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Hashem M, Mohandesi Khosroshahi E, Aliahmady M, Ghanei M, Soofi Rezaie Y, alsadat Jafari Y, rezaei F, Khodaparast eskadehi R, Kia Kojoori K, jamshidian F, Nabavi N, Rashidi M, Hasani Sadi F, Taheriazam A, Entezari M. Non-coding RNA transcripts, incredible modulators of cisplatin chemo-resistance in bladder cancer through operating a broad spectrum of cellular processes and signaling mechanism. Noncoding RNA Res 2024; 9:560-582. [PMID: 38515791 PMCID: PMC10955558 DOI: 10.1016/j.ncrna.2024.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/12/2024] [Accepted: 01/14/2024] [Indexed: 03/23/2024] Open
Abstract
Bladder cancer (BC) is a highly frequent neoplasm in correlation with significant rate of morbidity, mortality, and cost. The onset of BC is predominantly triggered by environmental and/or occupational exposures to carcinogens, such as tobacco. There are two distinct pathways by which BC can be developed, including non-muscle-invasive papillary tumors (NMIBC) and non-papillary (or solid) muscle-invasive tumors (MIBC). The Cancer Genome Atlas project has further recognized key genetic drivers of MIBC along with its subtypes with particular properties and therapeutic responses; nonetheless, NMIBC is the predominant BC presentation among the suffering individuals. Radical cystoprostatectomy, radiotherapy, and chemotherapy have been verified to be the common therapeutic interventions in metastatic tumors, among which chemotherapeutics are more conventionally utilized. Although multiple chemo drugs have been broadly administered for BC treatment, cisplatin is reportedly the most effective chemo drug against the corresponding malignancy. Notwithstanding, tumor recurrence is usually occurred following the consumption of cisplatin regimens, particularly due to the progression of chemo-resistant trait. In this framework, non-coding RNAs (ncRNAs), as abundant RNA transcripts arise from the human genome, are introduced to serve as crucial contributors to tumor expansion and cisplatin chemo-resistance in bladder neoplasm. In the current review, we first investigated the best-known ncRNAs, i.e. microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), correlated with cisplatin chemo-resistance in BC cells and tissues. We noticed that these ncRNAs could mediate the BC-related cisplatin-resistant phenotype through diverse cellular processes and signaling mechanisms, reviewed here. Eventually, diagnostic and prognostic potential of ncRNAs, as well as their therapeutic capabilities were highlighted in regard to BC management.
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Affiliation(s)
- Mehrdad Hashem
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Mohandesi Khosroshahi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Melika Aliahmady
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Morvarid Ghanei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Yasamin Soofi Rezaie
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Yasamin alsadat Jafari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Biology, East Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Fatemeh rezaei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Biology, East Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Ramtin Khodaparast eskadehi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Biology, East Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Kimia Kia Kojoori
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Biology, East Tehran Branch, Islamic Azad University, Tehran, Iran
| | - faranak jamshidian
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Biology, East Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, V6H3Z6, Vancouver, BC, Canada
| | - Mohsen Rashidi
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Farzaneh Hasani Sadi
- General Practitioner, Kerman University of Medical Sciences, Kerman, 7616913555, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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Zheng D, Zhang Y, Yang S, Su N, Bakhoum M, Zhang G, Naderinezhad S, Mao Z, Wang Z, Zhou T, Li W. Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST. Cell Death Discov 2024; 10:246. [PMID: 38777812 PMCID: PMC11111810 DOI: 10.1038/s41420-024-02031-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 05/11/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor growth of PCa cells. As expected, ADT downregulates REST in PCa cells in culture and in mouse xenografts. Interestingly, CREB1 signaling represses REST expression. In studying the largely unclear mechanism underlying transcriptional repression of REST by ADT, we found that REST is a direct target of EZH2 epigenetic repression. Finally, genetic rescue experiments demonstrated that ADT induces NED through EZH2's repression of REST, which is enhanced by ADT-activated CREB1 signaling. In summary, our study has revealed a key pathway underlying NE gene upregulation by ADT, as well as established novel relationships between CREB1 and REST, and between EZH2 and REST, which may also have implications in other cancer types and in neurobiology.
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Affiliation(s)
- Dayong Zheng
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Oncology, Shunde Hospital, Southern Medical University, Foshan, China
- The First People's Hospital of Shunde, Foshan, China
| | - Yan Zhang
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Pain, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sukjin Yang
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ning Su
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Michael Bakhoum
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Guoliang Zhang
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Samira Naderinezhad
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
- University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Zhengmei Mao
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Zheng Wang
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ting Zhou
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Wenliang Li
- Texas Therapeutics Institute; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
- University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
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Liu J, Fan H, Liang X, Chen Y. Polycomb repressor complex: Its function in human cancer and therapeutic target strategy. Biomed Pharmacother 2023; 169:115897. [PMID: 37981459 DOI: 10.1016/j.biopha.2023.115897] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/07/2023] [Accepted: 11/13/2023] [Indexed: 11/21/2023] Open
Abstract
The Polycomb Repressor Complex (PRC) plays a pivotal role in gene regulation during development and disease, with dysregulation contributing significantly to various human cancers. The intricate interplay between PRC and cellular signaling pathways sheds light on cancer complexity. PRC presents promising therapeutic opportunities, with inhibitors undergoing rigorous evaluation in preclinical and clinical studies. In this review, we emphasize the critical role of PRC complex in gene regulation, particularly PcG proteins mediated chromatin compaction through phase separation. We also highlight the pathological implications of PRC complex dysregulation in various tumors, elucidating underlying mechanisms driving cancer progression. The burgeoning field of therapeutic strategies targeting PRC complexes, notably EZH2 inhibitors, has advanced significantly. However, we explore the need for combination therapies to enhance PRC targeted treatments efficacy, providing a glimpse into the future of cancer therapeutics.
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Affiliation(s)
- Jingrong Liu
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Hongjie Fan
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China
| | - Xinmiao Liang
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China; CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
| | - Yang Chen
- Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China; CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
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Phannasil P, Sukhuma C, Nauphar D, Nuamsee K, Svasti S. Up-regulation of microRNA 101-3p during erythropoiesis in β-thalassemia/HbE. Blood Cells Mol Dis 2023; 103:102781. [PMID: 37478523 DOI: 10.1016/j.bcmd.2023.102781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 06/18/2023] [Accepted: 07/14/2023] [Indexed: 07/23/2023]
Abstract
Ineffective erythropoiesis is the main cause of anemia in β-thalassemia. The crucial hallmark of ineffective erythropoiesis is the high proliferation of erythroblast. microRNA (miR/miRNA) involves several biological processes, including cell proliferation and erythropoiesis. miR-101 was widely studied and associated with proliferation in several types of cancer. However, the miR-101-3p has not been studied in β-thalassemia/HbE. Therefore, this study aims to investigate the expression of miR-101-3p during erythropoiesis in β-thalassemia/HbE. The results showed that miR-101-3p was upregulated in the erythroblast of β-thalassemia/HbE patients on day 7, indicating that miR-101-3p may be involved with high proliferation in β-thalassemia/HbE. Therefore, the mRNA targets of miR-101-3p including Rac1, SUB1, TET2, and TRIM44 were investigated to determine the mechanisms involved with high proliferation of β-thalassemia/HbE erythroblasts. Rac1 expression was significantly reduced at day 11 in severe β-thalassemia/HbE compared to normal controls and mild β-thalassemia/HbE. SUB1 gene expression was significantly lower in severe β-thalassemia/HbE compared to normal controls at day 9 of culture. For TET2 and TRIM44 expression, a significant difference was not observed among normal and β-thalassemia/HbE. However, the high expression of miR-101-3p at day 7 and these target genes was not correlated, suggesting that this miRNA may regulate ineffective erythropoiesis in β-thalassemia/HbE via other target genes.
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Affiliation(s)
- Phatchariya Phannasil
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Chanyanat Sukhuma
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Donny Nauphar
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand; Doctoral Program in Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta Pusat 10430, Indonesia; Department of Genetics, Faculty of Medicine, Universitas Swadaya Gunung Jati, Cirebon 45132, West-Java, Indonesia
| | - Khanita Nuamsee
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Saovaros Svasti
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand; Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
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Szczepanek J, Tretyn A. MicroRNA-Mediated Regulation of Histone-Modifying Enzymes in Cancer: Mechanisms and Therapeutic Implications. Biomolecules 2023; 13:1590. [PMID: 38002272 PMCID: PMC10669115 DOI: 10.3390/biom13111590] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/22/2023] [Accepted: 10/26/2023] [Indexed: 11/26/2023] Open
Abstract
In the past decade, significant advances in molecular research have provided a deeper understanding of the intricate regulatory mechanisms involved in carcinogenesis. MicroRNAs, short non-coding RNA sequences, exert substantial influence on gene expression by repressing translation or inducing mRNA degradation. In the context of cancer, miRNA dysregulation is prevalent and closely associated with various stages of carcinogenesis, including initiation, progression, and metastasis. One crucial aspect of the cancer phenotype is the activity of histone-modifying enzymes that govern chromatin accessibility for transcription factors, thus impacting gene expression. Recent studies have revealed that miRNAs play a significant role in modulating these histone-modifying enzymes, leading to significant implications for genes related to proliferation, differentiation, and apoptosis in cancer cells. This article provides an overview of current research on the mechanisms by which miRNAs regulate the activity of histone-modifying enzymes in the context of cancer. Both direct and indirect mechanisms through which miRNAs influence enzyme expression are discussed. Additionally, potential therapeutic implications arising from miRNA manipulation to selectively impact histone-modifying enzyme activity are presented. The insights from this analysis hold significant therapeutic promise, suggesting the utility of miRNAs as tools for the precise regulation of chromatin-related processes and gene expression. A contemporary focus on molecular regulatory mechanisms opens therapeutic pathways that can effectively influence the control of tumor cell growth and dissemination.
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Affiliation(s)
- Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, ul. Wilenska 4, 87-100 Torun, Poland
| | - Andrzej Tretyn
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, ul. Lwowska 1, 87-100 Torun, Poland;
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Li W, Zheng D, Zhang Y, Yang S, Su N, Bakhoum M, Zhang G, Naderinezhad S, Mao Z, Wang Z, Zhou T. Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST. RESEARCH SQUARE 2023:rs.3.rs-3270539. [PMID: 37886478 PMCID: PMC10602109 DOI: 10.21203/rs.3.rs-3270539/v1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor growth of PCa cells. As expected, ADT downregulates REST in PCa cells in culture and in mouse xenografts. Interestingly, CREB1 signaling represses REST expression. In studying the largely unclear mechanism underlying transcriptional repression of REST by ADT, we found that REST is a direct target of EZH2 epigenetic repression. Finally, genetic rescue experiments demonstrated that ADT induces NED through EZH2's repression of REST, which is enhanced by ADT-activated CREB signaling. In summary, our study has revealed a key pathway underlying NE gene upregulation by ADT, as well as established novel relationships between CREB1 and REST, and between EZH2 and REST, which may also have implications in other cancer types and in neurobiology.
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Affiliation(s)
- Wenliang Li
- The University of Texas Health Science Center at Houston
| | - Dayong Zheng
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University
| | - Yan Zhang
- The University of Texas Health Science Center at Houston
| | - Sukjin Yang
- The University of Texas Health Science Center at Houston
| | - Ning Su
- The University of Texas Health Science Center at Houston
| | | | - Guoliang Zhang
- Shanghai Sixth People's Hospital, Shanghai Jiaotong University
| | | | - Zhengmei Mao
- The University of Texas Health Science Center at Houston
| | - Zheng Wang
- The University of Texas Health Science Center at Houston
| | - Ting Zhou
- The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston
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Nakashiro KI, Tokuzen N, Saika M, Shirai H, Kuribayashi N, Goda H, Uchida D. MicroRNA-1289 Functions as a Novel Tumor Suppressor in Oral Squamous Cell Carcinoma. Cancers (Basel) 2023; 15:4138. [PMID: 37627167 PMCID: PMC10452613 DOI: 10.3390/cancers15164138] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/01/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Recently, numerous tumor-suppressive microRNAs (TS-miRs) have been identified in human malignancies. Here, we attempted to identify novel TS-miRs in oral squamous cell carcinoma (OSCC). First, we transfected human OSCC cells individually with 968 synthetic miRs mimicking human mature miRs individually, and the growth of these cells was evaluated using the WST-8 assay. Five miR mimics significantly reduced the cell growth rate by less than 30%, and the miR-1289 mimic had the most potent growth inhibitory effect among these miRs. Subsequently, we assessed the in vivo growth-inhibitory effects of miR-1289 using a mouse model. The administration of the miR-1289 mimic-atelocollagen complex significantly reduced the size of subcutaneously xenografted human OSCC tumors. Next, we investigated the expression of miR-1289 in OSCC tissues using reverse transcription-quantitative PCR. The expression level of miR-1289 was significantly lower in OSCC tissues than in the adjacent normal oral mucosa. Furthermore, 15 genes were identified as target genes of miR-1289 via microarray and Ingenuity Pathway Analysis (IPA) microRNA target filtering. Among these genes, the knockdown of magnesium transporter 1 (MAGT1) resulted in the most remarkable cell growth inhibition in human OSCC cells. These results suggested that miR-1289 functions as a novel TS-miR in OSCC and may be a useful therapeutic tool for patients with OSCC.
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Affiliation(s)
- Koh-ichi Nakashiro
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon 791-0295, Japan; (N.T.); (M.S.); (H.S.); (N.K.); (H.G.); (D.U.)
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Papadimitriou MA, Panoutsopoulou K, Pilala KM, Scorilas A, Avgeris M. Epi-miRNAs: Modern mediators of methylation status in human cancers. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1735. [PMID: 35580998 DOI: 10.1002/wrna.1735] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 02/01/2023]
Abstract
Methylation of the fundamental macromolecules, DNA/RNA, and proteins, is remarkably abundant, evolutionarily conserved, and functionally significant in cellular homeostasis and normal tissue/organism development. Disrupted methylation imprinting is strongly linked to loss of the physiological equilibrium and numerous human pathologies, and most importantly to carcinogenesis, tumor heterogeneity, and cancer progression. Mounting recent evidence has documented the active implication of miRNAs in the orchestration of the multicomponent cellular methylation machineries and the deregulation of methylation profile in the epigenetic, epitranscriptomic, and epiproteomic levels during cancer onset and progression. The elucidation of such regulatory networks between the miRNome and the cellular methylation machineries has led to the emergence of a novel subclass of miRNAs, namely "epi-miRNAs" or "epi-miRs." Herein, we have summarized the existing knowledge on the functional role of epi-miRs in the methylation dynamic landscape of human cancers and their clinical utility in modern cancer diagnostics and tailored therapeutics. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Maria-Alexandra Papadimitriou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantina Panoutsopoulou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Katerina-Marina Pilala
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Margaritis Avgeris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.,Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
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Li T, Yan Z, Fan Y, Fan X, Li A, Qi Z, Zhang J. Cardiac repair after myocardial infarction: A two-sided role of inflammation-mediated. Front Cardiovasc Med 2023; 9:1077290. [PMID: 36698953 PMCID: PMC9868426 DOI: 10.3389/fcvm.2022.1077290] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 12/19/2022] [Indexed: 01/11/2023] Open
Abstract
Myocardial infarction is the leading cause of death and disability worldwide, and the development of new treatments can help reduce the size of myocardial infarction and prevent adverse cardiovascular events. Cardiac repair after myocardial infarction can effectively remove necrotic tissue, induce neovascularization, and ultimately replace granulation tissue. Cardiac inflammation is the primary determinant of whether beneficial cardiac repair occurs after myocardial infarction. Immune cells mediate inflammatory responses and play a dual role in injury and protection during cardiac repair. After myocardial infarction, genetic ablation or blocking of anti-inflammatory pathways is often harmful. However, enhancing endogenous anti-inflammatory pathways or blocking endogenous pro-inflammatory pathways may improve cardiac repair after myocardial infarction. A deficiency of neutrophils or monocytes does not improve overall cardiac function after myocardial infarction but worsens it and aggravates cardiac fibrosis. Several factors are critical in regulating inflammatory genes and immune cells' phenotypes, including DNA methylation, histone modifications, and non-coding RNAs. Therefore, strict control and timely suppression of the inflammatory response, finding a balance between inflammatory cells, preventing excessive tissue degradation, and avoiding infarct expansion can effectively reduce the occurrence of adverse cardiovascular events after myocardial infarction. This article reviews the involvement of neutrophils, monocytes, macrophages, and regulatory T cells in cardiac repair after myocardial infarction. After myocardial infarction, neutrophils are the first to be recruited to the damaged site to engulf necrotic cell debris and secrete chemokines that enhance monocyte recruitment. Monocytes then infiltrate the infarct site and differentiate into macrophages and they release proteases and cytokines that are harmful to surviving myocardial cells in the pre-infarct period. As time progresses, apoptotic neutrophils are cleared, the recruitment of anti-inflammatory monocyte subsets, the polarization of macrophages toward the repair phenotype, and infiltration of regulatory T cells, which secrete anti-inflammatory factors that stimulate angiogenesis and granulation tissue formation for cardiac repair. We also explored how epigenetic modifications regulate the phenotype of inflammatory genes and immune cells to promote cardiac repair after myocardial infarction. This paper also elucidates the roles of alarmin S100A8/A9, secreted frizzled-related protein 1, and podoplanin in the inflammatory response and cardiac repair after myocardial infarction.
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Affiliation(s)
- Tingting Li
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Zhipeng Yan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yajie Fan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xinbiao Fan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Aolin Li
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhongwen Qi
- Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China,*Correspondence: Zhongwen Qi,
| | - Junping Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China,Junping Zhang,
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Awadalla A, Abol-Enein H, Hamam ET, Ahmed AE, Khirallah SM, El-Assmy A, Mostafa SA, Babalghith AO, Ali M, Abdel-Rahim M, Shokeir AA, Harraz AM. Identification of Epigenetic Interactions between miRNA and Gene Expression as Potential Prognostic Markers in Bladder Cancer. Genes (Basel) 2022; 13:genes13091629. [PMID: 36140796 PMCID: PMC9498328 DOI: 10.3390/genes13091629] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 09/03/2022] [Accepted: 09/05/2022] [Indexed: 11/20/2022] Open
Abstract
Purpose: To identify the role of a set of microRNAs and their target genes and protein expression levels in the pathogenesis of bladder cancer with a muscular invasion (T2−T4) and non-muscular invasion (T1). Methods: In 157 patients, bladder specimen was examined for the expression of a set of miRNAs including let-7a-5p, miRNA-449a-5p, miRNA-145-3P, miRNA-124-3P, miRNA-138-5p, and miRNA-23a-5p and their targeted genes; β-catenin, WNT7A, IRS2, FZD4, SOS1, HDAC1, HDAC2, HIF1α, and PTEN using the qRT-PCR technique. The prognostic effect of miRNAs and their targeted genes on cancer-specific survival (CSS) was evaluated in pT2−pT4 stages. Results: pT1 was found in 40 patients while pT2−4 was found in 117 patients. The expression of let-7a-5P, miR-124-3P, miR-449a-5P, and miR-138-5P significantly decreased in pT2−4 compared with pT1 (p < 0.001), in contrast, miR-23a-5P increased significantly in pT2−pT4 compared with pT1 (p < 0.001). Moreover, the expression of miR-145 did not show a significant change (p = 0.31). Higher expression levels of WNT7A, β-catenin, IRS2, FZD4, and SOS1 genes were observed in pT2−pT4 compared with pT1, whereas HDAC1, HDAC2, HIF1α, and PTEN genes were downregulated in pT2−pT4 compared with pT1. Lower CSS was significantly associated with lower expression of let-7a-5P, miR-124-3P, miR-449a-5P, and miR-138-5P. Higher expression of β-catenin, FZD4, IRS2, WNT7a, and SOS1 was significantly associated with worse CSS. In contrast, lower levels of HDAC1, HDAC2, HIF1α, and PTEN were associated with lower CSS. Conclusion: Our results support let-7a-5P, miR-124-3P, miR-138-5P, and their target genes can be developed as accurate biomarkers for prognosis in bladder cancer with a muscular invasion.
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Affiliation(s)
- Amira Awadalla
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Hassan Abol-Enein
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Eman T. Hamam
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Asmaa E. Ahmed
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Salma M. Khirallah
- Biochemistry Division, Chemistry Department, Faculty of Science, Port Said University, Port Said 42526, Egypt
| | - Ahmed El-Assmy
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Sally Abdallah Mostafa
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Ahmed O. Babalghith
- Medical Genetics Department, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mohamed Ali
- Biochemistry Division, Chemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
| | - Mona Abdel-Rahim
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Ahmed A. Shokeir
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
- Correspondence: ; Tel.: +20-50-2202222; Fax: +20-50-2202717
| | - Ahmed M. Harraz
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
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11
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Dudakovic A, Jerez S, Deosthale PJ, Denbeigh JM, Paradise CR, Gluscevic M, Zan P, Begun DL, Camilleri ET, Pichurin O, Khani F, Thaler R, Lian JB, Stein GS, Westendorf JJ, Plotkin LI, van Wijnen AJ. MicroRNA-101a enhances trabecular bone accrual in male mice. Sci Rep 2022; 12:13361. [PMID: 35922466 PMCID: PMC9349183 DOI: 10.1038/s41598-022-17579-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 07/27/2022] [Indexed: 11/09/2022] Open
Abstract
High-throughput microRNA sequencing was performed during differentiation of MC3T3-E1 osteoblasts to develop working hypotheses for specific microRNAs that control osteogenesis. The expression data show that miR-101a, which targets the mRNAs for the epigenetic enzyme Ezh2 and many other proteins, is highly upregulated during osteoblast differentiation and robustly expressed in mouse calvaria. Transient elevation of miR-101a suppresses Ezh2 levels, reduces tri-methylation of lysine 27 in histone 3 (H3K27me3; a heterochromatic mark catalyzed by Ezh2), and accelerates mineralization of MC3T3-E1 osteoblasts. We also examined skeletal phenotypes of an inducible miR-101a transgene under direct control of doxycycline administration. Experimental controls and mir-101a over-expressing mice were exposed to doxycycline in utero and postnatally (up to 8 weeks of age) to maximize penetrance of skeletal phenotypes. Male mice that over-express miR-101a have increased total body weight and longer femora. MicroCT analysis indicate that these mice have increased trabecular bone volume fraction, trabecular number and trabecular thickness with reduced trabecular spacing as compared to controls. Histomorphometric analysis demonstrates a significant reduction in osteoid volume to bone volume and osteoid surface to bone surface. Remarkably, while female mice also exhibit a significant increase in bone length, no significant changes were noted by microCT (trabecular bone parameters) and histomorphometry (osteoid parameters). Hence, miR-101a upregulation during osteoblast maturation and the concomitant reduction in Ezh2 mediated H3K27me3 levels may contribute to the enhanced trabecular bone parameters in male mice. However, the sex-specific effect of miR-101a indicates that more intricate epigenetic mechanisms mediate physiological control of bone formation and homeostasis.
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Affiliation(s)
- Amel Dudakovic
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.
- Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN, USA.
| | - Sofia Jerez
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Padmini J Deosthale
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Janet M Denbeigh
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Christopher R Paradise
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
| | - Martina Gluscevic
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
| | - Pengfei Zan
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Orthopedic Surgery, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, China
- Department of Orthopedic Surgery, School of Medicine, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Dana L Begun
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | | | - Oksana Pichurin
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Farzaneh Khani
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Roman Thaler
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Jane B Lian
- Department of Biochemistry, University of Vermont, Burlington, VT, USA
| | - Gary S Stein
- Department of Biochemistry, University of Vermont, Burlington, VT, USA
| | - Jennifer J Westendorf
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Lilian I Plotkin
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA.
- Richard L Roudebush VA Medical Center, Indianapolis, IN, USA.
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12
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Qu J, Wu X, Wang Q, Wang J, Sun X, Ji D, Li Y. Effect of miR-101 on the Proliferation and Apoptosis of Goat Hair Follicle Stem Cells. Genes (Basel) 2022; 13:genes13061035. [PMID: 35741797 PMCID: PMC9222262 DOI: 10.3390/genes13061035] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/25/2022] [Accepted: 06/02/2022] [Indexed: 02/04/2023] Open
Abstract
The Yangtze River Delta white goat is a rare goat species capable of producing high-quality brush hair. Dual specificity protein phosphatase 1 (DUSP1) may play a role in the formation of high-quality brush hair, as evidenced by our previous research. We investigated the potential mechanisms that regulate the proliferation and apoptosis of goat hair follicle stem cells. We particularly focused on the relationship between DUSP1 and miR-101, which directly targets DUSP1, predicted and screened through bioinformatics websites. Then, fluorescence assays, flow cytometry, RT-qPCR, and Western blotting were used to investigate the effects of miR-101 on the proliferation and apoptosis of hair follicle stem cells. We found that miR-101 overexpression significantly decreased (p < 0.01) apoptosis and promoted the proliferation of hair follicle stem cells. Furthermore, the overexpression of miR-101 increased (p < 0.05) the mRNA and protein expression levels of the proliferation-related gene (PCNA) and anti-apoptotic gene (Bcl-2), and it decreased (p < 0.05) the mRNA and protein expression levels of the apoptotic gene (Bax). In conclusion, miR-101 can promote the proliferation of and inhibit the apoptosis of hair follicle stem cells by targeting DUSP1, which provides a theoretical basis for further elucidating the molecular mechanism that regulates the production of high-quality brush hair of Yangtze River Delta white goats.
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Affiliation(s)
| | | | | | | | | | | | - Yongjun Li
- Correspondence: ; Tel.: +86-514-8799-6481
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13
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Rojas-Pirela M, Andrade-Alviárez D, Medina L, Castillo C, Liempi A, Guerrero-Muñoz J, Ortega Y, Maya JD, Rojas V, Quiñones W, Michels PA, Kemmerling U. MicroRNAs: master regulators in host-parasitic protist interactions. Open Biol 2022; 12:210395. [PMID: 35702995 PMCID: PMC9198802 DOI: 10.1098/rsob.210395] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNAs present in a wide diversity of organisms. MiRNAs regulate gene expression at a post-transcriptional level through their interaction with the 3' untranslated regions of target mRNAs, inducing translational inhibition or mRNA destabilization and degradation. Thus, miRNAs regulate key biological processes, such as cell death, signal transduction, development, cellular proliferation and differentiation. The dysregulation of miRNAs biogenesis and function is related to the pathogenesis of diseases, including parasite infection. Moreover, during host-parasite interactions, parasites and host miRNAs determine the probability of infection and progression of the disease. The present review is focused on the possible role of miRNAs in the pathogenesis of diseases of clinical interest caused by parasitic protists. In addition, the potential role of miRNAs as targets for the design of drugs and diagnostic and prognostic markers of parasitic diseases is also discussed.
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Affiliation(s)
- Maura Rojas-Pirela
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile,Instituto de Biología, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, Chile,Facultad de Farmacia y Bioanálisis, Universidad de Los Andes, Mérida, Venezuela
| | - Diego Andrade-Alviárez
- Laboratorio de Enzimología de Parásitos, Facultad de Ciencias, Universidad de Los Andes, Mérida, Venezuela
| | - Lisvaneth Medina
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
| | - Christian Castillo
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile,Núcleo de Investigación Aplicada en Ciencias Veterinarias y Agronómicas, Facultad de Medicina Veterinaria y Agronomía, Universidad de Las Américas, Chile
| | - Ana Liempi
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
| | - Jesús Guerrero-Muñoz
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
| | - Yessica Ortega
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile,Facultad de Farmacia y Bioanálisis, Universidad de Los Andes, Mérida, Venezuela
| | - Juan Diego Maya
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
| | - Verónica Rojas
- Instituto de Biología, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, Chile
| | - Wilfredo Quiñones
- Laboratorio de Enzimología de Parásitos, Facultad de Ciencias, Universidad de Los Andes, Mérida, Venezuela
| | - Paul A. Michels
- Centre for Immunity, Infection and Evolution and Centre for Translational and Chemical Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh EH9 3FL, UK
| | - Ulrike Kemmerling
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
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14
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Liu T, Li T, Zheng Y, Xu X, Sun R, Zhan S, Guo X, Zhao Z, Zhu W, Feng B, Wei F, Jiang N, Wang J, Chen X, Fang F, Guo H, Yang R. Evaluating adipose-derived stem cell exosomes as miRNA drug delivery systems for the treatment of bladder cancer. Cancer Med 2022; 11:3687-3699. [PMID: 35441482 PMCID: PMC9554444 DOI: 10.1002/cam4.4745] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/10/2022] [Accepted: 03/31/2022] [Indexed: 12/24/2022] Open
Abstract
Objectives Exosomes are essential mediators of intercellular communication as they transport proteins and RNAs between cells. Owing to their tumor‐targeting capacity, immune compatibility, low toxicity, and long half‐life, mesenchymal stem cell‐derived exosomes have great potential for the development of novel antitumor strategies. In this context, the role of exosomes produced by adipose‐derived mesenchymal stem cells (ADSCs) for the treatment of bladder cancer (BC) remains unclear. Here, we investigated the use of ADSCs as a source of therapeutic exosomes, as well as their efficacy in delivering the tumor suppressor miR‐138‐5p in BC. Methods ADSCs stably expressing miR‐138‐5p were established using Lentivirus infection, and ADSC‐derived miR‐138‐5p exosomes (Exo‐miR‐138‐5p) were isolated from the cell culture medium. The effect of Exo‐miR‐138‐5p on BC cell migration, invasion, and proliferation was evaluated in vitro using wound healing, transwell invasion, and proliferation assays. The in vivo effect of Exo‐miR‐138‐5p was investigated using a subcutaneous xenograft mouse model. Results Exo‐miR‐138‐5p prevented the migration, invasion, and proliferation of BC cells in vitro. Moreover, ADSC‐derived exosomes could penetrate tumor tissues and successfully deliver miR‐138‐5p to suppress the growth of xenograft tumors in vivo. Conclusions The present results reveal that ADSC‐derived exosomes are an effective delivery vehicle for small molecule drugs in vivo, and exosome‐delivered miR‐138‐5p is a promising therapeutic agent for BC treatment.
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Affiliation(s)
- Tianyao Liu
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Tianhang Li
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yufeng Zheng
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Xinyan Xu
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Rui Sun
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Shoubin Zhan
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Xu Guo
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Zihan Zhao
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Wenjie Zhu
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Baofu Feng
- Department of Urology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Fayun Wei
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Ning Jiang
- Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, China
| | - Jin Wang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Xi Chen
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Feng Fang
- Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Hongqian Guo
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Rong Yang
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
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15
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Natural Bioactive Compounds Targeting Histone Deacetylases in Human Cancers: Recent Updates. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27082568. [PMID: 35458763 PMCID: PMC9027183 DOI: 10.3390/molecules27082568] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 12/13/2022]
Abstract
Cancer is a complex pathology that causes a large number of deaths worldwide. Several risk factors are involved in tumor transformation, including epigenetic factors. These factors are a set of changes that do not affect the DNA sequence, while modifying the gene’s expression. Histone modification is an essential mark in maintaining cellular memory and, therefore, loss of this mark can lead to tumor transformation. As these epigenetic changes are reversible, the use of molecules that can restore the functions of the enzymes responsible for the changes is therapeutically necessary. Natural molecules, mainly those isolated from medicinal plants, have demonstrated significant inhibitory properties against enzymes related to histone modifications, particularly histone deacetylases (HDACs). Flavonoids, terpenoids, phenolic acids, and alkaloids exert significant inhibitory effects against HDAC and exhibit promising epi-drug properties. This suggests that epi-drugs against HDAC could prevent and treat various human cancers. Accordingly, the present study aimed to evaluate the pharmacodynamic action of different natural compounds extracted from medicinal plants against the enzymatic activity of HDAC.
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16
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Shigeta S, Watanabe Y, Suzuki F, Nagase S, Shibuya Y, Ishibashi M, Nagai T, Shiga N, Toyoshima M, Tokunaga H, Shimada M, Yaegashi N. MicroRNA-152 Regulates Endometrial Serous Carcinoma Cell Motility by Suppressing Matrix Metalloproteinase 10 Expression. TOHOKU J EXP MED 2022; 256:249-258. [DOI: 10.1620/tjem.256.249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Shogo Shigeta
- Department of Obstetrics and Gynecology, Tohoku University School of Medicine
| | - Yoh Watanabe
- Division of Obstetrics and Gynecology, Tohoku Medical and Pharmaceutical University
| | - Fumihiko Suzuki
- Department of Obstetrics and Gynecology, Tohoku University School of Medicine
| | - Satoru Nagase
- Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine
| | - Yusuke Shibuya
- Department of Obstetrics and Gynecology, Tohoku University School of Medicine
| | - Masumi Ishibashi
- Department of Obstetrics and Gynecology, Tohoku University School of Medicine
| | - Tomoyuki Nagai
- Department of Obstetrics and Gynecology, Tohoku University School of Medicine
| | - Naomi Shiga
- Department of Obstetrics and Gynecology, Tohoku University School of Medicine
| | | | - Hideki Tokunaga
- Department of Obstetrics and Gynecology, Tohoku University School of Medicine
| | - Muneaki Shimada
- Department of Obstetrics and Gynecology, Tohoku University School of Medicine
| | - Nobuo Yaegashi
- Department of Obstetrics and Gynecology, Tohoku University School of Medicine
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17
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The Role of DNA Methylation and DNA Methyltransferases in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1389:317-348. [DOI: 10.1007/978-3-031-11454-0_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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18
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Ziemann M, Lim SC, Kang Y, Samuel S, Sanchez IL, Gantier M, Stojanovski D, McKenzie M. MicroRNA-101-3p Modulates Mitochondrial Metabolism via the Regulation of Complex II Assembly. J Mol Biol 2021; 434:167361. [PMID: 34808225 DOI: 10.1016/j.jmb.2021.167361] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/17/2021] [Accepted: 11/11/2021] [Indexed: 12/27/2022]
Abstract
MicroRNA-101-3p (miR-101-3p) is a tumour suppressor that regulates cancer proliferation and apoptotic signalling. Loss of miR-101-3p increases the expression of the Polycomb Repressive Complex 2 (PRC2) subunit enhancer of zeste homolog 2 (EZH2), resulting in alterations to the epigenome and enhanced tumorigenesis. MiR-101-3p has also been shown to modulate various aspects of cellular metabolism, however little is known about the mechanisms involved. To investigate the metabolic pathways that are regulated by miR-101-3p, we performed transcriptome and functional analyses of osteosarcoma cells transfected with miR-101-3p. We found that miR-101-3p downregulates multiple mitochondrial processes, including oxidative phosphorylation, pyruvate metabolism, the citric acid cycle and phospholipid metabolism. We also found that miR-101-3p transfection disrupts the transcription of mitochondrial DNA (mtDNA) via the downregulation of the mitochondrial transcription initiation complex proteins TFB2M and Mic60. These alterations in transcript expression disrupt mitochondrial function, with significant decreases in both basal (54%) and maximal (67%) mitochondrial respiration rates. Native gel electrophoresis revealed that this diminished respiratory capacity was associated with reduced steady-state levels of mature succinate dehydrogenase (complex II), with a corresponding reduction of complex II enzymatic activity. Furthermore, miR-101-3p transfection reduced the expression of the SDHB subunit, with a concomitant disruption of the assembly of the SDHC subunit into mature complex II. Overall, we describe a new role for miR-101-3p as a modulator of mitochondrial metabolism via its regulation of multiple mitochondrial processes, including mtDNA transcription and complex II biogenesis.
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Affiliation(s)
- Mark Ziemann
- School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 3216 Geelong, Australia. https://twitter.com/@mdziemann
| | - Sze Chern Lim
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 3168 Melbourne, Australia
| | - Yilin Kang
- Department of Biochemistry and Pharmacology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 3052 Melbourne, Australia
| | - Sona Samuel
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria 3002, Australia
| | - Isabel Lopez Sanchez
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria 3002, Australia; Ophthalmology, University of Melbourne, Department of Surgery Melbourne, Victoria 3000, Australia. https://twitter.com/@DrIsabelLopez
| | - Michael Gantier
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 3168 Melbourne, Australia; Department of Molecular and Translational Science, Monash University, 3168 Melbourne, Australia. https://twitter.com/@GantierLab
| | - Diana Stojanovski
- Department of Biochemistry and Pharmacology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 3052 Melbourne, Australia
| | - Matthew McKenzie
- School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 3216 Geelong, Australia; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 3168 Melbourne, Australia; Department of Molecular and Translational Science, Monash University, 3168 Melbourne, Australia.
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19
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Dong L, Huang J, Zu P, Liu J, Gao X, Du J, Li Y. Transcription factor 3 (TCF3) combined with histone deacetylase 3 (HDAC3) down-regulates microRNA-101 to promote Burkitt lymphoma cell proliferation and inhibit apoptosis. Bioengineered 2021; 12:7995-8005. [PMID: 34658308 PMCID: PMC8806859 DOI: 10.1080/21655979.2021.1977557] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
To explore the function of transcription factor 3 (TCF3) on the proliferation and apoptosis of Burkitt lymphoma cells and its mechanism. qRT-PCR was performed to determine the expression of TCF3, histone deacetylase 3 (HDAC3), and microRNA-101 (miR-101) in the Burkitt lymphoma (BL) tumor tissues and lymph node tissues with reactive lymph node hyperplasia (RLNH). We found that the expression of TCF3 and HDAC3 was up-regulated in BL tumor tissues and lymphoma cells, and the miR-101 expression was down-regulated. And TCF3 and HDAC3 were negatively correlated with the expression of miR-101, respectively. In addition, knockdown of TCF3 can inhibit BL cell proliferation, reduce cell viability and promote cell apoptosis, retain the cell cycle in the G0/G1 phase, and inhibit the expression of Akt/mTOR pathway-related proteins (p-Akt and p-mTOR). When miR-101 was overexpressed, the results were the same as when TCF3 was knocked down. Moreover, we used Co-immunoprecipitation (Co-IP) to detect the interaction between TCF3 and HDAC3, and performed the Chromatin immunoprecipitation (ChIP) experiment to detect the enrichment of TCF3 and HDAC3 in the promoter region of miR-101. We found that TCF3 can interact with HDAC3 and is enriched in the miR-101 promoter region. In conclusion, TCF3 combined with HDAC3 down-regulates the expression of miR-101, thereby promoting the proliferation of BL cells and inhibiting their apoptosis.
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Affiliation(s)
- Lihua Dong
- Department of Hematology, Henan Institute of Hematology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Jingjing Huang
- Department of Hematology, Henan Institute of Hematology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Peng Zu
- Department of Hematology, Henan Institute of Hematology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Jing Liu
- Department of Hematology, Henan Institute of Hematology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Xue Gao
- Department of Hematology, Henan Institute of Hematology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Jianwei Du
- Department of Hematology, Henan Institute of Hematology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Yufu Li
- Department of Hematology, Henan Institute of Hematology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
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20
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Yang A, Peng F, Zhu L, Li X, Ou S, Huang Z, Wu S, Peng C, Liu P, Kong Y. Melatonin inhibits triple-negative breast cancer progression through the Lnc049808-FUNDC1 pathway. Cell Death Dis 2021; 12:712. [PMID: 34272359 PMCID: PMC8285388 DOI: 10.1038/s41419-021-04006-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 07/06/2021] [Accepted: 07/06/2021] [Indexed: 12/20/2022]
Abstract
Melatonin has been reported to have tumor-suppressive effects via comprehensive molecular mechanisms, and long non-coding RNAs (lncRNAs) may participate in this process. However, the mechanism by which melatonin affects the function of lncRNAs in triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is still unknown. Therefore, we aimed to investigate the differentially expressed mRNAs and lncRNAs in melatonin-treated TNBC cells and the interaction mechanisms. Microarray analyses were performed to identify differentially expressed mRNAs and lncRNAs in TNBC cell lines after melatonin treatment. To explore the functions and underlying mechanisms of the mRNAs and lncRNAs candidates, a series of in vitro experiments were conducted, including CCK-8, Transwell, colony formation, luciferase reporter gene, and RNA immunoprecipitation (RIP) assays, and mouse xenograft models were established. We found that after melatonin treatment, FUNDC1 and lnc049808 downregulated in TNBC cell lines. Knockdown of FUNDC1 and lnc049808 inhibited TNBC cell proliferation, invasion, and metastasis. Moreover, lnc049808 and FUNDC1 acted as competing endogenous RNAs (ceRNAs) for binding to miR-101. These findings indicated that melatonin inhibited TNBC progression through the lnc049808-FUNDC1 pathway and melatonin could be used as a potential therapeutic agent for TNBC.
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Affiliation(s)
- Anli Yang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Fu Peng
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, P. R. China.,West China School of Pharmacy, Sichuan University, Chengdu, P. R. China
| | - Lewei Zhu
- Department of Breast Surgery, The First People's Hospital, Foshan, Guangdong, People's Republic of China
| | - Xing Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Shunling Ou
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Zhongying Huang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Song Wu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Cheng Peng
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, P. R. China.
| | - Peng Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China.
| | - Yanan Kong
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China.
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21
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Saran U, Chandrasekaran B, Kolluru V, Tyagi A, Nguyen KD, Valadon CL, Shaheen SP, Kong M, Poddar T, Ankem MK, Damodaran C. Diagnostic molecular markers predicting aggressive potential in low-grade prostate cancer. Transl Res 2021; 231:92-101. [PMID: 33279680 DOI: 10.1016/j.trsl.2020.11.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 11/05/2020] [Accepted: 11/30/2020] [Indexed: 12/14/2022]
Abstract
Currently, clinicians rely on clinical nomograms to stratify progression risk at the time of diagnosis in patients with prostate cancer (CaP). However, these tools may not accurately distinguish aggressive potential in low-grade CaP. The current study determined the diagnostic potential of 3 molecular markers (ROCK1, RUNX3, and miR-301a) in terms of their ability to identify which low-grade tumors are likely to progress. Real-time PCR and immunohistochemical analysis were used to assess ROCK1, RUNX3, and miR-301a expression profiles in 118 serum and needle biopsy specimens. Expressions of ROCK1 and miR-301a were found to be significantly higher in Gleason 6 and 7 CaP as compared to BPH, while an inverse trend was observed with RUNX3. Further, incorporation of all 3 molecular markers significantly improved clinical nomograms' diagnostic accuracy and correlated with disease progression. Hence, in conclusion, the inclusion of these 3 molecular markers identified aggressive phenotype and predicted disease progression in low-grade CaP tumors at the time of diagnosis.
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Affiliation(s)
- Uttara Saran
- Department of Urology, University of Louisville, Louisville, KY
| | | | | | - Ashish Tyagi
- Department of Urology, University of Louisville, Louisville, KY
| | - Kristy D Nguyen
- Department of Urology, University of Louisville, Louisville, KY
| | | | - Saad P Shaheen
- Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY
| | | | | | - Murali K Ankem
- Department of Urology, University of Louisville, Louisville, KY
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22
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Singh M, Kumar V, Sehrawat N, Yadav M, Chaudhary M, Upadhyay SK, Kumar S, Sharma V, Kumar S, Dilbaghi N, Sharma AK. Current paradigms in epigenetic anticancer therapeutics and future challenges. Semin Cancer Biol 2021; 83:422-440. [PMID: 33766649 DOI: 10.1016/j.semcancer.2021.03.013] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/14/2020] [Accepted: 03/16/2021] [Indexed: 12/16/2022]
Abstract
Any alteration at the genetic or epigenetic level, may result in multiplex of diseases including tumorigenesis which ultimately results in the cancer development. Restoration of the normal epigenome by reversing the epigenetic alterations have been reported in tumors paving the way for development of an effective epigenetic treatment in cancer. However, delineating various epigenetic events has been a challenging task so far despite substantial progress in understanding DNA methylation and histone modifications during transcription of genes. Many inhibitors in the form of epigenetic drugs mostly targeting chromatin and histone modifying enzymes including DNA methyltransferase (DNMT) enzyme inhibitors and a histone deacetylases (HDACs) inhibitor, have been in use subsequent to the approval by FDA for cancer treatment. Similarly, other inhibitory drugs, such as FK228, suberoylanilide hydroxamic acid (SAHA) and MS-275, have been successfully tested in clinical studies. Despite all these advancements, still we see a hazy view as far as a promising epigenetic anticancer therapy is concerned. The challenges are to have more specific and effective inhibitors with negligible side effects. Moreover, the alterations seen in tumors are not well understood for which one has to gain deeper insight into the tumor pathology as well. Current review focusses on such epigenetic alterations occurring in cancer and the effective strategies to utilize such alterations for potential therapeutic use and treatment in cancer.
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Affiliation(s)
- Manoj Singh
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Vikas Kumar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Nirmala Sehrawat
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Mukesh Yadav
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Mayank Chaudhary
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Sushil K Upadhyay
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Sunil Kumar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India
| | - Varruchi Sharma
- Department of Biotechnology, Sri Guru Gobind Singh College Sector-26, Chandigarh, UT, 160019, India
| | - Sandeep Kumar
- Department of Bio& Nanotechnology, Guru Jambheshwar University of Science & Technology, Hisar, Haryana, 125001, India
| | - Neeraj Dilbaghi
- Department of Bio& Nanotechnology, Guru Jambheshwar University of Science & Technology, Hisar, Haryana, 125001, India
| | - Anil K Sharma
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, 133207, Haryana, India.
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23
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Clinton SM, Shupe EA, Glover ME, Unroe KA, McCoy CR, Cohen JL, Kerman IA. Modeling heritability of temperamental differences, stress reactivity, and risk for anxiety and depression: Relevance to research domain criteria (RDoC). Eur J Neurosci 2021; 55:2076-2107. [PMID: 33629390 PMCID: PMC8382785 DOI: 10.1111/ejn.15158] [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: 11/04/2020] [Revised: 01/29/2021] [Accepted: 02/20/2021] [Indexed: 01/04/2023]
Abstract
Animal models provide important tools to study biological and environmental factors that shape brain function and behavior. These models can be effectively leveraged by drawing on concepts from the National Institute of Mental Health Research Domain Criteria (RDoC) Initiative, which aims to delineate molecular pathways and neural circuits that underpin behavioral anomalies that transcend psychiatric conditions. To study factors that contribute to individual differences in emotionality and stress reactivity, our laboratory utilized Sprague-Dawley rats that were selectively bred for differences in novelty exploration. Selective breeding for low versus high locomotor response to novelty produced rat lines that differ in behavioral domains relevant to anxiety and depression, particularly the RDoC Negative Valence domains, including acute threat, potential threat, and loss. Bred Low Novelty Responder (LR) rats, relative to their High Responder (HR) counterparts, display high levels of behavioral inhibition, conditioned and unconditioned fear, avoidance, passive stress coping, anhedonia, and psychomotor retardation. The HR/LR traits are heritable, emerge in the first weeks of life, and appear to be driven by alterations in the developing amygdala and hippocampus. Epigenomic and transcriptomic profiling in the developing and adult HR/LR brain suggest that DNA methylation and microRNAs, as well as differences in monoaminergic transmission (dopamine and serotonin in particular), contribute to their distinct behavioral phenotypes. This work exemplifies ways that animal models such as the HR/LR rats can be effectively used to study neural and molecular factors driving emotional behavior, which may pave the way toward improved understanding the neurobiological mechanisms involved in emotional disorders.
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Affiliation(s)
- Sarah M Clinton
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Elizabeth A Shupe
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Matthew E Glover
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Keaton A Unroe
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Chelsea R McCoy
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Joshua L Cohen
- Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, USA
| | - Ilan A Kerman
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.,Behavioral Health Service Line, Veterans Affairs Pittsburgh Health System, Pittsburgh, PA, USA
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24
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Fernández-Ponce C, Navarro Quiroz R, Díaz Perez A, Aroca Martinez G, Cadena Bonfanti A, Acosta Hoyos A, Gómez Escorcia L, Hernández Agudelo S, Orozco Sánchez C, Villarreal Camacho J, Atencio Ibarra L, Consuegra Machado J, Espinoza Garavito A, García-Cózar F, Navarro Quiroz E. MicroRNAs overexpressed in Crohn's disease and their interactions with mechanisms of epigenetic regulation explain novel aspects of Crohn's disease pathogenesis. Clin Epigenetics 2021; 13:39. [PMID: 33602320 PMCID: PMC7890887 DOI: 10.1186/s13148-021-01022-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/02/2021] [Indexed: 12/14/2022] Open
Abstract
Background In this review, we were interested to identify the wide universe of enzymes associated with epigenetic modifications, whose gene expression is regulated by miRNAs with a high relative abundance in Crohn's disease (CD) affected tissues, with the aim to determine their impact in the pathogenesis and evolution of the disease. Methods We used HMDD and Bibliometrix R-package in order to identify the miRNAs overexpressed in CD. The identified enzymes associated with epigenetic mechanisms and post-translational modifications, regulated by miRNAs upregulated in CD, were analyzed using String v11 database. Results We found 190 miRNAs with great abundance in patients with CD, of which 26 miRNAs regulate the gene expression of enzymes known to catalyze epigenetic modifications involved in essentials pathophysiological processes, such as chromatin architecture reorganization, immune response regulation including CD4+ T cells polarization, integrity of gut mucosa, gut microbiota composition and tumorigenesis. Conclusion The integrated analysis of miRNAs with a high relative abundance in patients with CD showed a combined and superimposed gene expression regulation of enzymes associated with relevant epigenetic mechanisms and that could explain, in part, the pathogenesis of CD. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-021-01022-8.
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Affiliation(s)
- Cecilia Fernández-Ponce
- Department of Biomedicine, Biotechnology and Public Health, University of Cadiz, Cadiz, Spain
| | - Roberto Navarro Quiroz
- CMCC-Centro de Matemática, Computação E Cognição, Laboratório do Biología Computacional e Bioinformática-LBCB, Universidade Federal Do ABC, Sao Paulo, 01023, Brazil
| | - Anderson Díaz Perez
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Universidad Rafael Nuñez, 130001, Cartagena, Colombia
| | - Gustavo Aroca Martinez
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Department of Nephrology, Clinica de La Costa, 080001, Barranquilla, Colombia
| | - Andrés Cadena Bonfanti
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Department of Nephrology, Clinica de La Costa, 080001, Barranquilla, Colombia
| | - Antonio Acosta Hoyos
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia
| | - Lorena Gómez Escorcia
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Universidad Rafael Nuñez, 130001, Cartagena, Colombia
| | - Sandra Hernández Agudelo
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Department of Nephrology, Clinica de La Costa, 080001, Barranquilla, Colombia
| | - Christian Orozco Sánchez
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia
| | | | | | | | - Alberto Espinoza Garavito
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia
| | - Francisco García-Cózar
- Department of Biomedicine, Biotechnology and Public Health, University of Cadiz, Cadiz, Spain
| | - Elkin Navarro Quiroz
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia. .,Centro de Investigación E Innovación en Biomoléculas, C4U S.A.S, 080001, Barranquilla, Colombia.
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25
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Rehman S, Aatif M, Rafi Z, Khan MY, Shahab U, Ahmad S, Farhan M. Effect of non-enzymatic glycosylation in the epigenetics of cancer. Semin Cancer Biol 2020; 83:543-555. [DOI: 10.1016/j.semcancer.2020.11.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/24/2020] [Accepted: 11/25/2020] [Indexed: 02/09/2023]
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26
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Parizi PK, Yarahmadi F, Tabar HM, Hosseini Z, Sarli A, Kia N, Tafazoli A, Esmaeili SA. MicroRNAs and target molecules in bladder cancer. Med Oncol 2020; 37:118. [PMID: 33216248 DOI: 10.1007/s12032-020-01435-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023]
Abstract
Bladder cancer (BC) is considered as one of the most common malignant tumors in humans with complex pathogenesis including gene expression variation, protein degradation, and changes in signaling pathways. Many studies on involved miRNAs in BC have demonstrated that they could be used as potential biomarkers in the prognosis, response to treatment, and screening before the cancerous phenotype onset. MicroRNAs (miRNAs) regulate many cellular processes through their different effects on special targets along with modifying signaling pathways, apoptosis, cell growth, and differentiation. The diverse expression of miRNAs in cancerous tissues could mediate procedures leading to the oncogenic or suppressor behavior of certain genes in cancer cells. Since a specific miRNA may have multiple targets, an mRNA could also be regulated by multiple miRNAs which further demonstrates the actual role of miRNAs in cancer. In addition, miRNAs can be utilized as biomarkers in some cancers that cannot be screened in the early stages. Hence, finding blood, urine, or tissue miRNA biomarkers by novel or routine gene expression method could be an essential step in the prognosis and control of cancer. In the present review, we have thoroughly evaluated the recent findings on different miRNAs in BC which can provide comprehensive information on better understanding the role of diverse miRNAs and better decision making regarding the new approaches in the diagnosis, prognosis, prevention, and treatment of BC.
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Affiliation(s)
- Payam Kheirmand Parizi
- Cellular, Molecular and Genetics Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.,Genome Medical Genetics Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | | | - Zohreh Hosseini
- Faculty of Veterinary Medicine, Shahid Chamran University, Ahvaz, Iran
| | - Abdolazim Sarli
- Department of Medical Genetic, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Nadia Kia
- Agostino Gemelli University Hospital, Torvergata University of Medical Sciences, Rome, Italy
| | - Alireza Tafazoli
- Department of Analysis and Bioanalysis of Medicines, Faculty of Pharmacy With the Division of Laboratory Medicine, Medical University of Bialystok, Bialystok, Poland.,Clinical Research Center, Medical University of Bialystok, Bialystok, Poland
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. .,Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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27
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Setti Boubaker N, Gurtner A, Trabelsi N, Manni I, Ayed H, Saadi A, Naimi Z, Ksontini M, Ayadi M, Blel A, Rammeh S, Chebil M, Piaggio G, Ouerhani S. Uncovering the expression patterns and the clinical significance of miR-182, miR-205, miR-27a and miR-369 in patients with urinary bladder cancer. Mol Biol Rep 2020; 47:8819-8830. [PMID: 33128684 DOI: 10.1007/s11033-020-05932-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 10/17/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND Given the high recurrence and progression rates and the absence of reliable markers for early detection and prognosis prediction of patients with urothelial bladder cancer (BCa), the exploration of new biomarkers with high specificity is imperative. Mainly, microRNAs (miRNAs), which are involved in the initiation and the progression of BCa. Herein, the expression patterns of miR-182, miR-205, miR-27a and miR-369 were evaluated in patients with urothelial BCa. METHODS AND RESULTS The expression levels of the miRNAs were investigated in 90 FFPE tissue samples (23 LG NMIBC, 44 HG NMIBC, 23 MIBC) and 10 non tumoral bladder tissues using TaqMan based RT-qPCR. Data analysis was performed using 2-ΔΔCT method. Correlation to clinical characteristics of the patients was performed using descriptive statistics and the receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic value of all miRNAs. MiR-27a, miR-205 and miR-369 were down-regulated whereas miR-182 was up-regulated in patients compared to controls (p < 0.001). MiR-205 and miR-182 positively segregate between NMIBC and MIBC (p = 0.002 and p = 0.000 respectively) whereas the distribution of miR-27a's expression among these tumor groups was almost significant (p = 0.05) and that of miR-369's expression was irrelevant (p = 0.618). Interestingly, miR-182 was discriminative between LG NMIBC and HG NMIBC (p < 0.001) and Ta/T1 tumors (p = 0.000). Furthermore, high levels of miR-182 were potentially predictive of progression in NMIBC patients (p = 0.01). CONCLUSION Collectively, a selection of miRNAs was found to be aberrantly expressed in BCa suggesting a potential diagnostic value in BCa. In addition, the clinical value of miR-182 and miR-205 as potential prognosis biomarkers was highlighted. Indeed, our data provide additional insights into cancer biology. Further functional or target studies are mandatory to strengthen these findings.
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Affiliation(s)
- Nouha Setti Boubaker
- Laboratory of proteins engineering and bioactive molecules (LIP-MB), INSAT, University of Tunis Carthage, Tunis, Tunisia.
- UOSD SAFU, Department of Research, Diagnosis and Innovative Technologies, IRCCS-Regina Elena National Cancer Institute, Rome, Italy.
| | - Aymone Gurtner
- UOSD SAFU, Department of Research, Diagnosis and Innovative Technologies, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
- Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Nesrine Trabelsi
- Laboratory of proteins engineering and bioactive molecules (LIP-MB), INSAT, University of Tunis Carthage, Tunis, Tunisia
| | - Isabella Manni
- UOSD SAFU, Department of Research, Diagnosis and Innovative Technologies, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | - Haroun Ayed
- Laboratory of proteins engineering and bioactive molecules (LIP-MB), INSAT, University of Tunis Carthage, Tunis, Tunisia
- Urology Department, Charles Nicolle Hospital, Faculty of Medicine, University of Tunis-El Manar, Tunis, Tunisia
| | - Ahmed Saadi
- Laboratory of proteins engineering and bioactive molecules (LIP-MB), INSAT, University of Tunis Carthage, Tunis, Tunisia
- Urology Department, Charles Nicolle Hospital, Faculty of Medicine, University of Tunis-El Manar, Tunis, Tunisia
| | - Zeineb Naimi
- Medical Oncology Department, Salah Azaiez Institute, Faculty of Medicine, University of Tunis-El Manar, Tunis, Tunisia
| | - Meriem Ksontini
- Pathology Department, Charles Nicolle Hospital, Faculty of Medicine, University of Tunis-El Manar, Tunis, Tunisia
| | - Mouna Ayadi
- Medical Oncology Department, Salah Azaiez Institute, Faculty of Medicine, University of Tunis-El Manar, Tunis, Tunisia
| | - Ahlem Blel
- Pathology Department, Charles Nicolle Hospital, Faculty of Medicine, University of Tunis-El Manar, Tunis, Tunisia
| | - Soumaya Rammeh
- Pathology Department, Charles Nicolle Hospital, Faculty of Medicine, University of Tunis-El Manar, Tunis, Tunisia
| | - Mohamed Chebil
- Urology Department, Charles Nicolle Hospital, Faculty of Medicine, University of Tunis-El Manar, Tunis, Tunisia
| | - Giulia Piaggio
- UOSD SAFU, Department of Research, Diagnosis and Innovative Technologies, IRCCS-Regina Elena National Cancer Institute, Rome, Italy.
| | - Slah Ouerhani
- Laboratory of proteins engineering and bioactive molecules (LIP-MB), INSAT, University of Tunis Carthage, Tunis, Tunisia
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28
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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: 100] [Impact Index Per Article: 20.0] [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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29
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Das P, Taube JH. Regulating Methylation at H3K27: A Trick or Treat for Cancer Cell Plasticity. Cancers (Basel) 2020; 12:E2792. [PMID: 33003334 PMCID: PMC7600873 DOI: 10.3390/cancers12102792] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/21/2020] [Accepted: 09/23/2020] [Indexed: 12/13/2022] Open
Abstract
Properly timed addition and removal of histone 3 lysine 27 tri-methylation (H3K27me3) is critical for enabling proper differentiation throughout all stages of development and, likewise, can guide carcinoma cells into altered differentiation states which correspond to poor prognoses and treatment evasion. In early embryonic stages, H3K27me3 is invoked to silence genes and restrict cell fate. Not surprisingly, mutation or altered functionality in the enzymes that regulate this pathway results in aberrant methylation or demethylation that can lead to malignancy. Likewise, changes in expression or activity of these enzymes impact cellular plasticity, metastasis, and treatment evasion. This review focuses on current knowledge regarding methylation and de-methylation of H3K27 in cancer initiation and cancer cell plasticity.
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Affiliation(s)
| | - Joseph H. Taube
- Department of Biology, Baylor University, Waco, TX 76706, USA;
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30
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Jiang H, Li L, Zhang J, Wan Z, Wang Y, Hou J, Yu Y. MiR-101-3p and Syn-Cal14.1a Synergy in Suppressing EZH2-Induced Progression of Breast Cancer. Onco Targets Ther 2020; 13:9599-9609. [PMID: 33061442 PMCID: PMC7532305 DOI: 10.2147/ott.s264600] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 08/03/2020] [Indexed: 01/20/2023] Open
Abstract
Objective EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and has been documented as an oncogene in breast cancer. The microRNA (miR)-101-3p can suppress breast cancer progression by targeting with EZH2. Syn-cal14.1a, a synthetic peptide derived from Californiconus californicus (Cal14.1a), can decrease the cell viability and activate the cell apoptosis in cancer. In this study, we explored whether the synergy of miR-101-3p mimic and syn-cal14.1a could inhibit the expression of EZH2. We also investigated this binding treatment’s effects on the suppression of breast cancer cells. Methods MiR-101-3p mimic was transfected and syn-cal14.1a was added in SK-BR-3 and MCF-7 breast cancer cells. The expression of EZH2 protein level was determined. Then, cell proliferation, migration, invasion, and apoptosis were observed. Results MiR-101-3p and syn-cal14.1a, when applied together, exerted a synergistic anti-EZH2 expression in breast cancer cells. The combination of miR-101-3p and syn-cal14.1a synergistically suppressed the EZH2-induced breast cancer cell migration, invasion, and proliferation. In parallel, this synergy treatment was able to promote the apoptosis of breast cancer cells. To our knowledge, this is the first report describing inhibition of EZH2 in human breast cancer cell lines by syn-cal14.1a. Conclusion The anti-EZH2 roles of miR-101-3p and/or syn-cal14.1a could provide an effective therapeutic strategy in breast cancer. These data provide significant insights into molecular mechanisms of breast cancer and may have benefits in clinical therapeutics for breast cancer.
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Affiliation(s)
- Huabo Jiang
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Li Li
- Assisted Reproduction Technology Center, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Jingjing Zhang
- Department of Plastic Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Zhong Wan
- Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yuanyuan Wang
- Department of Health Medicine, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Jingjing Hou
- Department of Gastrointestinal Surgery, Institute of Gastrointestinal Oncology, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Yongsheng Yu
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
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31
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MicroRNAs: Diverse Mechanisms of Action and Their Potential Applications as Cancer Epi-Therapeutics. Biomolecules 2020; 10:biom10091285. [PMID: 32906681 PMCID: PMC7565521 DOI: 10.3390/biom10091285] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/10/2020] [Accepted: 09/02/2020] [Indexed: 12/23/2022] Open
Abstract
Usually, miRNAs function post-transcriptionally, by base-pairing with the 3′UTR of target mRNAs, repressing protein synthesis in the cytoplasm. Furthermore, other regions including gene promoters, as well as coding and 5′UTR regions of mRNAs are able to interact with miRNAs. In recent years, miRNAs have emerged as important regulators of both translational and transcriptional programs. The expression of miRNA genes, similar to protein-coding genes, can be epigenetically regulated, in turn miRNA molecules (named epi-miRs) are able to regulate epigenetic enzymatic machinery. The most recent line of evidence indicates that miRNAs can influence physiological processes, such as embryonic development, cell proliferation, differentiation, and apoptosis as well as pathological processes (e.g., tumorigenesis) through epigenetic mechanisms. Some tumor types show repression of tumor-suppressor epi-miRs resulting in cancer progression and metastasis, hence these molecules have become novel therapeutic targets in the last few years. This review provides information about miRNAs involvement in the various levels of transcription and translation regulation, as well as discusses therapeutic potential of tumor-suppressor epi-miRs used in in vitro and in vivo anti-cancer therapy.
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32
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Luo H, Wang P, Ye H, Shi J, Dai L, Wang X, Song C, Zhang J, Li J. Serum-Derived microRNAs as Prognostic Biomarkers in Osteosarcoma: A Meta-Analysis. Front Genet 2020; 11:789. [PMID: 32849795 PMCID: PMC7431663 DOI: 10.3389/fgene.2020.00789] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 07/02/2020] [Indexed: 12/31/2022] Open
Abstract
Recent reports suggest that microRNAs (miRNAs) may serve as prognostic biomarkers in osteosarcoma. Due to osteosarcoma's early metastasis and poor prognosis, it is very important to find novel prognostic biomarkers for improving osteosarcoma's prognosis. Herein we propose a meta-analysis for serum miRNA's prognostic value in osteosarcoma. In this study, the literature available from PubMed, Web of Science, Embase, and Cochrane Library databases was reviewed. The pooled hazard ratios (HRs) with their 95% confidence intervals (CIs) were calculated to evaluate miRNAs prognostic values. A total of 20 studies investigating serum miRNAs were included in this meta-analysis; the initial terminal point of these reports included overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and recurrence-free survival (RFS). For prognostic meta-analyses, the pooled HR for terminal events of higher expression of miRNAs and lower expression of miRNAs were 5.68 (95% CI 4.73-6.82, P < 0.05) and 3.78 (95% CI 3.27-4.37, P < 0.05), respectively. Additionally, subgroup analyses were conducted based on the analysis methods applied and clinicopathological features reported. In the pooled analyses, the miRNA expression levels are associated with poor prognosis according to both univariate and multivariate analyses. Furthermore, serum miRNAs (miRNA-195, miRNA-27a, miRNA-191, miRNA-300, miRNA-326, miRNA-497, miRNA-95-3p, miRNA-223, miRNA-491-5p, miRNA-124, miRNA-101, miRNA-139-5p, miRNA-194) were associated with poor OS and found to be closely correlated with clinical stage and distant metastasis in osteosarcoma. The results illustrate that low or high expression of these specific miRNAs are both potentially useful as prognostic serum biomarkers in osteosarcoma, and miRNAs (miRNA-195, miRNA-27a, miRNA-191, miRNA-300, miRNA-326, miRNA-497, miRNA-95-3p, miRNA-223, miRNA-491-5p, miRNA-124, miRNA-101, miRNA-139-5p, miRNA-194) may indicate clinical stage and metastasis in this form of cancer.
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Affiliation(s)
- Huan Luo
- College of Public Health, Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China
| | - Peng Wang
- College of Public Health, Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China
| | - Hua Ye
- College of Public Health, Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China
| | - Jianxiang Shi
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China.,Zhengzhou University, Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou, China
| | - Liping Dai
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China.,Zhengzhou University, Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou, China
| | - Xiao Wang
- Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China.,Zhengzhou University, Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou, China
| | - Chunhua Song
- College of Public Health, Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China
| | - Jianying Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Tumor Epidemiology, Zhengzhou University, Zhengzhou, China.,Zhengzhou University, Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou, China
| | - Jitian Li
- Laboratory of Molecular Biology, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, China
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33
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Chien YC, Chen JN, Chen YH, Chou RH, Lee HC, Yu YL. Epigenetic Silencing of miR-9 Promotes Migration and Invasion by EZH2 in Glioblastoma Cells. Cancers (Basel) 2020; 12:cancers12071781. [PMID: 32635336 PMCID: PMC7408254 DOI: 10.3390/cancers12071781] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 07/01/2020] [Indexed: 12/14/2022] Open
Abstract
Glioblastoma (GBM) is the most common primary brain tumor in adults. Tumor invasion is the major reason for treatment failure and poor prognosis in GBM. Inhibiting migration and invasion has become an important therapeutic strategy for GBM treatment. Enhancer of zeste homolog 2 (EZH2) and C-X-C motif chemokine receptor 4 (CXCR4) have been determined to have important roles in the occurrence and development of tumors, but the specific relationship between EZH2 and CXCR4 expression in GBM is less well characterized. In this study, we report that EZH2 and CXCR4 were overexpressed in glioma patients. Furthermore, elevated EZH2 and CXCR4 were correlated with shorter disease-free survival. In three human GBM cell lines, EZH2 modulated the expression of miR-9, which directly targeted the oncogenic signaling of CXCR4 in GBM. The ectopic expression of miR-9 dramatically inhibited the migratory capacity of GBM cells in vitro. Taken together, our results indicate that miR-9, functioning as a tumor-suppressive miRNA in GBM, is suppressed through epigenetic silencing by EZH2. Thus, miR-9 may be an attractive target for therapeutic intervention in GBM.
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Affiliation(s)
- Yi-Chung Chien
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; (Y.-C.C.); (J.-N.C.); (Y.-H.C.); (R.-H.C.)
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
| | - Jia-Ni Chen
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; (Y.-C.C.); (J.-N.C.); (Y.-H.C.); (R.-H.C.)
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
| | - Ya-Huey Chen
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; (Y.-C.C.); (J.-N.C.); (Y.-H.C.); (R.-H.C.)
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
- Drug Development Center, China Medical University, Taichung 404, Taiwan
| | - Ruey-Hwang Chou
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; (Y.-C.C.); (J.-N.C.); (Y.-H.C.); (R.-H.C.)
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
- Drug Development Center, China Medical University, Taichung 404, Taiwan
- Department of Biotechnology, Asia University, Taichung 413, Taiwan
| | - Han-Chung Lee
- School of Medicine, College of Medicine, China Medical University, Taichung 404, Taiwan
- Department of Neurosurgery, China Medical University Hospital, Taichung 404, Taiwan
- Correspondence: (H.-C.L.); (Y.-L.Y.); Tel.: +886-4-22052121 (ext. 7911) (Y.-L.Y.)
| | - Yung-Luen Yu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; (Y.-C.C.); (J.-N.C.); (Y.-H.C.); (R.-H.C.)
- Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan
- Drug Development Center, China Medical University, Taichung 404, Taiwan
- Department of Biotechnology, Asia University, Taichung 413, Taiwan
- Correspondence: (H.-C.L.); (Y.-L.Y.); Tel.: +886-4-22052121 (ext. 7911) (Y.-L.Y.)
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Li Y, Li G, Guo X, Yao H, Wang G, Li C. Non-coding RNA in bladder cancer. Cancer Lett 2020; 485:38-44. [PMID: 32437725 DOI: 10.1016/j.canlet.2020.04.023] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/26/2020] [Accepted: 04/24/2020] [Indexed: 12/24/2022]
Abstract
Bladder cancer is the tenth most common cancer worldwide and has been associated with high mortality and morbidity. Although the treatment of bladder cancer is based on well-defined tumor classifications and gradings, patients still experience different clinical response. The heterogeneity of this disease calls for substantial research with more in-depth molecular characterization, with the hope of identifying new diagnostic and treatment options. In recent years, non-coding RNAs (ncRNAs), particularly, microRNAs (miRNAs), long non-coding RNA (lncRNAs), and circular RNAs (circRNAs) were found to be associated with bladder cancer occurrence and development. This review highlights the recent findings concerning ncRNAs and their relevance to the pathogenesis of bladder cancer. This may provide a foundation for developing highly specific diagnostic tools and more robust therapeutic strategies in the future.
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Affiliation(s)
- Yi Li
- Department of Anesthesiology, Peking University Third Hospital (PUTH), Beijing, China
| | - Gang Li
- Department of Anesthesiology, Peking University Third Hospital (PUTH), Beijing, China
| | - Xiangyang Guo
- Department of Anesthesiology, Peking University Third Hospital (PUTH), Beijing, China
| | - Haochen Yao
- College of Basic Medical Science, Jilin University (JUT), Changchun, Jilin, China
| | - Guoqing Wang
- College of Basic Medical Science, Jilin University (JUT), Changchun, Jilin, China.
| | - Chong Li
- Core Facility for Protein Research, Institute of Biophysics Chinese Academy of Sciences (IBPCAS), Beijing, China; Beijing Jianlan Institute of Medicine, Beijing, China; Beijing Zhongke Jianlan Biotechnology Co., Ltd., Beijing, China.
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35
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Qiu BQ, Lin XH, Ye XD, Huang W, Pei X, Xiong D, Long X, Zhu SQ, Lu F, Lin K, Zhang XQ, Xu JJ, Sheng LL, Zhang XM, Zhang PF, Wu YB. Long non-coding RNA PSMA3-AS1 promotes malignant phenotypes of esophageal cancer by modulating the miR-101/EZH2 axis as a ceRNA. Aging (Albany NY) 2020; 12:1843-1856. [PMID: 32005028 PMCID: PMC7053621 DOI: 10.18632/aging.102716] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 01/02/2020] [Indexed: 12/11/2022]
Abstract
Backgrounds: Emerging evidences has demonstrated that dysregulation of long non-coding RNAs (lncRNAs) is critically involved in esophageal squamous cell carcinoma (ESCC) progression. However, the function of lncRNA PSMA3-AS1 in ESCC is unclear. Therefore, we aimed to explore the functions and potential mechanisms of PSMA3-AS1 in ESCC cells progression. Results: Here, we found that PSMA3-AS1 expression was significantly up-regulated in ESCC tissues. Forced PSMA3-AS1 expression was correlated with tumor size, distant metastasis, and poor prognosis in ESCC patients. Functionally, PSMA3-AS1-overexpression promoted ESCC cells proliferation, invasion, and migration in vitro. Mechanistically, PSMA3-AS1 up-regulated EZH2 expression by competitively binding to miR-101. Conclusion: PSMA3-AS1 is significantly up-regulated in ESCC tissues, and the PSMA3-AS1/miR-101/EZH2 axis plays a critical role in ESCC progression. Taken together, our results may provide promising targets for ESCC therapy. Methods: PSMA3-AS1 and miR-101 expression were explored using qRT-PCR in ESCC tissues and cell lines. Immunohistochemistry assays were carried out to analyze EZH2 (enhancer of zeste homolog) protein expression. RIP, dual-luciferase reporter, fluorescence in situ hybridization, and biotin pull-down assays were used to detect the interactions of PSMA3-AS1, miR-101 and EZH2. The biological functions of PSMA3-AS1 in PSMA3-AS1-altered cells were explored using CCK-8, colony formation, wound healing, and transwell assays in vitro.
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Affiliation(s)
- Bai-Quan Qiu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xia-Hui Lin
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xu-Dong Ye
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Wei Huang
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xu Pei
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Dian Xiong
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiang Long
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Shu-Qiang Zhu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Feng Lu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Kun Lin
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiao-Qiang Zhang
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jian-Jun Xu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Lu-Lu Sheng
- Department of Emergency Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xue-Mei Zhang
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Peng-Fei Zhang
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yong-Bing Wu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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36
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Shibayama Y, Kubo Y, Nakagawa T, Iseki K. MicroRNA-101-5p Suppresses the Expression of the Ras-Related Protein RAP1A. Biol Pharm Bull 2020; 42:1332-1336. [PMID: 31366868 DOI: 10.1248/bpb.b19-00068] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
MicroRNAs (miRs) are small, non-coding RNAs that negatively regulate gene expression. The stem-loop sequence miR-101-1 generates mature miR-101-5p and miR-101-3p. The function and target mRNA of miR-101-5p have not yet been elucidated in detail. Here, we demonstrate that miR-101-5p inhibits the expression of RAP1A, a member of the RAS gene family. Transfection of a miR-101-5p mimic significantly inhibited the expression of RAP1A mRNA in HeLa, HEK293, A549, and COLO201 cells. The same treatment significantly inhibited cell proliferation. The cytostatic effect with transfection of miR-101-5p was antagonized by treatment with the RAP inhibitor salirasib. These results suggested that miR-101-5p inhibits RAP1A, and thus, the expression levels of miR-101-5p regulate cell proliferation.
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Affiliation(s)
- Yoshihiko Shibayama
- Department of Drug Formulation, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido
| | - Yoshitada Kubo
- Department of Drug Formulation, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido
| | - Tsutomu Nakagawa
- Department of Drug Formulation, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido
| | - Ken Iseki
- Laboratory of Clinical Pharmaceutics and Therapeutics, Graduate School of Pharmaceutical Sciences, Hokkaido University
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37
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Davis FM, Gallagher KA. Epigenetic Mechanisms in Monocytes/Macrophages Regulate Inflammation in Cardiometabolic and Vascular Disease. Arterioscler Thromb Vasc Biol 2020; 39:623-634. [PMID: 30760015 DOI: 10.1161/atvbaha.118.312135] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Cardiometabolic and vascular disease, with their associated secondary complications, are the leading cause of morbidity and mortality in Western society. Chronic inflammation is a common theme that underlies initiation and progression of cardiovascular disease. In this regard, monocytes/macrophages are key players in the development of a chronic inflammatory state. Over the past decade, epigenetic modifications, such as DNA methylation and posttranslational histone processing, have emerged as important regulators of immune cell phenotypes. Accumulating studies reveal the importance of epigenetic enzymes in the dynamic regulation of key signaling pathways that alter monocyte/macrophage phenotypes in response to environmental stimuli. In this review, we highlight the current paradigms of monocyte/macrophage polarization and the emerging role of epigenetic modification in the regulation of monocyte/macrophage phenotype in obesity, diabetes mellitus, atherosclerosis, and abdominal aortic aneurysms.
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Affiliation(s)
- Frank M Davis
- From the Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor
| | - Katherine A Gallagher
- From the Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor
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38
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Cheng Y, He C, Wang M, Ma X, Mo F, Yang S, Han J, Wei X. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Ther 2019; 4:62. [PMID: 31871779 PMCID: PMC6915746 DOI: 10.1038/s41392-019-0095-0] [Citation(s) in RCA: 679] [Impact Index Per Article: 113.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 10/16/2019] [Accepted: 10/24/2019] [Indexed: 02/05/2023] Open
Abstract
Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence. Epigenetic dysregulation is often linked to human disease, notably cancer. With the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. In this review, we summarize the aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.
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Affiliation(s)
- Yuan Cheng
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Cai He
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Manni Wang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xuelei Ma
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Fei Mo
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Shengyong Yang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Junhong Han
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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Shao Q, Xu J, Deng R, Wei W, Zhou B, Yue C, Zhu M, Zhu H. SNHG 6 promotes the progression of Colon and Rectal adenocarcinoma via miR-101-3p and Wnt/β-catenin signaling pathway. BMC Gastroenterol 2019; 19:163. [PMID: 31533634 PMCID: PMC6749705 DOI: 10.1186/s12876-019-1080-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 09/04/2019] [Indexed: 01/20/2023] Open
Abstract
Background Small nucleolar RNA host gene 6 (SNHG6) regulates diverse biological processes in cancers. Potential function of SNHG6 in human colon and rectal adenocarcinoma (CRC) was evaluated. Methods Quantitative real-time polymerase chain reaction, MTT assays, Colony formation assays, Transwell assay, Western Blotting and Luciferase reporter assays were performed to measure the biological functions and potential molecular mechanisms of SNHG6 in CRC. Results SNHG6 was over-expressed in CRC, and high expression of s SNHG6 were associated with short survival times. We then identified miR-101-3p as an inhibitory target of SNHG6. Knockdown of SNHG6 significantly decreased miR-101-3p expression. Moreover, silenced SNHG6 obviously inhibited CRC cell growth, weakened cell invasion capacity and blocked the Wnt/β-catenin signaling pathway. Conclusion SNHG6 could regulate the progression of CRC via modulating the expression levels of miR-101-3p and the activity of Wnt/β-catenin signaling.
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Affiliation(s)
- Qianwen Shao
- Department of oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China, 210029
| | - Jing Xu
- Genetic testing center, department of oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China, 210029
| | - Rong Deng
- General Department, Cancer hospital of NanJing Medical University, Nanjing, Jiangsu, People's Republic of China, 210009
| | - Wei Wei
- General Department, Cancer hospital of NanJing Medical University, Nanjing, Jiangsu, People's Republic of China, 210009
| | - Bing Zhou
- General Department, Cancer hospital of NanJing Medical University, Nanjing, Jiangsu, People's Republic of China, 210009
| | - Chao Yue
- General Department, Cancer hospital of NanJing Medical University, Nanjing, Jiangsu, People's Republic of China, 210009
| | - Miaoling Zhu
- Pathology department, Cancer hospital of NanJing Medical University, Nanjing, Jangsu, People's Republic of China, 210009
| | - Haitao Zhu
- Colorectal cancer center, general surgery department, Jiangsu province cancer hospital, Affiliated Cancer hospital of NanJing Medical University, Jiangsu Cancer Institute, No 42, Baiziting road, NanJing, Nanjing, Jiangsu, People's Republic of China, 210009.
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Shivram H, Le SV, Iyer VR. PRC2 activates interferon-stimulated genes indirectly by repressing miRNAs in glioblastoma. PLoS One 2019; 14:e0222435. [PMID: 31513636 PMCID: PMC6742368 DOI: 10.1371/journal.pone.0222435] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 08/30/2019] [Indexed: 12/21/2022] Open
Abstract
Polycomb repressive complex 2 (PRC2) is a chromatin binding complex that represses gene expression by methylating histone H3 at K27 to establish repressed chromatin domains. PRC2 can either regulate genes directly through the methyltransferase activity of its component EZH2 or indirectly by regulating other gene regulators. Gene expression analysis of glioblastoma (GBM) cells lacking EZH2 showed that PRC2 regulates hundreds of interferon-stimulated genes (ISGs). We found that PRC2 directly represses several ISGs and also indirectly activates a distinct set of ISGs. Assessment of EZH2 binding proximal to miRNAs showed that PRC2 directly represses miRNAs encoded in the chromosome 14 imprinted DLK1-DIO3 locus. We found that repression of this locus by PRC2 occurs in immortalized GBM-derived cell lines as well as in primary bulk tumors from GBM and anaplastic astrocytoma patients. Through repression of these miRNAs and several other miRNAs, PRC2 activates a set of ISGs that are targeted by these miRNAs. This PRC2-miRNA-ISG network is likely to be important in regulating gene expression programs in GBM.
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Affiliation(s)
- Haridha Shivram
- Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, Livestrong Cancer Institutes, University of Texas at Austin, Austin, Texas, United States of America
| | - Steven V. Le
- Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, Livestrong Cancer Institutes, University of Texas at Austin, Austin, Texas, United States of America
| | - Vishwanath R. Iyer
- Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, Livestrong Cancer Institutes, University of Texas at Austin, Austin, Texas, United States of America
- * E-mail:
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Yu W, Sun Z, Yang L, Han Y, Yue L, Deng L, Yao R. lncRNA PTAR promotes NSCLC cell proliferation, migration and invasion by sponging microRNA‑101. Mol Med Rep 2019; 20:4168-4174. [PMID: 31485653 PMCID: PMC6797984 DOI: 10.3892/mmr.2019.10646] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 07/26/2019] [Indexed: 02/06/2023] Open
Abstract
MicroRNA (miR)‑101 copy loss is an early event in the development of human lung cancer, and it occurs in 29% of all lung cancer incidences. In addition, miR‑101 expression in non‑small cell lung cancer (NSCLC) is known to be downregulated. The aim of the present study was to explore the roles and mechanisms of the long non‑coding (lnc)‑RNA pro‑transition associated RNA (PTAR) on NSCLC cell proliferation, migration and invasion in association with miR‑101. Reverse transcription‑quantitative PCR analysis was performed to detect the expression of lncRNA PTAR in 30 paired human NSCLC tissues and the corresponding para‑tumor tissues. PTAR was amplified and cloned into the expression vector pCDNA3.1. Then, PTAR‑overexpression plasmids or small interfering (si)‑RNA‑PTAR was transfected into A549 cells for 48 h, after which cell proliferation and the cell cycle distribution were evaluated. In addition, Transwell chamber and cell scratch‑wound assays were conducted to analyze A549 cell migration and invasion. A luciferase activity assay was evaluated to determine the interaction between PTAR and miR‑101. Furthermore, our results demonstrated that in human NSCLC tissues and cell lines, lncRNA PTAR expression was upregulated compared with normal lung tissues and cell lines, respectively. Additionally, PTAR transfection was observed to promote A549 cell proliferation, migration and invasion; opposing effects were observed with siRNA‑PTAR transfection. The luciferase activity assay revealed that PTAR could act as a sponge to bind miR‑101. Thus, miR‑101 plays a role in NSCLC tumorigenesis and progression. In conclusion, lncRNA PTAR was proposed to promote NSCLC cell growth through sponging and inactivating miR‑101, which may be a possible mechanism underlying miR‑101 copy loss in human NSCLC.
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Affiliation(s)
- Wenjun Yu
- Department of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Zhenni Sun
- Department of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Ling Yang
- Department of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Yafei Han
- Department of Central Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Lu Yue
- Department of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Lihua Deng
- Department of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Ruyong Yao
- Department of Central Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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Abstract
Bladder cancer (BC) is the second highest morbid malignancy of the urinary tract and the fifth most common cancer worldwide. BC is highly malignant with significant morbidity and mortality, especially muscle-invasive BC (MIBC), which has a poor prognosis and frequently recurs after the first resection. Therefore, more sensitive diagnostic tools and effective therapeutic methods are urgently needed. MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of protein-coding genes by repressing their translation or cleaving RNA transcripts in a sequence-specific manner. miRNAs play very important roles in regulating genes related to tumorigenesis, tumor development, progression, metastasis and angiogenesis. With the rapid development of high-throughput sequencing technology, an increasing number of miRNAs with aberrant expression between either BC patients and healthy volunteers or between BC tumor tissues and matched peripheral control tissues have been recently examined. The tumor etiopathogenesis must be determined to promote the development of new markers as diagnostic and prognostic tools and targets for bladder tumor therapy, it is therefore vital to elucidate the function of miRNAs with aberrant expression in BC. In the present study, we examined the published data of BC-related miRNAs by reviewing their expression levels, possible functions, potential target genes, related molecular regulatory networks, candidate markers for prognosis and diagnosis, and prospective therapeutic cases, and we summarized the status of research on BC-related miRNAs in recent years.
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Jones BA, Varambally S, Arend RC. Histone Methyltransferase EZH2: A Therapeutic Target for Ovarian Cancer. Mol Cancer Ther 2019; 17:591-602. [PMID: 29726819 DOI: 10.1158/1535-7163.mct-17-0437] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 09/28/2017] [Accepted: 01/02/2018] [Indexed: 12/18/2022]
Abstract
Ovarian cancer is the fifth leading cause of cancer-related deaths in females in the United States. There were an estimated 22,440 new cases and 14,080 deaths due to ovarian cancer in 2017. Most patients present with advanced-stage disease, revealing the urgent need for new therapeutic strategies targeting pathways of tumorigenesis and chemotherapy resistance. While multiple genomic changes contribute to the progression of this aggressive disease, it has become increasingly evident that epigenetic events play a pivotal role in ovarian cancer development. One of the well-studied epigenetic modifiers, the histone methyltransferase EZH2, is a member of polycomb repressive complex 2 (PRC2) and is commonly involved in transcriptional repression. EZH2 is the enzymatic catalytic subunit of the PRC2 complex that can alter gene expression by trimethylating lysine 27 on histone 3 (H3K27). In ovarian cancer, EZH2 is commonly overexpressed and therefore potentially serves as an effective therapeutic target. Multiple small-molecule inhibitors are being developed to target EZH2, which are now in clinical trials. Thus, in this review, we highlight the progress made in EZH2-related research in ovarian cancer and discuss the potential utility of targeting EZH2 with available small-molecule inhibitors for ovarian cancer. Mol Cancer Ther; 17(3); 591-602. ©2018 AACR.
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Affiliation(s)
- Bayley A Jones
- University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
| | | | - Rebecca C Arend
- Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama.
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Chen CL, Lin CH, Li AL, Huang CC, Shen BY, Chiang YR, Fang PL, Chang HC, Li KL, Yang WC, Horng JT, Ma N. Plasma miRNA profile is a biomarker associated with urothelial carcinoma in chronic hemodialysis patients. Am J Physiol Renal Physiol 2019; 316:F1094-F1102. [PMID: 30892932 DOI: 10.1152/ajprenal.00014.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The incidence of urothelial carcinoma (UC) is higher in patients undergoing chronic dialysis than in the general population. This study investigated plasma miRNA profiling as the ancillary diagnosis biomarker associated with UC in patients undergoing chronic hemodialysis. We successfully screened out and detected miRNA expression from plasma in eight patients undergoing dialysis through quantitative real-time PCR array analysis and identified eight candidate miRNAs. The candidate miRNAs were then validated using single quantitative RT-PCR assays from 52 plasma samples. The miRNA classifier for ancillary UC detection was developed by multiple logistic regression analyses. Moreover, we validated the classifier by testing another nine samples. Expression levels of miR-150-5p, miR-150-5p/miR-155-5p, miR-378a-3p/miR-150-5p, miR-636/miR-150-5p, miR-150-5p/miR-210-3p, and miR-19b-1-5p/miR-378a-3p were shown to be significantly different between UC and non-UC samples (P = 0.035, 0.0048, 0.016, 0.024, 0.038, and 0.048). Kaplan-Meier curve analysis also showed that low miR-19b-1-5p expression was associated with a worse prognosis (P = 0.0382). We also developed a miRNA classifier based on five miRNA expression levels to predict UC and found that the area under curve was 0.882. The classifier had a sensitivity of 80% (95% confidence interval: 0.5191% to 0.9567%) and a specificity of 83.7% (95% confidence interval: 0.6799% to 0.9381%). This classifier was tested by nine samples with 100% accuracy. The miRNA classifier offers higher sensitivity and specificity than the existing makers. Thus, this approach will improve the prospective diagnosis of UC in patients undergoing chronic hemodialysis.
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Affiliation(s)
- Chien-Lung Chen
- Department of Biomedical Sciences and Engineering, Institute of Systems Biology and Bioinformatics, National Central University , Taoyuan , Taiwan.,Division of Nephrology, Department of Medicine, Taiwan Landseed Hospital , Taoyuan , Taiwan
| | - Chen-Huan Lin
- Department of Biomedical Sciences and Engineering, Institute of Systems Biology and Bioinformatics, National Central University , Taoyuan , Taiwan
| | - An-Lun Li
- Department of Biomedical Sciences and Engineering, Institute of Systems Biology and Bioinformatics, National Central University , Taoyuan , Taiwan
| | - Chiu-Ching Huang
- Division of Nephrology, Department of Internal Medicine, China Medical University , Taichung , Taiwan
| | - Biing-Yir Shen
- Division of Urology, Department of Surgery, Taiwan Landseed Hospital , Taoyuan , Taiwan
| | - Yun-Ru Chiang
- Department of Biomedical Sciences and Engineering, Institute of Systems Biology and Bioinformatics, National Central University , Taoyuan , Taiwan
| | - Pei-Luen Fang
- Department of Biomedical Sciences and Engineering, Institute of Systems Biology and Bioinformatics, National Central University , Taoyuan , Taiwan
| | - Huan-Cheng Chang
- Division of Nephrology, Department of Medicine, Taiwan Landseed Hospital , Taoyuan , Taiwan.,Department and Graduate Institute of Health Care Management, Chang Gung, University , Taoyuan , Taiwan
| | - Kay-Lun Li
- Division of Metabolism and Endocrinology, Department of Medicine, Landseed Hospital , Taoyuan , Taiwan
| | - Wu-Chang Yang
- Division of Nephrology, Department of Medicine, Taiwan Landseed Hospital , Taoyuan , Taiwan.,Kidney Disease Integrated Center, Taiwan Landseed Hospital , Taoyuan , Taiwan
| | - Jorng-Tzong Horng
- Department of computer science and information engineering, National Central University , Taoyuan , Taiwan
| | - Nianhan Ma
- Department of Biomedical Sciences and Engineering, Institute of Systems Biology and Bioinformatics, National Central University , Taoyuan , Taiwan.,Institute of Cognitive Neuroscience, National Central University , Taoyuan , Taiwan
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Monteiro-Reis S, Lobo J, Henrique R, Jerónimo C. Epigenetic Mechanisms Influencing Epithelial to Mesenchymal Transition in Bladder Cancer. Int J Mol Sci 2019; 20:E297. [PMID: 30642115 PMCID: PMC6358899 DOI: 10.3390/ijms20020297] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/02/2019] [Accepted: 01/09/2019] [Indexed: 12/27/2022] Open
Abstract
Bladder cancer is one of the most incident neoplasms worldwide, and its treatment remains a significant challenge, since the mechanisms underlying disease progression are still poorly understood. The epithelial to mesenchymal transition (EMT) has been proven to play an important role in the tumorigenic process, particularly in cancer cell invasiveness and metastatic potential. Several studies have reported the importance of epigenetic mechanisms and enzymes, which orchestrate them in several features of cancer cells and, specifically, in EMT. In this paper, we discuss the epigenetic enzymes, protein-coding and non-coding genes, and mechanisms altered in the EMT process occurring in bladder cancer cells, as well as its implications, which allows for improved understanding of bladder cancer biology and for the development of novel targeted therapies.
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Affiliation(s)
- Sara Monteiro-Reis
- Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
| | - João Lobo
- Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
- Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal.
| | - Rui Henrique
- Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
- Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal.
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal.
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Hemming ML, Lawlor MA, Andersen JL, Hagan T, Chipashvili O, Scott TG, Raut CP, Sicinska E, Armstrong SA, Demetri GD, Bradner JE, Ganz PA, Tomlinson G, Olopade OI, Couch FJ, Wang X, Lindor NM, Pankratz VS, Radice P, Manoukian S, Peissel B, Zaffaroni D, Barile M, Viel A, Allavena A, Dall'Olio V, Peterlongo P, Szabo CI, Zikan M, Claes K, Poppe B, Foretova L, Mai PL, Greene MH, Rennert G, Lejbkowicz F, Glendon G, Ozcelik H, Andrulis IL, Thomassen M, Gerdes AM, Sunde L, Cruger D, Birk Jensen U, Caligo M, Friedman E, Kaufman B, Laitman Y, Milgrom R, Dubrovsky M, Cohen S, Borg A, Jernström H, Lindblom A, Rantala J, Stenmark-Askmalm M, Melin B, Nathanson K, Domchek S, Jakubowska A, Lubinski J, Huzarski T, Osorio A, Lasa A, Durán M, Tejada MI, Godino J, Benitez J, Hamann U, Kriege M, Hoogerbrugge N, van der Luijt RB, van Asperen CJ, Devilee P, Meijers-Heijboer EJ, Blok MJ, Aalfs CM, Hogervorst F, Rookus M, Cook M, Oliver C, Frost D, Conroy D, Evans DG, Lalloo F, Pichert G, Davidson R, Cole T, Cook J, Paterson J, Hodgson S, Morrison PJ, Porteous ME, Walker L, Kennedy MJ, Dorkins H, Peock S, et alHemming ML, Lawlor MA, Andersen JL, Hagan T, Chipashvili O, Scott TG, Raut CP, Sicinska E, Armstrong SA, Demetri GD, Bradner JE, Ganz PA, Tomlinson G, Olopade OI, Couch FJ, Wang X, Lindor NM, Pankratz VS, Radice P, Manoukian S, Peissel B, Zaffaroni D, Barile M, Viel A, Allavena A, Dall'Olio V, Peterlongo P, Szabo CI, Zikan M, Claes K, Poppe B, Foretova L, Mai PL, Greene MH, Rennert G, Lejbkowicz F, Glendon G, Ozcelik H, Andrulis IL, Thomassen M, Gerdes AM, Sunde L, Cruger D, Birk Jensen U, Caligo M, Friedman E, Kaufman B, Laitman Y, Milgrom R, Dubrovsky M, Cohen S, Borg A, Jernström H, Lindblom A, Rantala J, Stenmark-Askmalm M, Melin B, Nathanson K, Domchek S, Jakubowska A, Lubinski J, Huzarski T, Osorio A, Lasa A, Durán M, Tejada MI, Godino J, Benitez J, Hamann U, Kriege M, Hoogerbrugge N, van der Luijt RB, van Asperen CJ, Devilee P, Meijers-Heijboer EJ, Blok MJ, Aalfs CM, Hogervorst F, Rookus M, Cook M, Oliver C, Frost D, Conroy D, Evans DG, Lalloo F, Pichert G, Davidson R, Cole T, Cook J, Paterson J, Hodgson S, Morrison PJ, Porteous ME, Walker L, Kennedy MJ, Dorkins H, Peock S, Godwin AK, Stoppa-Lyonnet D, de Pauw A, Mazoyer S, Bonadona V, Lasset C, Dreyfus H, Leroux D, Hardouin A, Berthet P, Faivre L, Loustalot C, Noguchi T, Sobol H, Rouleau E, Nogues C, Frénay M, Vénat-Bouvet L, Hopper JL, Daly MB, Terry MB, John EM, Buys SS, Yassin Y, Miron A, Goldgar D, Singer CF, Dressler AC, Gschwantler-Kaulich D, Pfeiler G, Hansen TVO, Jønson L, Agnarsson BA, Kirchhoff T, Offit K, Devlin V, Dutra-Clarke A, Piedmonte M, Rodriguez GC, Wakeley K, Boggess JF, Basil J, Schwartz PE, Blank SV, Toland AE, Montagna M, Casella C, Imyanitov E, Tihomirova L, Blanco I, Lazaro C, Ramus SJ, Sucheston L, Karlan BY, Gross J, Schmutzler R, Wappenschmidt B, Engel C, Meindl A, Lochmann M, Arnold N, Heidemann S, Varon-Mateeva R, Niederacher D, Sutter C, Deissler H, Gadzicki D, Preisler-Adams S, Kast K, Schönbuchner I, Caldes T, de la Hoya M, Aittomäki K, Nevanlinna H, Simard J, Spurdle AB, Holland H, Chen X, Platte R, Chenevix-Trench G, Easton DF. Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and Are Targetable by BET Bromodomain Inhibition. Cancer Res 2019. [PMID: 18483246 DOI: 10.1158/0008-5472] [Show More Authors] [Citation(s) in RCA: 750] [Impact Index Per Article: 125.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT and PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, resulting in high expression levels of the oncogene required for tumor growth. Although kinase inhibition is an effective therapy for many patients with GIST, disease progression from kinase-resistant mutations is common and no other effective classes of systemic therapy exist. In this study, we identify regulatory regions of the KIT enhancer essential for KIT gene expression and GIST cell viability. Given the dependence of GIST upon enhancer-driven expression of RTKs, we hypothesized that the enhancer domains could be therapeutically targeted by a BET bromodomain inhibitor (BBI). Treatment of GIST cells with BBIs led to cell-cycle arrest, apoptosis, and cell death, with unique sensitivity in GIST cells arising from attenuation of the KIT enhancer domain and reduced KIT gene expression. BBI treatment in KIT-dependent GIST cells produced genome-wide changes in the H3K27ac enhancer landscape and gene expression program, which was also seen with direct KIT inhibition using a tyrosine kinase inhibitor (TKI). Combination treatment with BBI and TKI led to superior cytotoxic effects in vitro and in vivo, with BBI preventing tumor growth in TKI-resistant xenografts. Resistance to select BBI in GIST was attributable to drug efflux pumps. These results define a therapeutic vulnerability and clinical strategy for targeting oncogenic kinase dependency in GIST. SIGNIFICANCE: Expression and activity of mutant KIT is essential for driving the majority of GIST neoplasms, which can be therapeutically targeted using BET bromodomain inhibitors.
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Affiliation(s)
- Matthew L Hemming
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. .,Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Matthew A Lawlor
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jessica L Andersen
- Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Timothy Hagan
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Otari Chipashvili
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Thomas G Scott
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Chandrajit P Raut
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Ewa Sicinska
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Scott A Armstrong
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - George D Demetri
- Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.,Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - James E Bradner
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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Serresi M, Siteur B, Hulsman D, Company C, Schmitt MJ, Lieftink C, Morris B, Cesaroni M, Proost N, Beijersbergen RL, van Lohuizen M, Gargiulo G. Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities. J Exp Med 2018; 215:3115-3135. [PMID: 30487290 PMCID: PMC6279402 DOI: 10.1084/jem.20180801] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 08/31/2018] [Accepted: 11/01/2018] [Indexed: 12/24/2022] Open
Abstract
Kras-driven non–small-cell-lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Serresi et al. show that inhibiting Ezh2 in orthotopic KrasG12D-driven NSCLC unleashes an inflammatory response rewiring tumor progression and amplifying associated vulnerabilities that could be therapeutically exploited. Kras-driven non–small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes residing in PRC2-regulated chromatin. During this process, tumor cells overcome GSK126 antiproliferative effects. We identified oncogenes that may mediate progression through an in vivo RNAi screen aimed at targets of PRC2/NF-κB. An in vitro compound screening linked GSK126-driven inflammation and therapeutic vulnerability in human cells to regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated NSCLCs in vivo also showed an enhanced response to a combination of nimesulide and bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote defined adaptive responses. Targeting these responses potentially improves outcomes in Kras-driven NSCLCs.
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Affiliation(s)
- Michela Serresi
- Molecular Oncology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Bjorn Siteur
- Mouse Cancer Clinic, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Danielle Hulsman
- Division of Molecular Genetics and Cancer Genomics Centre, Netherlands Cancer Institute, Amsterdam, Netherlands.,Oncode Institute, Utrecht, Netherlands
| | - Carlos Company
- Molecular Oncology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Matthias J Schmitt
- Molecular Oncology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Cor Lieftink
- Division of Molecular Carcinogenesis and Netherlands Cancer Institute Robotics and Screening Center, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Ben Morris
- Division of Molecular Carcinogenesis and Netherlands Cancer Institute Robotics and Screening Center, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Matteo Cesaroni
- Fels Institute, Temple University School of Medicine, Philadelphia, PA
| | - Natalie Proost
- Mouse Cancer Clinic, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Roderick L Beijersbergen
- Division of Molecular Carcinogenesis and Netherlands Cancer Institute Robotics and Screening Center, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Maarten van Lohuizen
- Division of Molecular Genetics and Cancer Genomics Centre, Netherlands Cancer Institute, Amsterdam, Netherlands .,Oncode Institute, Utrecht, Netherlands
| | - Gaetano Gargiulo
- Molecular Oncology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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Abstract
PURPOSE OF REVIEW Epigenetics refers to processes that alter gene expression without altering primary DNA. Over that past decade, there is a growing focus on epigenetic mechanisms in cancer research and its importance in cancer biology. This review summarizes epigenetic dysregulation in bladder cancer. RECENT FINDINGS Epigenetic alterations are overall shared across various grades and stages of bladder cancer. High grade invasive tumors demonstrate a greater degree and intensity of methylation and may have a unique methylation pattern. Environmental exposures may influence epigenetic alterations directly independent of genomic change. Non-coding RNAs play an important role in cancer phenotype, especially in the context of integrative genomic analyses. DNA hypermethylation and non-coding RNAs have potential as robust bladder cancer biomarkers; however, they require further study and validation. Changes in chromatin and histone modification are attractive targets for therapy and are currently in clinical trials. Epigenetic dysregulation may be an important key in improving the understanding of bladder cancer pathogenesis, especially through integrative genomic analyses. Deeper understanding of these pathways can help identify clinically relevant biomarkers and therapeutic targets to validate for diagnosis, monitoring, prognosis, and treatment for bladder cancer.
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Affiliation(s)
- Sima P Porten
- Department of Urology, University of California San Francisco (UCSF), Mailbox Code 1695, 550 16th Street, 6th Floor, San Francisco, CA, 94143, USA.
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He D, Yue Z, Li G, Chen L, Feng H, Sun J. Low Serum Levels of miR-101 Are Associated with Poor Prognosis of Colorectal Cancer Patients After Curative Resection. Med Sci Monit 2018; 24:7475-7481. [PMID: 30341274 PMCID: PMC6204656 DOI: 10.12659/msm.909768] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Recent studies showed low expression of microRNA (miR)-101 in various malignancies. However, the association of serum miR-101 and colorectal cancer (CRC) remains unknown. We investigated diagnostic and prognostic significance of serum miR-101 in CRC. MATERIAL AND METHODS A total of 263 consecutive CRC patients and 126 healthy controls were enrolled in this study. Serum miR-101 levels were measured using real-time quantitative reverse transcription polymerase chain reactions. The association between serum miR-101 level and survival outcome was analyzed. RESULTS Serum miR-101 in CRC patients was significantly lower than in healthy volunteers (P<0.001). Low serum miR-101 level was significantly associated with advanced cancer stage. Moreover, survival analysis demonstrated that patients with a low serum miR-101 had poorer 5-year overall survival than patients with a high serum miR-101 level (p=0.041). Serum miR-101 level also were confirmed as an independent risk factor for CRC in multivariate analysis (hazard ratio, 1.468; 95%CI, 0.981-1.976; p<0.001). CONCLUSIONS Serum miR-101 level was significantly downregulated in CRC patients and was closely correlated with poor clinical outcome, suggesting that serum miR-101 might be a useful diagnostic and prognostic marker for CRC.
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Affiliation(s)
- Dedong He
- Department of General Surgery, First Affiliated Hospital of Xin-Xiang Medical University, Xin-Xiang, Henan, China (mainland)
| | - Zhongyi Yue
- Department of General Surgery, First Affiliated Hospital of Xin-Xiang Medical University, Xin-Xiang, Henan, China (mainland)
| | - Guangjun Li
- Department of General Surgery, First Affiliated Hospital of Xin-Xiang Medical University, Xin-Xiang, Henan, China (mainland)
| | - Liping Chen
- Department of General Surgery, First Affiliated Hospital of Xin-Xiang Medical University, Xin-Xiang, Henan, China (mainland)
| | - Hailong Feng
- Department of General Surgery, First Affiliated Hospital of Xin-Xiang Medical University, Xin-Xiang, Henan, China (mainland)
| | - Jianwei Sun
- Scientific Research and Postgraduate Education, First Affiliated Hospital of Xin-Xiang Medical University, Xin-Xiang, Henan, China (mainland)
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Epigenetic regulation of MAGE family in human cancer progression-DNA methylation, histone modification, and non-coding RNAs. Clin Epigenetics 2018; 10:115. [PMID: 30185218 PMCID: PMC6126015 DOI: 10.1186/s13148-018-0550-8] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 08/30/2018] [Indexed: 12/20/2022] Open
Abstract
The melanoma antigen gene (MAGE) proteins are a group of highly conserved family members that contain a common MAGE homology domain. Type I MAGEs are relevant cancer-testis antigens (CTAs), and originally considered as attractive targets for cancer immunotherapy due to their typically high expression in tumor tissues but restricted expression in normal adult tissues. Here, we reviewed the recent discoveries and ideas that illustrate the biological functions of MAGE family in cancer progression. Furthermore, we also highlighted the current understanding of the epigenetic mechanism of MAGE family expression in human cancers.
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