PAX6 and miR-488 expression levels in GC tissues. Therefore, these studies demonstrated that miR-488 might act as a tumor suppressor miRNA in the development of GC.
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Affiliation(s)
- Yan Zhao
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Guifang Lu
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xiquan Ke
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xinlan Lu
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xin Wang
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Hongxia Li
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Mudan Ren
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Shuixiang He
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
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Zhao Y, Lu G, Ke X, Lu X, Wang X, Li H, Ren M, He S. miR-488 acts as a tumor suppressor gene in gastric cancer. Tumour Biol 2016; 37:8691-8. [PMID: 26738864 DOI: 10.1007/s13277-015-4645-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Accepted: 12/13/2015] [Indexed: 12/12/2022] Open
Affiliation(s)
- Yan Zhao
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Guifang Lu
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xiquan Ke
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xinlan Lu
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xin Wang
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Hongxia Li
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Mudan Ren
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Shuixiang He
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
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Yan W, Qian L, Chen J, Chen W, Shen B. Comparison of Prognostic MicroRNA Biomarkers in Blood and Tissues for Gastric Cancer. J Cancer 2016; 7:95-106. [PMID: 26722365 PMCID: PMC4679386 DOI: 10.7150/jca.13340] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Accepted: 10/18/2015] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) still keeps up high mortality worldwide with poor prognosis. Efficient and non-invasive prognostic biomarkers are urgently needed. MicroRNAs are non-coding RNAs playing roles in post-transcriptional gene regulation, which contribute to various biological processes such as development, differentiation and carcinogenesis. MicroRNA expression profiles have been associated with the prognosis and outcome in GC. MicroRNA prognostic biomarkers have been identified from blood or tissues samples, but with different prognostic features. Understanding the various roles of microRNAs in different sample sources of GC will provide deep insights into GC progression. In this review, we highlight the distinct prognostic roles of microRNAs biomarkers in blood and tissue according to their relationships with prognostic parameters, survival rates and target pathways. This will be useful for non-invasive biomarker development and selection in prognosis of GC.
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Affiliation(s)
- Wenying Yan
- 1. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China; ; 2. Taicang Center for Translational Bioinformatics, Taicang 215400, China; ; 3. Center for Systems Biology, Soochow University, Suzhou 215006, China
| | - Laijun Qian
- 4. Daibu Center Hospital, Liyang, 213330, China
| | - Jiajia Chen
- 5. School of Chemistry, Biology and Material Engineering, Suzhou University of Science and Technology, Suzhou 215011, China
| | - Weichang Chen
- 1. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Bairong Shen
- 3. Center for Systems Biology, Soochow University, Suzhou 215006, China
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Tuna M, Machado AS, Calin GA. Genetic and epigenetic alterations of microRNAs and implications for human cancers and other diseases. Genes Chromosomes Cancer 2015; 55:193-214. [PMID: 26651018 DOI: 10.1002/gcc.22332] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2015] [Revised: 10/27/2015] [Accepted: 10/28/2015] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) are a well-studied group of noncoding RNAs that control gene expression by interacting mainly with messenger RNA. It is known that miRNAs and their biogenesis regulatory machineries have crucial roles in multiple cell processes; thus, alterations in these genes often lead to disease, such as cancer. Disruption of these genes can occur through epigenetic and genetic alterations, resulting in aberrant expression of miRNAs and subsequently of their target genes. This review focuses on the disruption of miRNAs and their key regulatory machineries by genetic alterations, with emphasis on mutations and epigenetic changes in cancer and other diseases.
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Affiliation(s)
- Musaffe Tuna
- Department of Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, TX
| | - Andreia S Machado
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX
| | - George A Calin
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX
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45
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Tian Y, Wei W, Li L, Yang R. Down-Regulation of miR-148a Promotes Metastasis by DNA Methylation and is Associated with Prognosis of Skin Cancer by Targeting TGIF2. Med Sci Monit 2015; 21:3798-805. [PMID: 26638007 PMCID: PMC4692572 DOI: 10.12659/msm.894826] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNA) dysregulation has been considered to be significantly related to the occurrence and development of cancers. Several studies had proved that DNA methylation is an important cause of the abnormal expression of miRNAs. The purpose of this study was to investigate the methylation status of miR-148a and its effects on the metastasis and prognosis of skin cancer, as well as the interaction with TGIF2 gene. MATERIAL AND METHODS According to the qRT-PCR analysis, the expression of miR-148a was down-regulated in tumor tissues compared with the adjacent tissues and healthy controls (P<0.05). In vitro cell metastasis assay revealed that miR-148a could inhibit cell metastasis and its down-regulation promoted metastasis. Luciferase reporter assay found that TGIF2 gene was a target gene and its expression was suppressed by miR-148a in skin cancer. RESULTS Methylation-specific PCR demonstrated that DNA methylation rate of miR-148a was higher in tumor tissues than in adjacent tissues and healthy tissues (P<0.05). miR-148a expression was proved to be epigenetically regulated after the demethylation of it by 5-aza-20-deoxycytidine treatment and qRT-PCR analysis. miR-148a methylation was significantly influenced by many clinicopathologic characteristics such as age (P=0.000), pathological differentiation (P=0.000), and lymph node metastasis (P=0.000). Besides, Kaplan-Meier analysis showed patients with miR-148a methylation lived shorter than those without that (P<0.001). Cox regression analysis manifested that miR-148a methylation (HR=0.053, 95CI%=0.005-0.548, P=0.014) could be serve as an independent prognostic marker for skin cancer. CONCLUSIONS Taken together, the expression of miR-148a was regulated by DNA methylation and targeted by TGIF2. Its methylation may be a potential prognostic indicator in skin cancer.
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Affiliation(s)
- Yanli Tian
- Department of Dermatology, The General Hospital of Beijing Military Command, Beijing, China (mainland)
| | - Wei Wei
- Department of Dermatology, The General Hospital of Beijing Military Command, Beijing, China (mainland)
| | - Li Li
- Department of Dermatology, The General Hospital of Beijing Military Command, Beijing, China (mainland)
| | - Rongya Yang
- Department of Dermatology, The General Hospital of Beijing Military Command, Beijing, China (mainland)
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46
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Li HP, Huang HY, Lai YR, Huang JX, Chang KP, Hsueh C, Chang YS. Silencing of miRNA-148a by hypermethylation activates the integrin-mediated signaling pathway in nasopharyngeal carcinoma. Oncotarget 2015; 5:7610-24. [PMID: 25277193 PMCID: PMC4202148 DOI: 10.18632/oncotarget.2282] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
MicroRNAs (miRNAs) play a pivotal role in carcinogenesis by suppressing oncogenes or tumor suppressor genes. Various studies have identified numerous miRNAs and their diverse targets; however, the consequences of dysregulated miRNAs in nasopharyngeal carcinoma (NPC) remain unclear. For this study, we found that miR-148a is downregulated through hypermethylation in NPC biopsies and NPC cell lines compared with adjacent normal and NP cells respectively. Promoter assays demonstrated that upstream stimulatory factor 1 (USF1) is a crucial transcription factor that activates miR-148a promoter activity. EMSA assays confirmed that purified USF1 binds better toward the unmethylated than the methylated CG-containing USF1 consensus probe. The ectopic expression of miR-148a inhibits cell migration in NPC cells through the suppression of integrin-mediated signaling by targeting VAV2, WASL and ROCK1. Biochemical and functional assays provided supporting evidence that these 3 genes are the downstream targets of miR-148a in NPC cells. Furthermore, immunohistochemical staining and Western blotting analysis revealed that the 3 oncogenic targets of miR-148a were overexpressed in NPC biopsies, suggesting that the inactivation of miR-148a caused by DNA methylation promotes NPC progression. Overall, our findings revealed that miR-148a can act as tumor suppressor miRNA and serve as a biomarker as well as a therapeutic target for NPC.
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Affiliation(s)
- Hsin-Pai Li
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC). Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC). Department of Microbiology and Immunology, School of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC). Contributed equally to this work
| | - Hsin-Yi Huang
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC)
| | - Yi-Ru Lai
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC)
| | - Jing-Xuan Huang
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC)
| | - Kai-Ping Chang
- Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan, ROC
| | - Chuen Hsueh
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC). Pathology Core, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC). Department of Pathology, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan, ROC
| | - Yu-Sun Chang
- Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC). Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC). Department of Microbiology and Immunology, School of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China (ROC)
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47
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Joshi P, Jeon YJ, Laganà A, Middleton J, Secchiero P, Garofalo M, Croce CM. MicroRNA-148a reduces tumorigenesis and increases TRAIL-induced apoptosis in NSCLC. Proc Natl Acad Sci U S A 2015; 112:8650-5. [PMID: 26124099 PMCID: PMC4507199 DOI: 10.1073/pnas.1500886112] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Nonsmall cell lung cancer (NSCLC) is one of the leading causes of death worldwide. TNF-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in malignant cells without inducing significant toxicity in normal cells. However, several carcinomas, including lung cancer, remain resistant to TRAIL. MicroRNAs (miRNAs) are small noncoding RNAs of ∼ 24 nt that block mRNA translation and/or negatively regulate its stability. They are often aberrantly expressed in cancer and have been implicated in increasing susceptibility or resistance to TRAIL-induced apoptosis by inhibiting key functional proteins. Here we show that miR-148a is down-regulated in cells with acquired TRAIL-resistance compared with TRAIL-sensitive cells. Enforced expression of miR-148a sensitized cells to TRAIL and reduced lung tumorigenesis in vitro and in vivo through the down-modulation of matrix metalloproteinase 15 (MMP15) and Rho-associated kinase 1 (ROCK1). These findings suggest that miR-148a acts as a tumor suppressor and might have therapeutic application in the treatment of NSCLC.
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Affiliation(s)
- Pooja Joshi
- Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
| | - Young-Jun Jeon
- Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
| | - Alessandro Laganà
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Justin Middleton
- Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
| | - Paola Secchiero
- Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, 44100 Ferrara, Italy
| | - Michela Garofalo
- Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, United Kingdom
| | - Carlo M Croce
- Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;
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48
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Lombard AP, Mooso BA, Libertini SJ, Lim RM, Nakagawa RM, Vidallo KD, Costanzo NC, Ghosh PM, Mudryj M. miR-148a dependent apoptosis of bladder cancer cells is mediated in part by the epigenetic modifier DNMT1. Mol Carcinog 2015; 55:757-67. [PMID: 25865490 DOI: 10.1002/mc.22319] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 02/24/2015] [Accepted: 03/05/2015] [Indexed: 12/13/2022]
Abstract
Urothelial cell carcinoma of the bladder (UCCB) is the most common form of bladder cancer and it is estimated that ~15,000 people in the United States succumbed to this disease in 2013. Bladder cancer treatment options are limited and research to understand the molecular mechanisms of this disease is needed to design novel therapeutic strategies. Recent studies have shown that microRNAs play pivotal roles in the progression of cancer. miR-148a has been shown to serve as a tumor suppressor in cancers of the prostate, colon, and liver, but its role in bladder cancer has never been elucidated. Here we show that miR-148a is down-regulated in UCCB cell lines. We demonstrate that overexpression of miR-148a leads to reduced cell viability through an increase in apoptosis rather than an inhibition of proliferation. We additionally show that miR-148a exerts this effect partially by attenuating expression of DNA methyltransferase 1 (DNMT1). Finally, our studies demonstrate that treating cells with both miR-148a and either cisplatin or doxorubicin is either additive or synergistic in causing apoptosis. These data taken together suggest that miR-148a is a tumor suppressor in UCCB and could potentially serve as a novel therapeutic for this malignancy.
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Affiliation(s)
- Alan P Lombard
- Department of Medical Microbiology and Immunology, University of California, Davis, California.,Biochemistry, Molecular, Cellular, and Developmental Biology Graduate Group and Biotechnology Program, University of California, Davis, California.,Veterans Affairs-Northern California Health Care System, Mather, California
| | - Benjamin A Mooso
- Veterans Affairs-Northern California Health Care System, Mather, California
| | - Stephen J Libertini
- Department of Medical Microbiology and Immunology, University of California, Davis, California.,Veterans Affairs-Northern California Health Care System, Mather, California
| | - Rebecca M Lim
- Department of Medical Microbiology and Immunology, University of California, Davis, California
| | - Rachel M Nakagawa
- Department of Medical Microbiology and Immunology, University of California, Davis, California
| | - Kathleen D Vidallo
- Department of Medical Microbiology and Immunology, University of California, Davis, California
| | - Nicole C Costanzo
- Department of Medical Microbiology and Immunology, University of California, Davis, California
| | - Paramita M Ghosh
- Veterans Affairs-Northern California Health Care System, Mather, California.,Department of Urology, University of California, Davis, California
| | - Maria Mudryj
- Department of Medical Microbiology and Immunology, University of California, Davis, California.,Veterans Affairs-Northern California Health Care System, Mather, California
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49
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Porstner M, Winkelmann R, Daum P, Schmid J, Pracht K, Côrte-Real J, Schreiber S, Haftmann C, Brandl A, Mashreghi MF, Gelse K, Hauke M, Wirries I, Zwick M, Roth E, Radbruch A, Wittmann J, Jäck HM. miR-148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2. Eur J Immunol 2015; 45:1206-15. [PMID: 25678371 DOI: 10.1002/eji.201444637] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Revised: 01/09/2015] [Accepted: 02/09/2015] [Indexed: 12/18/2022]
Abstract
B cells undergo affinity maturation and class switch recombination of their immunoglobulin receptors during a germinal center (GC) reaction, before they differentiate into long-lived antibody-secreting plasma cells (PCs). Transcription factors such as Bach2 and Mitf are essential during this process, as they delay premature differentiation of GC B cells by repressing Blimp-1 and IRF4, two transcription factors required for terminal PC differentiation. Therefore, Bach2 and Mitf expression must be attenuated in activated B cells to allow terminal PC differentiation, but the precise mechanism remains enigmatic. Here, we provide evidence that miR-148a, a small noncoding microRNA, fosters PC differentiation and survival. Next-generation sequencing revealed that miR-148a is the most abundant microRNA in primary human and murine PCs, and its expression is upregulated in activated murine B cells and coincides with Blimp-1 synthesis. miR-148a targets Bach2, Mitf and proapoptotic factors such as PTEN and Bim. When prematurely expressed, miR-148a promotes the differentiation and survival of plasmablasts and reduces frequencies of IgG1(+) cells in primary B-cell cultures. In summary, we propose that miR-148a is a new player in the regulatory network controlling terminal PC differentiation and could, therefore, be a therapeutic target for interfering with PC differentiation and survival.
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Affiliation(s)
- Martina Porstner
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nürnberg, Erlangen, Germany
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50
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Niederwieser C, Kohlschmidt J, Volinia S, Whitman SP, Metzeler KH, Eisfeld AK, Maharry K, Yan P, Frankhouser D, Becker H, Schwind S, Carroll AJ, Nicolet D, Mendler JH, Curfman JP, Wu YZ, Baer MR, Powell BL, Kolitz JE, Moore JO, Carter TH, Bundschuh R, Larson RA, Stone RM, Mrózek K, Marcucci G, Bloomfield CD. Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia. Leukemia 2015; 29:567-75. [PMID: 25204569 PMCID: PMC4351165 DOI: 10.1038/leu.2014.267] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 08/26/2014] [Accepted: 08/29/2014] [Indexed: 02/06/2023]
Abstract
DNMT3B encodes a DNA methyltransferase implicated in aberrant epigenetic changes contributing to leukemogenesis. We tested whether DNMT3B expression, measured by NanoString nCounter assay, associates with outcome, gene and microRNA expression and DNA methylation profiles in 210 older (⩾60 years) adults with primary, cytogenetically normal acute myeloid leukemia (CN-AML). Patients were dichotomized into high versus low expressers using median cut. Outcomes were assessed in the context of known CN-AML prognosticators. Gene and microRNA expression, and DNA methylation profiles were analyzed using microarrays and MethylCap-sequencing, respectively. High DNMT3B expressers had fewer complete remissions (CR; P=0.002) and shorter disease-free (DFS; P=0.02) and overall (OS; P<0.001) survival. In multivariable analyses, high DNMT3B expression remained an independent predictor of lower CR rates (P=0.04) and shorter DFS (P=0.04) and OS (P=0.001). High DNMT3B expression associated with a gene expression profile comprising 363 genes involved in differentiation, proliferation and survival pathways, but with only four differentially expressed microRNAs (miR-133b, miR-148a, miR-122, miR-409-3p) and no differential DNA methylation regions. We conclude that high DNMT3B expression independently associates with adverse outcome in older CN-AML patients. Gene expression analyses suggest that DNMT3B is involved in the modulation of several genes, although the regulatory mechanisms remain to be investigated to devise therapeutic approaches specific for these patients.
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MESH Headings
- Age Factors
- Aged
- Aged, 80 and over
- Cytarabine/therapeutic use
- DNA (Cytosine-5-)-Methyltransferases/genetics
- DNA Methylation
- Daunorubicin/therapeutic use
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Leukemic
- Humans
- Induction Chemotherapy
- Karyotyping
- Leukemia, Myeloid, Acute/diagnosis
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/mortality
- Male
- MicroRNAs/genetics
- Microarray Analysis
- Middle Aged
- Prognosis
- Survival Analysis
- DNA Methyltransferase 3B
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Affiliation(s)
| | - Jessica Kohlschmidt
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
- Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN
| | - Stefano Volinia
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Susan P. Whitman
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | | | | | - Kati Maharry
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
- Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN
| | - Pearlly Yan
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | | | - Heiko Becker
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | | | | | - Deedra Nicolet
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
- Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN
| | - Jason H. Mendler
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - John P. Curfman
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Yue-Zhong Wu
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Maria R. Baer
- Greenebaum Cancer Center, University of Maryland, Baltimore, MD
| | - Bayard L. Powell
- Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC
| | - Jonathan E. Kolitz
- Monter Cancer Center, Hofstra North Shore-Long Island Jewish School of Medicine, Lake Success, NY
| | | | | | - Ralf Bundschuh
- Departments of Physics and Chemistry & Biochemistry, The Ohio State University, Columbus, OH
| | | | | | - Krzysztof Mrózek
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Guido Marcucci
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
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