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Wu R, Li D, Zhang S, Wang J, Yu Q, Feng D, Han P. Comprehensive pan-cancer analysis identifies PLAG1 as a key regulator of tumor immune microenvironment and prognostic biomarker. Front Immunol 2025; 16:1572108. [PMID: 40276502 PMCID: PMC12018345 DOI: 10.3389/fimmu.2025.1572108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 03/25/2025] [Indexed: 04/26/2025] Open
Abstract
Background The literature on the role of pleomorphic adenoma gene 1 (PLAG1) in malignant tumors is limited. This study aimed to perform pan-cancer analysis of PLAG1. Methods The expression of PLAG1 was analyzed by Human Protein Atlas (HPA). The differential expression and prognosis of PLAG1 were analyzed based on TCGA pan-cancer data. The relationship between PLAG1 expression and tumor heterogeneity, stemness and immune infiltration was investigated. The enrichment analysis and biological function of PLAG1 in bladder cancer were analyzed. Results The expression of PLAG1 was increased in a variety of tumors and significantly correlated with the prognosis of patients. Their expression levels were associated with key immune checkpoint genes (CD274, HAVCR2), immune infiltration and immune stimulation factors (CD48, CD27). In bladder cancer, functional enrichment analysis indicated that PLAG1 was involved in epidermal related processes and immune pathways. PLAG1 gene expression reduction can significantly inhibit the proliferation of bladder cancer cells. Conclusions PLAG1 has the potential to be a prognostic marker and a potential therapeutic target for patients with malignant tumors.
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Affiliation(s)
- Ruicheng Wu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
- Division of Surgery and Interventional Science, University College London, London, United Kingdom
| | - Dengxiong Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Shuxia Zhang
- Research Core Facilities, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jie Wang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Qingxin Yu
- Department of Pathology, Ningbo Clinical Pathology Diagnosis Center, Ningbo, Zhejiang, China
| | - Dechao Feng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
- Division of Surgery and Interventional Science, University College London, London, United Kingdom
| | - Ping Han
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
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2
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Afshari MK, Tejera Nevado P, Fehr A, Huang J, Jäwert F, Nilsson JA, Stenman G, Andersson MK. The Transcriptomic and Gene Fusion Landscape of Pleomorphic Salivary Gland Adenomas. Genes Chromosomes Cancer 2025; 64:e70023. [PMID: 39812386 PMCID: PMC11734380 DOI: 10.1002/gcc.70023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 12/29/2024] [Accepted: 12/31/2024] [Indexed: 01/16/2025] Open
Abstract
Pleomorphic adenoma (PA) is the most common salivary gland tumor. PAs are characterized by chromosomal rearrangements of 8q12 and 12q14-15, leading to gene fusions involving the PLAG1 and HMGA2 oncogenes. Here, we performed the first comprehensive study of the transcriptomic and gene fusion landscape of 38 cytogenetically characterized PAs. RNA-seq identified PLAG1 or HMGA2 fusions in 33/38 cases (87%), of which 15 were novel fusions. Fusions were found also in tumors with normal karyotype, demonstrating that they are generated by cryptic rearrangements. PLAG1 was mainly activated by promoter swapping and HMGA2 by truncation of its 3'-part. RNA-seq revealed upregulation of genes involved in extracellular matrix production, WNT-signaling, and epithelial-mesenchymal transition in PA compared to normal salivary tissue. Principal component analysis identified two PA subclusters characterized by PLAG1- and HMGA2-activation, respectively, that differed in expression of genes involved in the immune system, cell adhesion, and microenvironment remodeling. Moreover, comparative analyses of PA and salivary carcinomas revealed that PA resembles myoepithelial carcinoma. Our study reveals new oncogenic gene fusions and expands our knowledge about the molecular underpinnings of PA.
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Affiliation(s)
- Maryam Kakay Afshari
- Sahlgrenska Center for Cancer Research, Department of Laboratory MedicineUniversity of GothenburgGothenburgSweden
| | - Paloma Tejera Nevado
- Sahlgrenska Center for Cancer Research, Department of Laboratory MedicineUniversity of GothenburgGothenburgSweden
| | - André Fehr
- Sahlgrenska Center for Cancer Research, Department of Laboratory MedicineUniversity of GothenburgGothenburgSweden
- Department of Clinical PathologySahlgrenska University HospitalGothenburgSweden
| | - Junchi Huang
- Sahlgrenska Center for Cancer Research, Department of Laboratory MedicineUniversity of GothenburgGothenburgSweden
| | - Fredrik Jäwert
- Sahlgrenska Center for Cancer Research, Department of Laboratory MedicineUniversity of GothenburgGothenburgSweden
| | - Jonas A. Nilsson
- Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical SciencesUniversity of GothenburgGothenburgSweden
| | - Göran Stenman
- Sahlgrenska Center for Cancer Research, Department of Laboratory MedicineUniversity of GothenburgGothenburgSweden
- Department of Clinical PathologySahlgrenska University HospitalGothenburgSweden
| | - Mattias K. Andersson
- Sahlgrenska Center for Cancer Research, Department of Laboratory MedicineUniversity of GothenburgGothenburgSweden
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3
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Zhu Y, Hou H, Li Y, Zhang Y, Fang Y, Chen S, Zhang L, Jin W, Zhou Y. Hyperoxia exposure induces ferroptosis and apoptosis by downregulating PLAGL2 and repressing HIF-1α/VEGF signaling pathway in newborn alveolar typeII epithelial cell. Redox Rep 2024; 29:2387465. [PMID: 39102510 DOI: 10.1080/13510002.2024.2387465] [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] [Indexed: 08/07/2024] Open
Abstract
BACKGROUD Bronchopulmonary dysplasia (BPD) is one of the most important complications plaguing neonates and can lead to a variety of sequelae. the ability of the HIF-1α/VEGF signaling pathway to promote angiogenesis has an important role in neonatal lung development. METHOD Newborn rats were exposed to 85% oxygen. The effects of hyperoxia exposure on Pleomorphic Adenoma Gene like-2 (PLAGL2) and the HIF-1α/VEGF pathway in rats lung tissue were assessed through immunofluorescence and Western Blot analysis. In cell experiments, PLAGL2 was upregulated, and the effects of hyperoxia and PLAGL2 on cell viability were evaluated using scratch assays, CCK-8 assays, and EDU staining. The role of upregulated PLAGL2 in the HIF-1α/VEGF pathway was determined by Western Blot and RT-PCR. Apoptosis and ferroptosis effects were determined through flow cytometry and viability assays. RESULTS Compared with the control group, the expression levels of PLAGL2, HIF-1α, VEGF, and SPC in lung tissues after 3, 7, and 14 days of hyperoxia exposure were all decreased. Furthermore, hyperoxia also inhibited the proliferation and motility of type II alveolar epithelial cells (AECII) and induced apoptosis in AECII. Upregulation of PLAGL2 restored the proliferation and motility of AECII and suppressed cell apoptosis and ferroptosis, while the HIF-1α/VEGF signaling pathway was also revived. CONCLUSIONS We confirmed the positive role of PLAGL2 and HIF-1α/VEGF signaling pathway in promoting BPD in hyperoxia conditions, and provided a promising therapeutic targets.
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Affiliation(s)
- Yuting Zhu
- Department of Neonatology, The Affiliated Children's Hospital of Jiangnan University, Wuxi, People's Republic of China
| | - Hongmei Hou
- Department of Neonatology, The Affiliated Children's Hospital of Jiangnan University, Wuxi, People's Republic of China
| | - Yawen Li
- Department of Neonatology, The Affiliated Children's Hospital of Jiangnan University, Wuxi, People's Republic of China
| | - Yanyu Zhang
- Department of Neonatology, The Affiliated Children's Hospital of Jiangnan University, Wuxi, People's Republic of China
| | - Yuanyuan Fang
- Department of Neonatology, The Affiliated Children's Hospital of Jiangnan University, Wuxi, People's Republic of China
| | - Si Chen
- Department of Neonatology, The Affiliated Children's Hospital of Jiangnan University, Wuxi, People's Republic of China
| | - Le Zhang
- Department of Neonatology, The Affiliated Children's Hospital of Jiangnan University, Wuxi, People's Republic of China
| | - Weilai Jin
- Department of Neonatology, The Affiliated Children's Hospital of Jiangnan University, Wuxi, People's Republic of China
| | - Yahui Zhou
- Department of Neonatology, The Affiliated Children's Hospital of Jiangnan University, Wuxi, People's Republic of China
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Adduri A, Kim S. Ornaments for efficient allele-specific expression estimation with bias correction. Am J Hum Genet 2024; 111:1770-1781. [PMID: 39047729 PMCID: PMC11339617 DOI: 10.1016/j.ajhg.2024.06.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 06/22/2024] [Accepted: 06/24/2024] [Indexed: 07/27/2024] Open
Abstract
Allele-specific expression plays a crucial role in unraveling various biological mechanisms, including genomic imprinting and gene expression controlled by cis-regulatory variants. However, existing methods for quantification from RNA-sequencing (RNA-seq) reads do not adequately and efficiently remove various allele-specific read mapping biases, such as reference bias arising from reads containing the alternative allele that do not map to the reference transcriptome or ambiguous mapping bias caused by reads containing the reference allele that map differently from reads containing the alternative allele. We present Ornaments, a computational tool for rapid and accurate estimation of allele-specific transcript expression at unphased heterozygous loci from RNA-seq reads while correcting for allele-specific read mapping biases. Ornaments removes reference bias by mapping reads to a personalized transcriptome and ambiguous mapping bias by probabilistically assigning reads to multiple transcripts and variant loci they map to. Ornaments is a lightweight extension of kallisto, a popular tool for fast RNA-seq quantification, that improves the efficiency and accuracy of WASP, a popular tool for bias correction in allele-specific read mapping. In experiments with simulated and human lymphoblastoid cell-line RNA-seq reads with the genomes of the 1000 Genomes Project, we demonstrate that Ornaments improves the accuracy of WASP and kallisto, is nearly as efficient as kallisto, and is an order of magnitude faster than WASP per sample, with the additional cost of constructing a personalized index for multiple samples. Additionally, we show that Ornaments finds imprinted transcripts with higher sensitivity than WASP, which detects imprinted signals only at gene level.
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Affiliation(s)
- Abhinav Adduri
- Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA
| | - Seyoung Kim
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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5
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Gasperoni JG, Tran SC, Grommen SVH, De Groef B, Dworkin S. The Role of PLAG1 in Mouse Brain Development and Neurogenesis. Mol Neurobiol 2024; 61:5851-5867. [PMID: 38240991 PMCID: PMC11249490 DOI: 10.1007/s12035-024-03943-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 01/10/2024] [Indexed: 07/16/2024]
Abstract
The pleomorphic adenoma gene 1 (Plag1) is a transcription factor involved in the regulation of growth and cellular proliferation. Here, we report the spatial distribution and functional implications of PLAG1 expression in the adult mouse brain. We identified Plag1 promoter-dependent β-galactosidase expression in various brain structures, including the hippocampus, cortex, choroid plexus, subcommisural organ, ependymal cells lining the third ventricle, medial and lateral habenulae and amygdala. We noted striking spatial-restriction of PLAG1 within the cornu ammonis (CA1) region of the hippocampus and layer-specific cortical expression, with abundant expression noted in all layers except layer 5. Furthermore, our study delved into the role of PLAG1 in neurodevelopment, focusing on its impact on neural stem/progenitor cell proliferation. Loss of Plag1 resulted in reduced proliferation and decreased production of neocortical progenitors in vivo, although ex vivo neurosphere experiments revealed no cell-intrinsic defects in the proliferative or neurogenic capacity of Plag1-deficient neural progenitors. Lastly, we explored potential target genes of PLAG1 in the cortex, identifying that Neurogenin 2 (Ngn2) was significantly downregulated in Plag1-deficient mice. In summary, our study provides novel insights into the spatial distribution of PLAG1 expression in the adult mouse brain and its potential role in neurodevelopment. These findings expand our understanding of the functional significance of PLAG1 within the brain, with potential implications for neurodevelopmental disorders and therapeutic interventions.
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Affiliation(s)
- Jemma G Gasperoni
- Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, 3086, Australia
| | - Stephanie C Tran
- Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, 3086, Australia
| | - Sylvia V H Grommen
- Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, 3086, Australia
- Department of Biology, KU Leuven, B3000, Leuven, Belgium
| | - Bert De Groef
- Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, 3086, Australia
- Department of Biology, KU Leuven, B3000, Leuven, Belgium
| | - Sebastian Dworkin
- Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, 3086, Australia.
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6
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Izquierdo-Pujol J, Puertas MC, Martinez-Picado J, Morón-López S. Targeting Viral Transcription for HIV Cure Strategies. Microorganisms 2024; 12:752. [PMID: 38674696 PMCID: PMC11052381 DOI: 10.3390/microorganisms12040752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 04/05/2024] [Accepted: 04/05/2024] [Indexed: 04/28/2024] Open
Abstract
Combination antiretroviral therapy (ART) suppresses viral replication to undetectable levels, reduces mortality and morbidity, and improves the quality of life of people living with HIV (PWH). However, ART cannot cure HIV infection because it is unable to eliminate latently infected cells. HIV latency may be regulated by different HIV transcription mechanisms, such as blocks to initiation, elongation, and post-transcriptional processes. Several latency-reversing (LRA) and -promoting agents (LPA) have been investigated in clinical trials aiming to eliminate or reduce the HIV reservoir. However, none of these trials has shown a conclusive impact on the HIV reservoir. Here, we review the cellular and viral factors that regulate HIV-1 transcription, the potential pharmacological targets and genetic and epigenetic editing techniques that have been or might be evaluated to disrupt HIV-1 latency, the role of miRNA in post-transcriptional regulation of HIV-1, and the differences between the mechanisms regulating HIV-1 and HIV-2 expression.
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Affiliation(s)
- Jon Izquierdo-Pujol
- IrsiCaixa, 08916 Badalona, Spain; (J.I.-P.); (M.C.P.); (J.M.-P.)
- Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
| | - Maria C. Puertas
- IrsiCaixa, 08916 Badalona, Spain; (J.I.-P.); (M.C.P.); (J.M.-P.)
- Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
- CIBERINFEC, 28029 Madrid, Spain
| | - Javier Martinez-Picado
- IrsiCaixa, 08916 Badalona, Spain; (J.I.-P.); (M.C.P.); (J.M.-P.)
- Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
- CIBERINFEC, 28029 Madrid, Spain
- Department of Infectious Diseases and Immunity, School of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), 08500 Vic, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain
| | - Sara Morón-López
- IrsiCaixa, 08916 Badalona, Spain; (J.I.-P.); (M.C.P.); (J.M.-P.)
- Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
- CIBERINFEC, 28029 Madrid, Spain
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Murthy MHS, Jasbi P, Lowe W, Kumar L, Olaosebikan M, Roger L, Yang J, Lewinski N, Daniels N, Cowen L, Klein-Seetharaman J. Insulin signaling and pharmacology in humans and in corals. PeerJ 2024; 12:e16804. [PMID: 38313028 PMCID: PMC10838073 DOI: 10.7717/peerj.16804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 12/27/2023] [Indexed: 02/06/2024] Open
Abstract
Once thought to be a unique capability of the Langerhans islets in the pancreas of mammals, insulin (INS) signaling is now recognized as an evolutionarily ancient function going back to prokaryotes. INS is ubiquitously present not only in humans but also in unicellular eukaryotes, fungi, worms, and Drosophila. Remote homologue identification also supports the presence of INS and INS receptor in corals where the availability of glucose is largely dependent on the photosynthetic activity of the symbiotic algae. The cnidarian animal host of corals operates together with a 20,000-sized microbiome, in direct analogy to the human gut microbiome. In humans, aberrant INS signaling is the hallmark of metabolic disease, and is thought to play a major role in aging, and age-related diseases, such as Alzheimer's disease. We here would like to argue that a broader view of INS beyond its human homeostasis function may help us understand other organisms, and in turn, studying those non-model organisms may enable a novel view of the human INS signaling system. To this end, we here review INS signaling from a new angle, by drawing analogies between humans and corals at the molecular level.
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Affiliation(s)
| | - Paniz Jasbi
- School of Molecular Sciences, Arizona State University, Phoenix, AZ, USA
| | - Whitney Lowe
- Departments of Chemistry & Physics, Colorado School of Mines, Golden, CO, United States
| | - Lokender Kumar
- Departments of Chemistry & Physics, Colorado School of Mines, Golden, CO, United States
| | | | - Liza Roger
- School of Molecular Sciences, Arizona State University, Phoenix, AZ, USA
- School of Ocean Futures, Arizona State University, Tempe, AZ, United States of America
| | - Jinkyu Yang
- Department of Aeronautics & Astronautics, University of Washington, Seattle, WA, USA
| | - Nastassja Lewinski
- Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA, USA
| | - Noah Daniels
- Department of Computer Science, University of Rhode Island, Kingston, RI, USA
| | - Lenore Cowen
- Department of Computer Science, Tufts University, Medford, MA, USA
| | - Judith Klein-Seetharaman
- School of Molecular Sciences, Arizona State University, Phoenix, AZ, USA
- Departments of Chemistry & Physics, Colorado School of Mines, Golden, CO, United States
- College of Health Solutions, Arizona State University, Phoenix, AZ, United States
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8
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D’Occhio MJ, Campanile G, Baruselli PS, Porto Neto LR, Hayes BJ, Snr AC, Fortes MRS. Pleomorphic adenoma gene1 in reproduction and implication for embryonic survival in cattle: a review. J Anim Sci 2024; 102:skae103. [PMID: 38586898 PMCID: PMC11056886 DOI: 10.1093/jas/skae103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 04/05/2024] [Indexed: 04/09/2024] Open
Abstract
The pleomorphic adenoma gene1 (PLAG1) encodes a DNA-binding, C2H2 zinc-finger protein which acts as a transcription factor that regulates the expression of diverse genes across different organs and tissues; hence, the name pleomorphic. Rearrangements of the PLAG1 gene, and/or overexpression, are associated with benign tumors and cancers in a variety of tissues. This is best described for pleomorphic adenoma of the salivary glands in humans. The most notable expression of PLAG1 occurs during embryonic and fetal development, with lesser expression after birth. Evidence has accumulated of a role for PLAG1 protein in normal early embryonic development and placentation in mammals. PLAG1 protein influences the expression of the ike growth factor 2 (IGF2) gene and production of IGF2 protein. IGF2 is an important mitogen in ovarian follicles/oocytes, embryos, and fetuses. The PLAG1-IGF2 axis, therefore, provides one pathway whereby PLAG1 protein can influence embryonic survival and pregnancy. PLAG1 also influences over 1,000 other genes in embryos including those associated with ribosomal assembly and proteins. Brahman (Bos indicus) heifers homozygous for the PLAG1 variant, rs109815800 (G > T), show greater fertility than contemporary heifers with either one, or no copy, of the variant. Greater fertility in heifers homozygous for rs109815800 could be the result of early puberty and/or greater embryonic survival. The present review first looks at the broader roles of the PLAG1 gene and PLAG1 protein and then focuses on the emerging role of PLAG1/PLAG1 in embryonic development and pregnancy. A deeper understanding of factors which influence embryonic development is required for the next transformational increase in embryonic survival and successful pregnancy for both in vivo and in vitro derived embryos in cattle.
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Affiliation(s)
- Michael J D’Occhio
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, NSW, Australia
| | - Giuseppe Campanile
- Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy
| | - Pietro S Baruselli
- Faculty of Veterinary Medicine and Animal Science, Department of Animal Reproduction, University of Sao Paulo, Sao Paulo, Brazil
| | | | - Ben J Hayes
- Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, Brisbane, QLD, Australia
| | - Alf Collins Snr
- CBV Brahman, Marlborough, Central Queensland, QLD, Australia
| | - Marina R S Fortes
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
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9
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Pavičić I, Rokić F, Vugrek O. Effects of S-Adenosylhomocysteine Hydrolase Downregulation on Wnt Signaling Pathway in SW480 Cells. Int J Mol Sci 2023; 24:16102. [PMID: 38003292 PMCID: PMC10671441 DOI: 10.3390/ijms242216102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/31/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023] Open
Abstract
S-adenosylhomocysteine hydrolase (AHCY) deficiency results mainly in hypermethioninemia, developmental delay, and is potentially fatal. In order to shed new light on molecular aspects of AHCY deficiency, in particular any changes at transcriptome level, we enabled knockdown of AHCY expression in the colon cancer cell line SW480 to simulate the environment occurring in AHCY deficient individuals. The SW480 cell line is well known for elevated AHCY expression, and thereby represents a suitable model system, in particular as AHCY expression is regulated by MYC, which, on the other hand, is involved in Wnt signaling and the regulation of Wnt-related genes, such as the β-catenin co-transcription factor LEF1 (lymphoid enhancer-binding factor 1). We selected LEF1 as a potential target to investigate its association with S-adenosylhomocysteine hydrolase deficiency. This decision was prompted by our analysis of RNA-Seq data, which revealed significant changes in the expression of genes related to the Wnt signaling pathway and genes involved in processes responsible for epithelial-mesenchymal transition (EMT) and cell proliferation. Notably, LEF1 emerged as a common factor in these processes, showing increased expression both on mRNA and protein levels. Additionally, we show alterations in interconnected signaling pathways linked to LEF1, causing gene expression changes with broad effects on cell cycle regulation, tumor microenvironment, and implications to cell invasion and metastasis. In summary, we provide a new link between AHCY deficiency and LEF1 serving as a mediator of changes to the Wnt signaling pathway, thereby indicating potential connections of AHCY expression and cancer cell phenotype, as Wnt signaling is frequently associated with cancer development, including colorectal cancer (CRC).
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Affiliation(s)
| | | | - Oliver Vugrek
- Laboratory for Advanced Genomics, Divison of Molecular Medicine, Institute Ruđer Bošković, Bijenička Cesta 54, 10000 Zagreb, Croatia; (I.P.); (F.R.)
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Alimohammadi M, Gholinezhad Y, Mousavi V, Kahkesh S, Rezaee M, Yaghoobi A, Mafi A, Araghi M. Circular RNAs: novel actors of Wnt signaling pathway in lung cancer progression. EXCLI JOURNAL 2023; 22:645-669. [PMID: 37636026 PMCID: PMC10450211 DOI: 10.17179/excli2023-6209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 06/20/2023] [Indexed: 08/29/2023]
Abstract
Circular RNAs (CircRNAs) are a class of regulatory RNA transcripts, which are ubiquitously expressed in eukaryotes. CircRNA dysregulation has been shown to disrupt the interaction of the Wnt/β-catenin pathway, which regulates several biological processes involved in tumorigenesis, thereby contributing to the development and progression of cancer. Interactions of tumor-derived circRNAs with the Wnt/β-catenin signaling pathway provide both clinical diagnostic biomarkers and promising therapeutic targets. In this review, we outlined current evidence on the roles of circRNAs associated with the Wnt/β-catenin pathway in regulating lung cancer formation and development. We believe that our findings will assist in the advancement or establishment of circRNA-based lung cancer therapeutic approaches.
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Affiliation(s)
- Mina Alimohammadi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Gholinezhad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahide Mousavi
- School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Samaneh Kahkesh
- Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Malihe Rezaee
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Yaghoobi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahmood Araghi
- Department of Pathology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
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11
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Luo M, Deng X, Chen Z, Hu Y. Circular RNA circPOFUT1 enhances malignant phenotypes and autophagy-associated chemoresistance via sequestrating miR-488-3p to activate the PLAG1-ATG12 axis in gastric cancer. Cell Death Dis 2023; 14:10. [PMID: 36624091 PMCID: PMC9829716 DOI: 10.1038/s41419-022-05506-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 12/01/2022] [Accepted: 12/08/2022] [Indexed: 01/11/2023]
Abstract
Circular RNAs are key regulators in regulating the progression and chemoresistance of gastric cancer (GC), suggesting circular RNAs as potential therapeutic targets for GC. The roles of a novel circular RNA circPOFUT1 in GC are unknown. Here, we found that circPOFUT1 was upregulated in GC tissues and cells, and increased circPOFUT1 expression indicated poor prognosis. Overexpression of circPOFUT1 enhanced cell proliferation, migration, invasion and autophagy-associated chemoresistance in GC, which were suppressed by miR-488-3p overexpression. CircPOFUT1 reduced miR-488-3p expression via sponging miR-488-3p in GC cells. PLAG1 interacted with ATG12 and promoted its expression. MiR-488-3p bound to PLAG1 and suppressed the expression of PLAG1 and ATG12 in GC cells. Overexpression of circPOFUT1 enhanced autophagy-associated chemoresistance of GC cells in vivo, but it was inhibited by overexpression of miR-488-3p. Collectively, circPOFUT1 directly sponged miR-488-3p to activate the expression of PLAG1 and ATG12, thus enhancing malignant phenotypes and autophagy-associated chemoresistance in GC. Our findings show the potential of circPOFUT1 as biomarkers and targeting circPOFUT1 as a therapeutic strategy for GC.
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Affiliation(s)
- Ming Luo
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xiaofeng Deng
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Zonglin Chen
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Yongjun Hu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
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12
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Liang X, Fu Z, Tang L, Zheng M, Chen D, Liu A, Shi L, Yang L, Shao C, Dong X. PLAGL1 is associated with prognosis and cell proliferation in pancreatic adenocarcinoma. BMC Gastroenterol 2023; 23:2. [PMID: 36600208 PMCID: PMC9811725 DOI: 10.1186/s12876-022-02609-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 12/08/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Emerging evidence has shown the crucial roles of pleomorphic adenoma gene (PLAG) family genes in multiple cancers. However, their functions and mechanisms in pancreatic adenocarcinoma (PAAD) remain poorly understood. METHODS We analyzed the expression levels of PLAG family genes in both The Cancer Genome Atlas (TCGA) database and a Gene Expression Omnibus (GEO) database, and confirmed the results in our three independent cohorts of 382 PAAD tissues and 362 adjacent nontumor pancreatic tissues. Integrated analyses were carried out to explore the function, mechanism and prognostic value of the selected PLAG family gene in PAAD patients. RESULTS By analyzing the TCGA and GEO databases, PLAGL1 was identified to be downregulated in PAAD tissues, and its decreasing levels of both mRNA and protein were verified in our three independent PAAD cohorts. PLAGL1 expression was inversely correlated with clinicopathological factors including the Ki67+ cell rate and pathologic stage. Further GSEA of the TCGA-PAAD cohort demonstrated that multiple signaling pathways implicated in cell proliferation were enriched in the lower PLAGL1 expressing PAAD group. Moreover, we demonstrated that PLAGL1 expression was obviously negatively associated with patients' overall survival outcome in both the TCGA-PAAD cohort and our verification cohorts. Additionally, through MTS and BrdU assays, we further demonstrated in vitro that PLAGL1 had the impact of preventing the proliferation of pancreatic cancer cells. CONCLUSIONS Our present study suggested that downregulated PLAGL1 might act as a biomarker in predicts poor prognosis and one of important factors in increasing cell proliferation in PAAD. This study provides us with a novel prognostic marker and therapeutic strategy for PAAD, which deserves further study.
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Affiliation(s)
- Xing Liang
- grid.429222.d0000 0004 1798 0228Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 Jiangsu Province China ,grid.73113.370000 0004 0369 1660Department of Pancreatic-Biliary Surgery, Second Affiliated Hospital of Naval Medical University, Fengyang Road 415, Shanghai, 200003 China
| | - Zhiping Fu
- grid.73113.370000 0004 0369 1660Department of Pancreatic-Biliary Surgery, Second Affiliated Hospital of Naval Medical University, Fengyang Road 415, Shanghai, 200003 China
| | - Liang Tang
- grid.73113.370000 0004 0369 1660Department of Pancreatic-Biliary Surgery, Second Affiliated Hospital of Naval Medical University, Fengyang Road 415, Shanghai, 200003 China
| | - Minghui Zheng
- grid.73113.370000 0004 0369 1660Department of Pancreatic-Biliary Surgery, Second Affiliated Hospital of Naval Medical University, Fengyang Road 415, Shanghai, 200003 China
| | - Danlei Chen
- grid.73113.370000 0004 0369 1660Department of Pancreatic-Biliary Surgery, Second Affiliated Hospital of Naval Medical University, Fengyang Road 415, Shanghai, 200003 China
| | - Anan Liu
- grid.73113.370000 0004 0369 1660Department of Pancreatic-Biliary Surgery, Second Affiliated Hospital of Naval Medical University, Fengyang Road 415, Shanghai, 200003 China
| | - Ligang Shi
- grid.73113.370000 0004 0369 1660Department of Pancreatic-Biliary Surgery, Second Affiliated Hospital of Naval Medical University, Fengyang Road 415, Shanghai, 200003 China
| | - Linhua Yang
- grid.16821.3c0000 0004 0368 8293Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127 China
| | - Chenghao Shao
- grid.73113.370000 0004 0369 1660Department of Pancreatic-Biliary Surgery, Second Affiliated Hospital of Naval Medical University, Fengyang Road 415, Shanghai, 200003 China
| | - Xiaoqiang Dong
- grid.429222.d0000 0004 1798 0228Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 Jiangsu Province China
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13
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Pan Y, Wang M, Wu H, Akhatayeva Z, Lan X, Fei P, Mao C, Jiang F. Indel mutations of sheep PLAG1 gene and their associations with growth traits. Anim Biotechnol 2022; 33:1459-1465. [PMID: 33825658 DOI: 10.1080/10495398.2021.1906265] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Pleiomorphic adenoma gene 1 (PLAG1) is mainly expressed in embryonic development, and it is reported to take an effect on the growth performance of mice, cattle, pigs, and sheep. To explore how conservative the PLAG1 is in different sheep breeds, the effects of the two indel variants on the growth traits of the Chinese Luxi blackhead (LXBH) sheep were firstly detected. The P2-del 30 bp and P4-del 45 bp indel loci of the sheep PLAG1 gene were significantly related to 15 growth traits (P < 0.05). Genotype ID and genotype II were dominant for the P2-del 30 bp and P4-del 45 bp loci, respectively. The above findings indicated that the two indel mutations in the ovine PLAG1 gene were suggested to become the molecular markers for the selection of economic traits in sheep.
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Affiliation(s)
- Yun Pan
- College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Northwest A&F University, Yangling, Shaanxi, China
| | - Min Wang
- College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Northwest A&F University, Yangling, Shaanxi, China
| | - Hui Wu
- College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Northwest A&F University, Yangling, Shaanxi, China
| | - Zhanerke Akhatayeva
- College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Northwest A&F University, Yangling, Shaanxi, China
| | - Xianyong Lan
- College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Northwest A&F University, Yangling, Shaanxi, China
| | - Panfeng Fei
- College of Information Engineering, Northwest A&F University, Yangling, Shaanxi, China
| | - Cui Mao
- Shandong Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Fugui Jiang
- Shandong Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
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14
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Pedersen S, Kverneland M, Nakken KO, Rudi K, Iversen PO, Gervin K, Selmer KK. Genome-wide decrease in DNA methylation in adults with epilepsy treated with modified ketogenic diet: A prospective study. Epilepsia 2022; 63:2413-2426. [PMID: 35762681 PMCID: PMC9796519 DOI: 10.1111/epi.17351] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 06/27/2022] [Accepted: 06/27/2022] [Indexed: 01/01/2023]
Abstract
OBJECTIVE The aim of this study was to investigate the impact of the modified ketogenic diet on DNA methylation in adults with epilepsy. METHODS In this prospective study, we investigated the genome-wide DNA methylation in whole blood in 58 adults with epilepsy treated with the modified ketogenic for 12 weeks. Patients were recruited from the National Center for Epilepsy, Norway, from March 1, 2011 to February 28, 2017. DNA methylation was analyzed using the Illumina Infinium MethylationEPIC BeadChip array. Analysis of variance and paired t-test were used to identify differentially methylated loci after 4 and 12 weeks of dietary treatment. A false discovery rate approach with a significance threshold of <5% was used to adjust for multiple comparisons. RESULTS We observed a genome-wide decrease in DNA methylation, both globally and at specific sites, after 4 and 12 weeks of dietary treatment. A substantial share of the differentially methylated positions (CpGs) were annotated to genes associated with epilepsy (n = 7), lipid metabolism (n = 8), and transcriptional regulation (n = 10). Furthermore, five of the identified genes were related to inositol phosphate metabolism, which may represent a possible mechanism by which the ketogenic diet attenuates seizures. SIGNIFICANCE A better understanding of the modified ketogenic diet's influence at the molecular level may be the key to unraveling the mechanisms by which the diet can ameliorate seizures and possibly to identifying novel therapeutic targets for epilepsy.
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Affiliation(s)
- Sigrid Pedersen
- National Center for EpilepsyOslo University HospitalOsloNorway
| | | | | | - Knut Rudi
- Department of Chemistry, Biotechnology, and Food ScienceNorwegian University of Life SciencesÅsNorway
| | - Per Ole Iversen
- Department of NutritionUniversity of OsloOsloNorway,Department of HematologyOslo University HospitalOsloNorway
| | - Kristina Gervin
- Department of Research and InnovationOslo University HospitalOsloNorway
| | - Kaja Kristine Selmer
- National Center for EpilepsyOslo University HospitalOsloNorway,Department of Research and InnovationOslo University HospitalOsloNorway
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15
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Chromosome Translocations, Gene Fusions, and Their Molecular Consequences in Pleomorphic Salivary Gland Adenomas. Biomedicines 2022; 10:biomedicines10081970. [PMID: 36009517 PMCID: PMC9405559 DOI: 10.3390/biomedicines10081970] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/09/2022] [Accepted: 08/11/2022] [Indexed: 11/23/2022] Open
Abstract
Salivary gland tumors are a heterogeneous group of tumors originating from the major and minor salivary glands. The pleomorphic adenoma (PA), which is the most common subtype, is a benign lesion showing a remarkable morphologic diversity and that, upon recurrence or malignant transformation, can cause significant clinical problems. Cytogenetic studies of >500 PAs have revealed a complex and recurrent pattern of chromosome rearrangements. In this review, we discuss the specificity and frequency of these rearrangements and their molecular/clinical consequences. The genomic hallmark of PA is translocations with breakpoints in 8q12 and 12q13-15 resulting in gene fusions involving the transcription factor genes PLAG1 and HMGA2. Until recently, the association between these two oncogenic drivers was obscure. Studies of the Silver−Russel syndrome, a growth retardation condition infrequently caused by mutations in IGF2/HMGA2/PLAG1, have provided new clues to the understanding of the molecular pathogenesis of PA. These studies have demonstrated that HMGA2 is an upstream regulator of PLAG1 and that HMGA2 regulates the expression of IGF2 via PLAG1. This provides a novel explanation for the 8q12/12q13-15 aberrations in PA and identifies IGF2 as a major oncogenic driver and therapeutic target in PA. These studies have important diagnostic and therapeutic implications for patients with PA.
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16
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Panagopoulos I, Heim S. Interstitial Deletions Generating Fusion Genes. Cancer Genomics Proteomics 2021; 18:167-196. [PMID: 33893073 DOI: 10.21873/cgp.20251] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/15/2021] [Accepted: 03/16/2021] [Indexed: 12/16/2022] Open
Abstract
A fusion gene is the physical juxtaposition of two different genes resulting in a structure consisting of the head of one gene and the tail of the other. Gene fusion is often a primary neoplasia-inducing event in leukemias, lymphomas, solid malignancies as well as benign tumors. Knowledge about fusion genes is crucial not only for our understanding of tumorigenesis, but also for the diagnosis, prognostication, and treatment of cancer. Balanced chromosomal rearrangements, in particular translocations and inversions, are the most frequent genetic events leading to the generation of fusion genes. In the present review, we summarize the existing knowledge on chromosome deletions as a mechanism for fusion gene formation. Such deletions are mostly submicroscopic and, hence, not detected by cytogenetic analyses but by array comparative genome hybridization (aCGH) and/or high throughput sequencing (HTS). They are found across the genome in a variety of neoplasias. As tumors are increasingly analyzed using aCGH and HTS, it is likely that more interstitial deletions giving rise to fusion genes will be found, significantly impacting our understanding and treatment of cancer.
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Affiliation(s)
- Ioannis Panagopoulos
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway;
| | - Sverre Heim
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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17
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Genomic Imprinting at the Porcine PLAGL1 Locus and the Orthologous Locus in the Human. Genes (Basel) 2021; 12:genes12040541. [PMID: 33918057 PMCID: PMC8069715 DOI: 10.3390/genes12040541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 04/06/2021] [Indexed: 12/27/2022] Open
Abstract
Implementation of genomic imprinting in mammals often results in cis-acting silencing of a gene cluster and monoallelic expression, which are important for mammalian growth and function. Compared with widely documented imprinting status in humans and mice, current understanding of genomic imprinting in pigs is relatively limited. The objectives of this study were to identify DNA methylation status and allelic expression of alternative spliced isoforms at the porcine PLAGL1 locus and assess the conservation of the locus compared to the orthologous human locus. DNA methylome and transcriptome were constructed using porcine parthenogenetic or biparental control embryos. Using methylome, differentially methylated regions between those embryos were identified. Alternative splicing was identified by differential splicing analysis, and monoallelic expression was examined using single nucleotide polymorphism sites. Moreover, topological boundary regions were identified by analyzing CTCF binding sites and compared with the boundary of human orthologous locus. As a result, it was revealed that the monoallelic expression of the PLAGL1 gene in porcine embryos via genomic imprinting was maintained in the adult stage. The porcine PLAGL1 locus was largely conserved in regard to maternal hypermethylation, tissue distribution of mRNA expression, monoallelic expression, and biallelic CTCF-binding, with exceptions on transcript isoforms produced by alternative splicing instead of alternative promoter usage. These findings laid the groundwork for comparative studies on the imprinted PLAGL1 gene and related regulatory mechanisms across species.
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18
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A functional screen identifies transcriptional networks that regulate HIV-1 and HIV-2. Proc Natl Acad Sci U S A 2021; 118:2012835118. [PMID: 33836568 DOI: 10.1073/pnas.2012835118] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The molecular networks involved in the regulation of HIV replication, transcription, and latency remain incompletely defined. To expand our understanding of these networks, we performed an unbiased high-throughput yeast one-hybrid screen, which identified 42 human transcription factors and 85 total protein-DNA interactions with HIV-1 and HIV-2 long terminal repeats. We investigated a subset of these transcription factors for transcriptional activity in cell-based models of infection. KLF2 and KLF3 repressed HIV-1 and HIV-2 transcription in CD4+ T cells, whereas PLAGL1 activated transcription of HIV-2 through direct protein-DNA interactions. Using computational modeling with interacting proteins, we leveraged the results from our screen to identify putative pathways that define intrinsic transcriptional networks. Overall, we used a high-throughput functional screen, computational modeling, and biochemical assays to identify and confirm several candidate transcription factors and biochemical processes that influence HIV-1 and HIV-2 transcription and latency.
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19
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Hu W, Zheng S, Guo H, Dai B, Ni J, Shi Y, Bian H, Li L, Shen Y, Wu M, Tian Z, Liu G, Hossain MA, Yang H, Wang D, Zhang Q, Yu J, Birnbaumer L, Feng J, Yu D, Yang Y. PLAGL2-EGFR-HIF-1/2α Signaling Loop Promotes HCC Progression and Erlotinib Insensitivity. Hepatology 2021; 73:674-691. [PMID: 32335942 DOI: 10.1002/hep.31293] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 04/02/2020] [Accepted: 04/07/2020] [Indexed: 01/16/2023]
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, hence a major public health threat. Pleomorphic adenoma gene like-2 (PLAGL2) has been reported to play a role in tumorigenesis. However, its precise function in HCC remains poorly understood. APPROACH AND RESULTS In this study, we demonstrated that PLAGL2 was up-regulated in HCC compared with that of adjacent nontumorous tissues and also correlated with overall survival times. We further showed that PLAGL2 promoted HCC cell proliferation, migration, and invasion both in vitro and in vivo. PLAGL2 expression was positively correlated with epidermal growth factor receptor (EGFR) expression. Mechanistically, this study demonstrated that PLAGL2 functions as a transcriptional regulator of EGFR and promotes HCC cell proliferation, migration, and invasion through the EGFR-AKT pathway. Moreover, hypoxia was found to significantly induce high expression of PLAGL2, which promoted hypoxia inducible factor 1/2 alpha subunit (HIF1/2A) expression through EGFR. Therefore, this study demonstrated that a PLAGL2-EGFR-HIF1/2A signaling loop promotes HCC progression. More importantly, PLAGL2 expression reduced hepatoma cells' response to the anti-EGFR drug erlotinib. PLAGL2 knockdown enhanced the response to erlotinib. CONCLUSIONS This study reveals the pivotal role of PLAGL2 in HCC cell proliferation, metastasis, and erlotinib insensitivity. This suggests that PLAGL2 can be a potential therapeutic target of HCC.
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Affiliation(s)
- Weiwei Hu
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Shufang Zheng
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Haixin Guo
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Beiying Dai
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Jiaping Ni
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Yaohong Shi
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Hanrui Bian
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Lanxin Li
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Yumeng Shen
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Mo Wu
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Zhoutong Tian
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Guilai Liu
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Md Amir Hossain
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Hongbao Yang
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Duowei Wang
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
| | - Qin Zhang
- Department of ChemotherapyJiangsu Cancer Hospital, Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical UniversityNanjingChina
| | - Jun Yu
- Department of ChemotherapyJiangsu Cancer Hospital, Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical UniversityNanjingChina
| | - Lutz Birnbaumer
- Institute of Biomedical ResearchCatholic University of ArgentinaBuenos AiresArgentina
| | - Jifeng Feng
- Department of ChemotherapyJiangsu Cancer Hospital, Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical UniversityNanjingChina
| | - Decai Yu
- Department of general SurgeryAffiliated Drum Tower HospitalMedical School of Nanjing UniversityNanjingChina
| | - Yong Yang
- Center for New Drug Safety Evaluation and ResearchState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingChina
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20
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Wei M, Zhang C, Tian Y, Du X, Wang Q, Zhao H. Expression and Function of WNT6: From Development to Disease. Front Cell Dev Biol 2021; 8:558155. [PMID: 33425886 PMCID: PMC7794017 DOI: 10.3389/fcell.2020.558155] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 09/04/2020] [Indexed: 11/17/2022] Open
Abstract
WNT family member 6 (WNT6) is a member of the highly conserved WNT protein family. It plays an essential role in the normal development process, not only in embryonic morphogenesis, but also in post-natal homeostasis. WNT6 functions in mice and humans. This review summarizes the current findings on the biological functions of WNT6, describing its involvement in regulating embryogenesis, decidualization, and organ development. Aberrant WNT6 signaling is related to various pathologies, such as promoting cancer development, lung tuberculosis, and kidney fibrosis and improving the symptoms of Rett syndrome (RTT). Thus, due to its various functions, WNT6 has great potential for in-depth research. This work not only describes the signaling mechanism and function of WNT6 under physiological and pathological conditions, but also provides a theoretical basis for targeted therapy.
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Affiliation(s)
- Ming Wei
- Department of Respiratory Medicine, The Second Hospital of Dalian Medical University, Dalian, China
| | - Congmin Zhang
- Department of Scientific Research Center, The Second Hospital of Dalian Medical University, Dalian, China
| | - Yujia Tian
- Department of Scientific Research Center, The Second Hospital of Dalian Medical University, Dalian, China
| | - Xiaohui Du
- Department of Scientific Research Center, The Second Hospital of Dalian Medical University, Dalian, China
| | - Qi Wang
- Department of Respiratory Medicine, The Second Hospital of Dalian Medical University, Dalian, China
| | - Hui Zhao
- The Health Check Up Center, The Second Hospital of Dalian Medical University, Dalian, China
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21
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Effect of Pleomorphic Adenoma Gene 1 Deficiency on Selected Behaviours in Adult Mice. Neuroscience 2020; 455:30-38. [PMID: 33346119 DOI: 10.1016/j.neuroscience.2020.12.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 12/03/2020] [Accepted: 12/05/2020] [Indexed: 12/16/2022]
Abstract
The proto-oncogene pleomorphic adenoma gene 1 (Plag1) encodes a zinc finger transcription factor. PLAG1 is part of the high motility group AT hook-2 (HGMA2)-PLAG1-insulin-like growth factor 2 (IGF2) pathway that, when disrupted, leads to Silver-Russell syndrome, a severe form of intrauterine growth restriction. With little known about PLAG1's role in normal physiology, this study is the first to characterise the behavioural phenotype of PLAG1-deficient mice. Mice were tested for differences in circadian locomotor activity and body temperature, sleep-like behaviour, anxiety-like behaviour, cognition, social behaviour, and sensorimotor gating. Overall, the behavioural phenotype of the Plag1 knock-out (KO) mice was mild: no significant differences were seen in circadian activity levels, locomotion, object recognition, spatial memory or sociability compared to wild-type mice. However, the cued test of fear conditioning, prepulse inhibition of the startle response and Preyer's reflex test suggest that Plag1 KO mice may have a hearing impairment. This implies that PLAG1 plays an important role in proper functioning and/or development of the neural circuitry behind the auditory processes or interacts with genes involved in those processes.
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22
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Panagopoulos I, Gorunova L, Andersen K, Lund-Iversen M, Lobmaier I, Micci F, Heim S. NDRG1-PLAG1 and TRPS1-PLAG1 Fusion Genes in Chondroid Syringoma. Cancer Genomics Proteomics 2020; 17:237-248. [PMID: 32345665 DOI: 10.21873/cgp.20184] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 02/04/2020] [Accepted: 02/06/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIM Chondroid syringoma is a rare benign tumor emanating from sweat glands. Although rearrangements of the pleomorphic adenoma gene 1 (PLAG1) have been reported in such tumors, information on PLAG1 fusion genes is very limited. MATERIALS AND METHODS Cytogenetic, fluorescence in situ hybridization, RNA sequencing, array comparative genomic hybridization, reverse transcription polymerase chain reaction, and Sanger sequencing analyses were performed on two chondroid syringoma cases. RESULTS Both tumors had structural rearrangements of chromosome 8. An NDRG1-PLAG1 transcript was found in the first tumor in which exon 3 of PLAG1 was fused with exon 1 of NDRG1. A TRPS1-PLAG1 chimeric transcript was detected in the second chondroid syringoma in which exon 2 or exon 3 of PLAG1 was fused with exon 1 of TRPS1. CONCLUSION The NDRG1-PLAG1 and TRPS1-PLAG1 resemble other PLAG1 fusion genes inasmuch as the expression of PLAG1 comes under the control of the NDRG1 or TRPS1 promoter.
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Affiliation(s)
- Ioannis Panagopoulos
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ludmila Gorunova
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Kristin Andersen
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Marius Lund-Iversen
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ingvild Lobmaier
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Francesca Micci
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Sverre Heim
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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23
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Afshari MK, Fehr A, Nevado PT, Andersson MK, Stenman G. Activation of PLAG1 and HMGA2 by gene fusions involving the transcriptional regulator gene NFIB. Genes Chromosomes Cancer 2020; 59:652-660. [PMID: 32654217 DOI: 10.1002/gcc.22885] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 12/22/2022] Open
Abstract
The pleomorphic adenoma (PA), which is the most common salivary gland neoplasm, is a benign tumor characterized by recurrent chromosome rearrangements involving 8q12 and 12q14-15. We have previously shown that the PLAG1 and HMGA2 oncogenes are the targets of these rearrangements. Here, we have identified previously unrecognized subsets of PAs with ins(9;8)/t(8;9) (n = 5) and ins(9;12)/t(9;12) (n = 8) and breakpoints located in the vicinity of the PLAG1 and HMGA2 loci. RNA-sequencing and reverse transcriptase (RT)-PCR analyses of a case with an ins(9;8) revealed a novel NFIB-PLAG1 fusion in which NFIB exon 4 is linked to PLAG1 exon 3. In contrast to the developmentally regulated PLAG1 gene, NFIB was highly expressed in normal salivary gland, indicating that PLAG1 in this case, as in other variant fusions, is activated by promoter swapping. RT-PCR analysis of three PAs with t(9;12) revealed two tumors with chimeric transcripts consisting of HMGA2 exon 4 linked to NFIB exons 9 or 3 and one case with a fusion linking HMGA2 exon 3 to NFIB exon 9. The NFIB fusion events resulted in potent activation of PLAG1 and HMGA2. Analysis of the chromatin landscape surrounding NFIB revealed several super-enhancers in the 5'- and 3'-parts of the NFIB locus and its flanking sequences. These findings indicate that PLAG1 and HMGA2, similar to MYB in adenoid cystic carcinoma, may be activated by enhancer-hijacking events, in which super-enhancers in NFIB are translocated upstream of PLAG1 or downstream of HMGA2. Our results further emphasize the role of NFIB as a fusion partner to multiple oncogenes in histopathologically different types of salivary gland tumors.
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Affiliation(s)
- Maryam Kakay Afshari
- Sahlgrenska Center for Cancer Research, Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - André Fehr
- Sahlgrenska Center for Cancer Research, Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Paloma Tejera Nevado
- Sahlgrenska Center for Cancer Research, Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mattias K Andersson
- Sahlgrenska Center for Cancer Research, Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Göran Stenman
- Sahlgrenska Center for Cancer Research, Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
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Grigoletto L, Ferraz JBS, Oliveira HR, Eler JP, Bussiman FO, Abreu Silva BC, Baldi F, Brito LF. Genetic Architecture of Carcass and Meat Quality Traits in Montana Tropical ® Composite Beef Cattle. Front Genet 2020; 11:123. [PMID: 32180796 PMCID: PMC7057717 DOI: 10.3389/fgene.2020.00123] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 02/03/2020] [Indexed: 12/16/2022] Open
Abstract
The Montana Tropical® Composite is a recently developed beef cattle population that is rapidly expanding in Brazil and other tropical countries. This is mainly due to its improved meat quality and adaptation to tropical climate conditions compared to Zebu and Taurine cattle breeds, respectively. This study aimed to investigate the genetic architecture of ultrasound-based carcass and meat quality traits in Montana Tropical® Composite beef cattle. Therefore, we estimated variance components and genetic parameters and performed genome-wide association studies using the weighted single-step Genomic Best Linear Unbiased Prediction (GBLUP) approach. A pedigree dataset containing 28,480 animals was used, in which 1,436 were genotyped using a moderate-density Single Nucleotide Polymorphism panel (30K; 30,105 SNPs). A total of 9,358, 5,768, 7,996, and 1,972 phenotypic records for the traits Longissimus muscle area (LMA), backfat thickness (BFT), rump fat thickness (RFT), and for marbling score (MARB), respectively, were used for the analyses. Moderate to high heritability estimates were obtained and ranged from 0.16 ± 0.03 (RFT) to 0.33 ± 0.05 (MARB). A high genetic correlation was observed between BFT and RFT (0.97 ± 0.02), suggesting that a similar set of genes affects both traits. The most relevant genomic regions associated with LMA, BFT, RFT, and MARB were found on BTA10 (5.4–5.8 Mb), BTA27 (25.2–25.5 Mb), BTA18 (60.6–61.0 Mb), and BTA21 (14.8–15.4 Mb). Two overlapping genomic regions were identified for RFT and MARB (BTA13:47.9–48.1 Mb) and for BFT and RFT (BTA13:61.5–62.3 Mb). Candidate genes identified in this study, including PLAG1, LYN, WWOX, and PLAGL2, were previously reported to be associated with growth, stature, skeletal muscle growth, fat thickness, and fatty acid composition. Our results indicate that ultrasound-based carcass and meat quality traits in the Montana Tropical® Composite beef cattle are heritable, and therefore, can be improved through selective breeding. In addition, various novel and already known genomic regions related to these traits were identified, which contribute to a better understanding of the underlying genetic background of LMA, BFT, RFT, and MARB in the Montana Tropical Composite population.
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Affiliation(s)
- Laís Grigoletto
- Department of Animal Sciences, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil.,Department of Animal Sciences, Purdue University, West Lafayette, IN, United States
| | - José B S Ferraz
- Department of Animal Sciences, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Hinayah R Oliveira
- Department of Animal Sciences, Purdue University, West Lafayette, IN, United States
| | - Joanir P Eler
- Department of Animal Sciences, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Fernando O Bussiman
- Department of Animal Sciences, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Barbara C Abreu Silva
- Department of Animal Sciences, College of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Fernando Baldi
- Department of Animal Sciences, College of Agricultural and Veterinary Sciences, São Paulo State University, Jaboticabal, Brazil
| | - Luiz F Brito
- Department of Animal Sciences, Purdue University, West Lafayette, IN, United States
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25
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Zhao Z, Shelton SD, Oviedo A, Baker AL, Bryant CP, Omidvarnia S, Du L. The PLAGL2/MYCN/miR-506-3p interplay regulates neuroblastoma cell fate and associates with neuroblastoma progression. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:41. [PMID: 32087738 PMCID: PMC7036248 DOI: 10.1186/s13046-020-1531-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 01/21/2020] [Indexed: 12/17/2022]
Abstract
Background The oncogene MYCN is critical for tumorigenesis of several types of cancers including neuroblastoma. We previously reported that miR-506-3p repressed MYCN expression in neuroblastoma cells. However, the mechanism underlying such regulation was undetermined since there is no miR-506-3p target site in MYCN 3’UTR. Methods By a systematic investigation combining microarray, informatics and luciferase reporter assay, we identified that the transcriptional factor pleiomorphic adenoma gene-like 2 (PLAGL2) is a direct target of miR-506-3p that mediates its regulation on MYCN expression. Using CHIP-PCR and luciferase reporter assay, we validated the transcriptional regulation of MYCN by PLAGL2 and we further demonstrated the transcriptional regulation of PLAGL2 by MYCN. We examined the function of PLAGL2 in regulating neuroblastoma cell fate by cell viability assay, colony formation and Western blotting of differentiation markers. We examined the effect of retinoic acid, the differentiation agent used in neuroblastoma therapy, on miR-506-3p, PLAGL2 and MYCN expressions by quantitative PCR and Western blots. We investigated the clinical relevance of PLAGL2 expression by examining the correlation of tumor PLAGL2 mRNA levels with MYCN mRNA expression and patient survival using public neuroblastoma patient datasets. Results We found that miR-506-3p directly down-regulated PLAGL2 expression, and we validated a PLAGL2 binding site in the MYCN promoter region responsible for promoting MYCN transcription, thereby establishing a mechanism through which miR-506-3p regulates MYCN expression. Conversely, we discovered that MYCN regulated PLAGL2 transcription through five N-Myc-binding E-boxes in the PLAGL2 promoter region. We further confirmed the reciprocal regulation between endogenous PLAGL2 and MYCN in multiple neuroblastoma cell lines. Moreover, we found that PLAGL2 knockdown induced neuroblastoma cell differentiation and reduced cell proliferation, and combined knockdown of PLAGL2 and MYCN showed a synergistic effect. More strikingly, we found that high tumor PLAGL2 mRNA levels were significantly correlated with high MYCN mRNA levels and poor patient survival in neuroblastoma patients. Furthermore, we found that retinoic acid increased expression of miR-506-3p and repressed expression of MYCN and PLAGL2. Conclusions Our findings altogether suggest that the interplay network formed by PLAGL2, MYCN and miR-506-3p is an important mechanism in regulating neuroblastoma cell fate, determining neuroblastoma prognosis, and mediating the therapeutic function of retinoic acid.
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Affiliation(s)
- Zhenze Zhao
- Department of Chemistry and Biochemistry, Texas State University, 601 University Drive, San Marcos, TX, 78666, USA
| | - Spencer D Shelton
- Department of Chemistry and Biochemistry, Texas State University, 601 University Drive, San Marcos, TX, 78666, USA
| | - Alejandro Oviedo
- Department of Chemistry and Biochemistry, Texas State University, 601 University Drive, San Marcos, TX, 78666, USA
| | - Amy L Baker
- Department of Chemistry and Biochemistry, Texas State University, 601 University Drive, San Marcos, TX, 78666, USA
| | - Collin P Bryant
- Department of Chemistry and Biochemistry, Texas State University, 601 University Drive, San Marcos, TX, 78666, USA
| | - Soroush Omidvarnia
- Department of Chemistry and Biochemistry, Texas State University, 601 University Drive, San Marcos, TX, 78666, USA
| | - Liqin Du
- Department of Chemistry and Biochemistry, Texas State University, 601 University Drive, San Marcos, TX, 78666, USA.
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Insertion/deletion (InDel) variations in sheep PLAG1 gene locating in growth-related major QTL are associated with adult body weight and morphometric traits. Small Rumin Res 2019. [DOI: 10.1016/j.smallrumres.2019.08.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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27
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Andersson MK, Åman P, Stenman G. IGF2/IGF1R Signaling as a Therapeutic Target in MYB-Positive Adenoid Cystic Carcinomas and Other Fusion Gene-Driven Tumors. Cells 2019; 8:cells8080913. [PMID: 31426421 PMCID: PMC6721700 DOI: 10.3390/cells8080913] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/13/2019] [Accepted: 08/15/2019] [Indexed: 12/12/2022] Open
Abstract
Chromosome rearrangements resulting in pathogenetically important gene fusions are a common feature of many cancers. They are often potent oncogenic drivers and have key functions in central cellular processes and pathways and encode transcription factors, transcriptional co-regulators, growth factor receptors, tyrosine kinases, and chromatin modifiers. In addition to being useful diagnostic biomarkers, they are also targets for development of new molecularly targeted therapies. Studies in recent decades have shown that several oncogenic gene fusions interact with the insulin-like growth factor (IGF) signaling pathway. For example, the MYB-NFIB fusion in adenoid cystic carcinoma is regulated by IGF1R through an autocrine loop, and IGF1R is a downstream target of the EWSR1-WT1 and PAX3-FKHR fusions in desmoplastic small round cell tumors and alveolar rhabdomyosarcoma, respectively. Here, we will discuss the mechanisms behind the interactions between oncogenic gene fusions and the IGF signaling pathway. We will also discuss the role of therapeutic inhibition of IGF1R in fusion gene driven malignancies.
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Affiliation(s)
- Mattias K Andersson
- Sahlgrenska Cancer Center, Department of Pathology, University of Gothenburg, 405 30 Gothenburg, Sweden.
| | - Pierre Åman
- Sahlgrenska Cancer Center, Department of Pathology, University of Gothenburg, 405 30 Gothenburg, Sweden
| | - Göran Stenman
- Sahlgrenska Cancer Center, Department of Pathology, University of Gothenburg, 405 30 Gothenburg, Sweden
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28
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Li Z, Wu M, Zhao H, Fan L, Zhang Y, Yuan T, He S, Wang P, Zhang Y, Sun X, Wang S. The PLAG1 mRNA expression analysis among genetic variants and relevance to growth traits in Chinese cattle. Anim Biotechnol 2019; 31:504-511. [PMID: 31253059 DOI: 10.1080/10495398.2019.1632207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Pleomorphic adenoma gene 1 (PLAG1) encodes a developmentally regulated zinc finger protein, locating in growth-related QTNs. The mRNA expression of this gene was investigated in different tissues and from two different developmental periods, whilst to explore the functions of PLAG1 in growth traits of cattle. The results showed that PLAG1 was expressed in all examined tissues. However, PLAG1 expression levels in all examined tissues were significantly different between the 5-month fetus and 36-month adult cattle. Our juvenile results indicated PLAG1 is primarily expressed in embryonic tissues of Chinese cattle. Furthermore, two variations were identified. Association analysis revealed that the two variations were associated with growth traits (p < 0.05 or p < 0.01). These new findings provide a comprehensive overview of the critical roles of PLAG1 in growth traits modulation and can be highlighted as candidate molecular markers in cattle breeding.
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Affiliation(s)
- Ze Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Mingli Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Haidong Zhao
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Lujie Fan
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Yu Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Tingting Yuan
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Shuai He
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Pengfei Wang
- Department of Agricultural and Rural Affairs of Shaanxi Province, Xian, China
| | - Yunhai Zhang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
| | - Xiuzhu Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Shuhui Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
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29
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PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor Cells. Stem Cell Reports 2019; 10:1384-1397. [PMID: 29641991 PMCID: PMC5998603 DOI: 10.1016/j.stemcr.2018.03.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 03/07/2018] [Accepted: 03/08/2018] [Indexed: 01/16/2023] Open
Abstract
MSI2, which is expressed predominantly in hematopoietic stem and progenitor cells (HSPCs), enforces HSPC expansion when overexpressed and is upregulated in myeloid leukemias, indicating its regulated transcription is critical to balanced self-renewal and leukemia restraint. Despite this, little is understood of the factors that enforce appropriate physiological levels of MSI2 in the blood system. Here, we define a promoter region that reports on endogenous expression of MSI2 and identify USF2 and PLAG1 as transcription factors whose promoter binding drives reporter activity. We show that these factors co-regulate, and are required for, efficient transactivation of endogenous MSI2. Coincident overexpression of USF2 and PLAG1 in primitive cord blood cells enhanced MSI2 transcription and yielded cellular phenotypes, including expansion of CD34+ cells in vitro, consistent with that achieved by direct MSI2 overexpression. Global chromatin immunoprecipitation sequencing analyses confirm a preferential co-binding of PLAG1 and USF2 at the promoter of MSI2, as well as regulatory regions corresponding to genes with roles in HSPC homeostasis. PLAG1 and USF2 cooperation is thus an important contributor to stem cell-specific expression of MSI2 and HSPC-specific transcriptional circuitry.
We define a regulatory region governing physiological MSI2 expression in human HSPCs USF2 and PLAG1 collaboratively control endogenous HSPC-specific MSI2 expression MSI2 expression and stemness is maintained in culture upon USF2 and PLAG1 co-overexpression USF2 and PLAG1 exhibit genomic co-localization and associate with autophagy genes
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Tanaka S, Honda Y, Takaku S, Koike T, Oe S, Hirahara Y, Yoshida T, Takizawa N, Takamori Y, Kurokawa K, Kodama T, Yamada H. Involvement of PLAGL1/ZAC1 in hypocretin/orexin transcription. Int J Mol Med 2019; 43:2164-2176. [PMID: 30896835 PMCID: PMC6445593 DOI: 10.3892/ijmm.2019.4143] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Accepted: 03/19/2019] [Indexed: 12/16/2022] Open
Abstract
The hypocretin/orexin neuropeptide system coordinates the regulation of various physiological processes. Our previous study reported that a reduction in the expression of pleomorphic adenoma gene-like 1 (Plagl1), which encodes a C2H2 zinc-finger transcription factor, occurs in hypocretin neuron-ablated transgenic mice, suggesting that PLAGL1 is co-expressed in hypocretin neurons and regulates hypocretin transcription. The present study examined whether canonical prepro-hypocretin transcription is functionally modulated by PLAGL1. Double immunostaining indicated that the majority of hypocretin neurons were positive for PLAGL1 immunore-activity in the nucleus. Notably, PLAGL1 immunoreactivity in hypocretin neurons was altered in response to several conditions affecting hypocretin function. An uneven localization of PLAGL1 was detected in the nuclei of hypocretin neurons following sleep deprivation. Chromatin immunoprecipitation revealed that endogenous PLAGL1 may bind to a putative PLAGL1-binding site in the proximal region of the hypocretin gene, in the murine hypothalamus. In addition, electroporation of the PLAGL1 expression vector into the fetal hypothalamus promoted hypothalamic hypocretin transcription. These results suggested that PLAGL1 may regulate hypothalamic hypocretin transcription.
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Affiliation(s)
- Susumu Tanaka
- Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Osaka 573‑1010, Japan
| | - Yoshiko Honda
- SLEEP Disorders Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156‑8506, Japan
| | - Shizuka Takaku
- SLEEP Disorders Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156‑8506, Japan
| | - Taro Koike
- Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Osaka 573‑1010, Japan
| | - Souichi Oe
- Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Osaka 573‑1010, Japan
| | - Yukie Hirahara
- Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Osaka 573‑1010, Japan
| | - Takashi Yoshida
- Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka 573‑1191, Japan
| | - Nae Takizawa
- Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Osaka 573‑1010, Japan
| | - Yasuharu Takamori
- Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Osaka 573‑1010, Japan
| | - Kiyoshi Kurokawa
- Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Osaka 573‑1010, Japan
| | - Tohru Kodama
- SLEEP Disorders Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156‑8506, Japan
| | - Hisao Yamada
- Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Osaka 573‑1010, Japan
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Croce S, Lesluyes T, Delespaul L, Bonhomme B, Pérot G, Velasco V, Mayeur L, Rebier F, Ben Rejeb H, Guyon F, McCluggage WG, Floquet A, Querleu D, Chakiba C, Devouassoux-Shisheboran M, Mery E, Arnould L, Averous G, Soubeyran I, Le Guellec S, Chibon F. GREB1-CTNNB1 fusion transcript detected by RNA-sequencing in a uterine tumor resembling ovarian sex cord tumor (UTROSCT): A novel CTNNB1 rearrangement. Genes Chromosomes Cancer 2019; 58:155-163. [PMID: 30350331 DOI: 10.1002/gcc.22694] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 10/14/2018] [Accepted: 10/16/2018] [Indexed: 12/14/2022] Open
Abstract
Mutations of CTNNB1 have been implicated in tumorigenesis in many organs. However, tumors harboring a CTNNB1 translocation are extremely rare and this translocation has never been reported in a uterine mesenchymal neoplasm. We report a novel translocation t(2;3)(p25;p22) involving the GREB1 (intron 8) and CTNNB1 (exon 3) in a uterine tumor resembling ovarian sex cord tumor (UTROSCT), which exhibited extrauterine metastasis. The translocation detected by RNA-sequencing was validated by RT-PCR, and resulted in nuclear expression of β-catenin. Juxtapositioning with GREB1, which is overexpressed in response to estrogens, resulted in overexpression of a truncated and hypophosphorylated nuclear β-catenin in the primary and recurrent tumors. This accumulation of nuclear β-catenin results in a constitutive activation of the Wnt/β-catenin signaling pathway with a major oncogenic effect. The CTNNB1 gene fusion, promoted by an estrogen-responsive gene (GREB1), could be a potential driver of tumorigenesis in this case and a therapeutic target with adapted inhibitors. RT-PCR and immunohistochemistry performed on 11 additional UTROSCTs showed no CTNNB1 fusion transcript or nuclear β-catenin immunoreactivity.
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Affiliation(s)
- Sabrina Croce
- Department of Biopathology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
| | - Tom Lesluyes
- Comprehensive Cancer Center, INSERM U1218, Institut Bergonié, Bordeaux, France.,University of Bordeaux, Bordeaux, France.,Cancer Research Center of Toulouse, Oncosarc, INSERM UMR1037, Toulouse, France.,Department of Pathology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France
| | - Lucile Delespaul
- University of Bordeaux, Bordeaux, France.,Cancer Research Center of Toulouse, Oncosarc, INSERM UMR1037, Toulouse, France
| | - Benjamin Bonhomme
- Department of Biopathology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
| | - Gaëlle Pérot
- Department of Biopathology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
| | - Valérie Velasco
- Department of Biopathology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
| | - Laetitia Mayeur
- Department of Biopathology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
| | - Flora Rebier
- Department of Biopathology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
| | - Houda Ben Rejeb
- Department of Biopathology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
| | - Frédéric Guyon
- Department of Surgery, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
| | - W Glenn McCluggage
- Department of Pathology, Belfast Health and Social Care Trust, Belfast, United Kingdom
| | - Anne Floquet
- Department of Oncology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
| | - Denis Querleu
- University of Bordeaux, Bordeaux, France.,Department of Surgery, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
| | - Camille Chakiba
- Department of Oncology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
| | | | - Eliane Mery
- Department of Pathology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France
| | - Laurent Arnould
- Department of Pathology, Centre JF Leclerc, Comprehensive Cancer Center, Dijon, France
| | | | - Isabelle Soubeyran
- Department of Biopathology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
| | - Sophie Le Guellec
- Cancer Research Center of Toulouse, Oncosarc, INSERM UMR1037, Toulouse, France.,Department of Pathology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France
| | - Frédéric Chibon
- Cancer Research Center of Toulouse, Oncosarc, INSERM UMR1037, Toulouse, France.,Department of Pathology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France
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Li N, Li D, Du Y, Su C, Yang C, Lin C, Li X, Hu G. Overexpressed PLAGL2 transcriptionally activates Wnt6 and promotes cancer development in colorectal cancer. Oncol Rep 2018; 41:875-884. [PMID: 30535429 PMCID: PMC6313070 DOI: 10.3892/or.2018.6914] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Accepted: 11/28/2018] [Indexed: 12/25/2022] Open
Abstract
Researchers hold the view that PLAGL2 is overexpressed in many malignancies and that it can promote tumor proliferation, migration, invasion and self-renewal; however, there is no evidence revealing a relationship between PLAGL2 and colorectal cancer (CRC). In the present study, genes that are overexpressed in CRC were screened using the COSMIC database and GEPIA database and the expression of PLAGL2 in carcinoma tissues and pericarcinomatous tissues was detected by RT-qPCR and western blot assays. A Cell Counting Kit-8 assay, a cell cycle analysis experiment and a xenograft model were used to explore the influence of PLAGL2 on CRC after knocking down PLAGL2 expression in HCT116 and SW480 cells. Using ChIP assays and Dual-Luciferase Reporter assays, the promoter regions to which PLAGL2 binds were discovered. It was observed that PLAGL2 was overexpressed in colorectal cancer and that it influenced the colorectal cancer cell cycle and promoted colorectal cancer proliferation in vivo and in vitro. The expression of some genes in the Wnt/β-catenin pathway, were downregulated after knocking down the expression of PLAGL2; Wnt6 was altered the most. PLAGL2 could bind to the promoter region of Wnt6 and promote its expression. These results indicated that PLAGL2 was overexpressed in CRC as a proto-oncogene and that it could active the Wnt/β-catenin pathway as a transcription factor by binding with the promoter region of Wnt6. PALGL2 was revealed to play an important role in colorectal cancer and may be a new therapeutic target for targeted medicine.
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Affiliation(s)
- Nanpeng Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Daojiang Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Yuheng Du
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Chen Su
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Chunxing Yang
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Changwei Lin
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Xiaorong Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Gui Hu
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
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Adnani L, Dixit R, Chen X, Balakrishnan A, Modi H, Touahri Y, Logan C, Schuurmans C. Plag1 and Plagl2 have overlapping and distinct functions in telencephalic development. Biol Open 2018; 7:bio.038661. [PMID: 30361413 PMCID: PMC6262857 DOI: 10.1242/bio.038661] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The Plag gene family has three members; Plagl1/Zac1, which is a tumor suppressor gene, and Plag1 and Plagl2, which are proto-oncogenes. All three genes are known to be expressed in embryonic neural progenitors, and Zac1 regulates proliferation, neuronal differentiation and migration in the developing neocortex. Here we examined the functions of Plag1 and Plagl2 in neocortical development. We first attempted, and were unable to generate, E12.5 Plag1;Plagl2 double mutants, indicating that at least one Plag1 or Plagl2 gene copy is required for embryonic survival. We therefore focused on single mutants, revealing a telencephalic patterning defect in E12.5 Plagl2 mutants and a proliferation/differentiation defect in Plag1 mutant neocortices. Specifically, the ventral pallium, a dorsal telencephalic territory, expands into the ventral telencephalon in Plagl2 mutants. In contrast, Plag1 mutants develop normal regional territories, but neocortical progenitors proliferate less and instead produce more neurons. Finally, in gain-of-function studies, both Plag1 and Plagl2 reduce neurogenesis and increase BrdU-uptake, indicative of enhanced proliferation, but while Plagl2 effects on proliferation are more immediate, Plag1 effects are delayed. Taken together, we found that the Plag proto-oncogenes genes are essential regulators of neocortical development and although Plag1 and Plagl2 functions are similar, they do not entirely overlap. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Lata Adnani
- Sunnybrook Research Institute, Biological Sciences, Room S1-16A, 2075 Bayview Ave, Toronto, ON, Canada M4N 3M5.,Department of Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Rajiv Dixit
- Sunnybrook Research Institute, Biological Sciences, Room S1-16A, 2075 Bayview Ave, Toronto, ON, Canada M4N 3M5.,Department of Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Xingyu Chen
- Department of Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Anjali Balakrishnan
- Sunnybrook Research Institute, Biological Sciences, Room S1-16A, 2075 Bayview Ave, Toronto, ON, Canada M4N 3M5.,Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8
| | - Harshil Modi
- Sunnybrook Research Institute, Biological Sciences, Room S1-16A, 2075 Bayview Ave, Toronto, ON, Canada M4N 3M5
| | - Yacine Touahri
- Sunnybrook Research Institute, Biological Sciences, Room S1-16A, 2075 Bayview Ave, Toronto, ON, Canada M4N 3M5
| | - Cairine Logan
- Department of Cell Biology and Anatomy, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1
| | - Carol Schuurmans
- Sunnybrook Research Institute, Biological Sciences, Room S1-16A, 2075 Bayview Ave, Toronto, ON, Canada M4N 3M5 .,Department of Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.,Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8
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Provenzi L, Carli PD, Fumagalli M, Giorda R, Casavant S, Beri S, Citterio A, D'Agata A, Morandi F, Mosca F, Borgatti R, Montirosso R. Very preterm birth is associated with PLAGL1 gene hypomethylation at birth and discharge. Epigenomics 2018; 10:1121-1130. [PMID: 30070601 DOI: 10.2217/epi-2017-0123] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
AIM Recent findings show that DNA methylation is susceptible to very preterm (VPT) birth and to the experience of the early stay in the neonatal intensive care unit. The aim of the study was to compare PLAGL1 methylation between VPT and full-term (FT) infants at birth as well as between VPT infants at discharge and FT infants at birth. METHODS DNA was collected from cord blood of 56 VPT and 27 FT infants at birth and from peripheral blood in VPT infants at neonatal intensive care unit discharge. Sociodemographic and neonatal variables were considered. RESULTS PLAGL1 methylation at birth and at discharge were highly correlated in VPT infants. Lower methylation emerged in VPT infants at birth and discharge compared to FT counterparts. CONCLUSION PLAGL1 hypomethylation emerged as a potential epigenetic mark of VPT birth. Future research is warranted to assess the functional consequences of PLAGL1 diminished methylation in VPT infants' development.
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Affiliation(s)
- Livio Provenzi
- 0-3 Center for the at-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, 238422, Bosisio Parini, Italy
| | - Pietro De Carli
- 0-3 Center for the at-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, 238422, Bosisio Parini, Italy
| | - Monica Fumagalli
- NICU, Department of Clinical Sciences & Community Health, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 201223, Milan, Italy
| | - Roberto Giorda
- Molecular Biology Laboratory, Scientific Institute, IRCCS Eugenio Medea, 238424, Bosisio Parini, Italy
| | - Sharon Casavant
- School of Nursing, University of Connecticut, Storrs, CT, 060325, USA
| | - Silvana Beri
- Molecular Biology Laboratory, Scientific Institute, IRCCS Eugenio Medea, 238424, Bosisio Parini, Italy
| | - Andrea Citterio
- Molecular Biology Laboratory, Scientific Institute, IRCCS Eugenio Medea, 238424, Bosisio Parini, Italy
| | - Amy D'Agata
- College of Nursing, University of Rhode Island, Kingston, RI, 028816, USA
| | | | - Fabio Mosca
- NICU, Department of Clinical Sciences & Community Health, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 201223, Milan, Italy
| | - Renato Borgatti
- Neuropsychiatry & Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea, 238422, Bosisio Parini, Italy
| | - Rosario Montirosso
- 0-3 Center for the at-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, 238422, Bosisio Parini, Italy
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Qu G, Xu Y, Wan SP, Yang G. Expression of PLAGL2 in bladder urothelial carcinoma and its relationship to lymph node metastasis and survival. Sci Rep 2018; 8:6044. [PMID: 29662235 PMCID: PMC5902583 DOI: 10.1038/s41598-018-24526-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 04/03/2018] [Indexed: 11/09/2022] Open
Abstract
The purpose of this study was to investigate PLAGL2 expression associated with pathological features and prognosis and predicted lymph node metastases in the bladder urothelial carcinoma (BUC) tissue. The pathologic specimens and clinical data of 203 patients with bladder urothelial carcinoma after radical resection were collected. The expression of PLAGL2 was detected by immunohistochemically staining. The influence on lymph node metastasis and the prognoses of BUC patients were analyzed. The expression of PLAGL2 in BUC and positive lymph nodes was significantly higher than the normal bladder tissues (89.06% and 76.56% vs 21.88%, P < 0.001). Logistic regression analysis showed that PLAGL2 expression was an independent risk factor for BUC lymph node metastasis (P < 0.05). COX proportional hazards regression model showed that the time to recurrence and overall survival of patients with overexpression of PLAGL2 were significantly lower than those with low expression (P < 0.05). PLAGL2 is highly expressed in the BUC tissue and metastatic lymph node relative to the normal bladder tissue. This expression correlates to tumor size and number, and tumor grade and stage. Overexpression of PLAGL2 can be an independent predictor for lymph node metastasis and patient survival.
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Affiliation(s)
- Genyi Qu
- Department of Urology, ZhuZhou Central Hospital, South Changjiang Road, Tianyuan district, ZhuZhou, 412007, China
| | - Yong Xu
- Department of Urology, ZhuZhou Central Hospital, South Changjiang Road, Tianyuan district, ZhuZhou, 412007, China.
| | - Shaw P Wan
- Department of Urology, The First People's Hospital of Xiaoshan, 199# Xinnan Road, Xiaoshan district, Hangzhou, 311200, China
| | - Guang Yang
- Department of Urology, ZhuZhou Central Hospital, South Changjiang Road, Tianyuan district, ZhuZhou, 412007, China
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36
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Su C, Li D, Li N, Du Y, Yang C, Bai Y, Lin C, Li X, Zhang Y. Studying the mechanism of PLAGL2 overexpression and its carcinogenic characteristics based on 3'-untranslated region in colorectal cancer. Int J Oncol 2018; 52:1479-1490. [PMID: 29512763 PMCID: PMC5873895 DOI: 10.3892/ijo.2018.4305] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 03/02/2018] [Indexed: 12/12/2022] Open
Abstract
Pleomorphic adenoma gene like-2 (PLAGL2) is a zinc finger protein transcription factor, which is upregulated and serves an oncogenic function in multiple human malignancies, including colorectal cancer (CRC). First, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression levels of PLAGL2 in CRC tissues and normal tissues. Then, bioinformatics analysis, RT-qPCR, western blotting, luciferase reporter assays and RNA-binding protein immunoprecipitation assays were performed to explore whether the underlying mechanisms, including copy number variation (CNV), microRNAs (miRNAs/miRs) and RNA-binding proteins (RBPs) led to the abnormal expression of PLAGL2. Finally, cell counting kit-8 assays, Transwell assays and xenograft models were used to detect carcinogenesis-associated characteristics based on the 3′-untranslated region (3′-UTR) of PLAGL2. In the present study, PLAGL2 was revealed to be upregulated in CRC tissues compared with normal CRC tissues. CNV was one of the causes leading to the upregulation of PLAGL2. miRNA, including downregulated miR-486-5p, and RBPs, including upregulated human antigen R (HuR), were other key underlying causes. In addition, PLAGL2 3′-UTR was revealed to promote the progression of CRC in vitro and in vivo, and to regulate the expression of C-MYC and CD44. To conclude, these results suggested that high expression of PLAGL2 in CRC was associated with CNV, miR-486-5p and HuR expression, whose 3′-UTR may promote colon carcinogenesis and serve as a novel potential biomarker for CRC therapies.
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Affiliation(s)
- Chen Su
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Daojiang Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Nanpeng Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Yuheng Du
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Chunxing Yang
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Yang Bai
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Changwei Lin
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Xiaorong Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Yi Zhang
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
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MiR-449a suppresses cell migration and invasion by targeting PLAGL2 in breast cancer. Pathol Res Pract 2018; 214:790-795. [PMID: 29653747 DOI: 10.1016/j.prp.2017.12.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/12/2017] [Accepted: 12/28/2017] [Indexed: 11/21/2022]
Abstract
BACKGROUND Breast cancer is one of the most common malignancies worldwide. However, the detailed molecular mechanisms underlying breast cancer metastasis are still incompletely clear. MicroRNAs (miRNAs) play a crucial role in cancer metastasis. In this study, we aimed to analyze the expression and function of miR-449a in breast cancer. MATERIAL AND METHODS A total of 15 human primary breast cancer tissues and adjacent non-cancerous tissues (10 pairs) were obtained. MiR-449a was examined in tumor tissues and adjacent nontumorous tissues of breast cancer patients and cell lines by real-time PCR. The protein expression levels were analyzed by western blot and immunohistochemistry staining. Luciferase reporter assays was used to validate the target of miR-449a. The effect of miR-449a on breast cancer cell migration and invasion were studied in vitro and in vivo. RESULTS The expression levels of miR-449a were significantly decreased in breast cancer tissues and cell lines. Overexpression of miR-449a suppressed breast cancer cell proliferation, clone formation, migration, invasion and metastasis in vitro and in vivo. Pleomorphic adenoma gene like-2 (PLAGL2) was identified as a major target of miR-449a. Both overexpression of miR-449a inhibited the expression of PLAGL2 significantly and the knockdown of PLAGL2 expression inhibited the breast cancer cell proliferation and metastasis. CONCLUSION We demonstrate the miR-449a tumor suppressor role in breast cancer cell migration and invasion via targeting PLAGL2. These findings suggesting that miR-449a/PLAGL2 could serve as a therapeutic strategy for targeting breast cancer.
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Zhang H, Zhang C, Feng R, Zhang H, Gao M, Ye L. Investigating the microRNA-mRNA regulatory network in acute myeloid leukemia. Oncol Lett 2017; 14:3981-3988. [PMID: 28989535 PMCID: PMC5620483 DOI: 10.3892/ol.2017.6686] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 05/25/2017] [Indexed: 12/26/2022] Open
Abstract
Acute myeloid leukemia (AML) is a common myelogenous malignancy in adults that is often characterized by disease relapse. The pathophysiological mechanism of AML has not yet been elucidated. The present study aimed to identify the crucial microRNAs (miRNAs/miRs) and target genes in AML, and to uncover the potential oncogenic mechanism of AML. miRNA and mRNA expression-profiling microarray datasets were downloaded from the Gene Expression Omnibus database. Differential expression analysis was performed and a regulatory network between miRNAs and target genes was constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were used to predict the biological functions of the differentially expressed genes. Reverse transcription-quantitative polymerase chain reaction analysis was employed to verify the expression levels of miRNAs and target genes in AML patient samples. A total of 86 differentially expressed miRNAs and 468 differentially expressed mRNAs between AML and healthy blood samples were identified. In total, 47 miRNAs and 401 mRNAs were found to be upregulated, and 39 miRNAs and 67 mRNAs were found to be downregulated in AML. A total of 223 miRNA-target genes pairs were subjected to the construction of a regulatory network. Differentially expressed target genes were significantly enriched in the Wnt signaling pathway (hsa04310), melanogenesis (hsa04916) and pathways in cancer (hsa05200). Significantly differentially expressed miRNAs and genes, including hsa-miR-155, hsa-miR-192, annexin A2 (ANXA2), frizzled class receptor 3 (FZD3), and pleomorphic adenoma gene 1 (PLAG1), may serve essential roles in AML oncogenesis. Overall, hsa-miR-155, hsa-miR-192, ANXA2, FZD3 and PLAG1 may be associated with the development of AML via the involvement of the Wnt signaling pathway, melanogenesis and other cancer-associated signaling pathways.
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Affiliation(s)
- Haiguo Zhang
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
- Department of Hematology, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Chengfang Zhang
- Department of Clinical Laboratory, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Rui Feng
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
- Department of Hematology, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
| | - Haixia Zhang
- Department of Pharmacy, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
| | - Min Gao
- Department of Clinical Laboratory, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Ling Ye
- Department of Hematology, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
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Chu YW, Liu ST, Yang YL, Huang SM, Wang WM. The cytotoxic mechanism of epigallocatechin gallate on proliferative HaCaT keratinocytes. J Biomed Sci 2017; 24:55. [PMID: 28810862 PMCID: PMC5556358 DOI: 10.1186/s12929-017-0363-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 08/09/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Epigallocatechin gallate (EGCG) is the major ingredient of sinecatechins ointment, approved for the treatment of external genital and perianal warts. However, the molecular mechanism for EGCG's effect on warts resulting from the human papillomavirus (HPV) infection of keratinocytes is not well understood. HPV may survive in proliferative keratinocytes and may be involved in cell cycle regulation and progression. The objective of this study was to investigate the mechanism underlying EGCG's treatment on external genital warts of HPV infection through the cultured keratinocyte cells from the HaCaT cell line. METHODS MTT and flow cytometry assays were used to measure cell viability and the cell cycle profile, with and without EGCG treatment, for HaCaT keratinocyte cells cultured in a calcium-free medium and 1.8 mM calcium which induced proliferative and differentiated keratinocytes, respectively, for 24 h. The expression levels of cytotoxic proteins and factors were evaluated with the RT-PCR and western blotting analysis. RESULTS EGCG influenced the proliferation stage but not the differentiation stage of keratinocytes. We suggest that apoptosis and autophagy might be the possible mechanism for the EGCG's effect on the proliferative HaCaT cells. Furthermore, we found that EGCG reduced the protein levels of cyclin D1 and Zac1 (a zinc-finger protein which regulates apoptosis and cell cycle arrest 1) dose-dependently in proliferative as compared to differentiated keratinocytes. It also induced the expression of p21 and DEC1 (differentiated embryo-chondrocyte expressed gene 1), and promoted G1 arrest of cell cycle in proliferative keratinocytes. CONCLUSIONS These results help clarify the mechanisms of EGCG treatment of HPV-infected keratinocytes and may contribute to new targets, such as Zac1 and DEC1 for external genital and perianal warts.
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Affiliation(s)
- Yu-Wen Chu
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, 114, Taiwan, Republic of China.,Department of Pharmacy, Taichung Veterans General Hospital, Taichung, 407, Taiwan, Republic of China
| | - Shu-Ting Liu
- Department of Biochemistry, National Defense Medical Center, Taipei, 114, Taiwan, Republic of China
| | - Ya-Lan Yang
- Department of Biochemistry, National Defense Medical Center, Taipei, 114, Taiwan, Republic of China
| | - Shih-Ming Huang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, 114, Taiwan, Republic of China. .,Department of Biochemistry, National Defense Medical Center, Taipei, 114, Taiwan, Republic of China.
| | - Wei-Ming Wang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, 114, Taiwan, Republic of China. .,Department of Dermatology, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114, Taiwan, Republic of China.
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Vega-Benedetti AF, Saucedo C, Zavattari P, Vanni R, Zugaza JL, Parada LA. PLAGL1: an important player in diverse pathological processes. J Appl Genet 2016; 58:71-78. [PMID: 27311313 DOI: 10.1007/s13353-016-0355-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 05/02/2016] [Accepted: 06/02/2016] [Indexed: 12/23/2022]
Abstract
The PLAGL1 gene encodes a homonymous zinc finger protein that promotes cell cycle arrest and apoptosis through multiple pathways. The protein has been implicated in metabolic, genetic, and neoplastic illnesses, but the molecular mechanisms by which the protein PLAGL1 participates in such diverse processes remains to be elucidated. In this review, we focus mainly on the molecular biology of PLAGL1 and the relevance of its abnormalities to several pathological processes.
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Affiliation(s)
- Ana F Vega-Benedetti
- Institute of Experimental Pathology, UNSa-CONICET, Ave. Bolivia 5150, 4400, Salta, Argentina
| | - Cinthia Saucedo
- Institute of Experimental Pathology, UNSa-CONICET, Ave. Bolivia 5150, 4400, Salta, Argentina
| | - Patrizia Zavattari
- Biochemistry, Biology and Genetics Unit, Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SP 8, Km 0.700, 09042, Monserrato, Cagliari, Italy
| | - Roberta Vanni
- Biochemistry, Biology and Genetics Unit, Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SP 8, Km 0.700, 09042, Monserrato, Cagliari, Italy
| | - José L Zugaza
- IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain.,Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Building 205, Zamudio, Spain.,Department of Genetics, Physic Anthropology and Animal Physiology, Faculty of Medicine and Dentistry, University of the Basque Country, Barrio Sarriena s/n, 48940, Leioa, Spain
| | - Luis Antonio Parada
- Institute of Experimental Pathology, UNSa-CONICET, Ave. Bolivia 5150, 4400, Salta, Argentina.
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Juma AR, Damdimopoulou PE, Grommen SVH, Van de Ven WJM, De Groef B. Emerging role of PLAG1 as a regulator of growth and reproduction. J Endocrinol 2016; 228:R45-56. [PMID: 26577933 DOI: 10.1530/joe-15-0449] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/17/2015] [Indexed: 12/15/2022]
Abstract
Pleomorphic adenoma gene 1 (PLAG1) belongs to the PLAG family of zinc finger transcription factors along with PLAG-like 1 and PLAG-like 2. The PLAG1 gene is best known as an oncogene associated with certain types of cancer, most notably pleomorphic adenomas of the salivary gland. While the mechanisms of PLAG1-induced tumorigenesis are reasonably well understood, the role of PLAG1 in normal physiology is less clear. It is known that PLAG1 is involved in cell proliferation by directly regulating a wide array of target genes, including a number of growth factors such as insulin-like growth factor 2. This is likely to be a central mode of action for PLAG1 both in embryonic development and in cancer. The phenotype of Plag1 knockout mice suggests an important role for PLAG1 also in postnatal growth and reproduction, as PLAG1 deficiency causes growth retardation and reduced fertility. A role for PLAG1 in growth and reproduction is further corroborated by genome-wide association studies in humans and domestic animals in which polymorphisms in the PLAG1 genomic region are associated with body growth and reproductive traits. Here we review the current evidence for PLAG1 as a regulator of growth and fertility and discuss possible endocrine mechanisms involved.
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Affiliation(s)
- Almas R Juma
- Department of PhysiologyAnatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria 3086, AustraliaDepartment of Clinical SciencesIntervention and Technology, Karolinska Institutet and Karolinska University Hospital, Huddinge, 141 86 Stockholm, SwedenDepartment of Human GeneticsKU Leuven, B-3000 Leuven, Belgium
| | - Pauliina E Damdimopoulou
- Department of PhysiologyAnatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria 3086, AustraliaDepartment of Clinical SciencesIntervention and Technology, Karolinska Institutet and Karolinska University Hospital, Huddinge, 141 86 Stockholm, SwedenDepartment of Human GeneticsKU Leuven, B-3000 Leuven, Belgium
| | - Sylvia V H Grommen
- Department of PhysiologyAnatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria 3086, AustraliaDepartment of Clinical SciencesIntervention and Technology, Karolinska Institutet and Karolinska University Hospital, Huddinge, 141 86 Stockholm, SwedenDepartment of Human GeneticsKU Leuven, B-3000 Leuven, Belgium
| | - Wim J M Van de Ven
- Department of PhysiologyAnatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria 3086, AustraliaDepartment of Clinical SciencesIntervention and Technology, Karolinska Institutet and Karolinska University Hospital, Huddinge, 141 86 Stockholm, SwedenDepartment of Human GeneticsKU Leuven, B-3000 Leuven, Belgium
| | - Bert De Groef
- Department of PhysiologyAnatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria 3086, AustraliaDepartment of Clinical SciencesIntervention and Technology, Karolinska Institutet and Karolinska University Hospital, Huddinge, 141 86 Stockholm, SwedenDepartment of Human GeneticsKU Leuven, B-3000 Leuven, Belgium
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Abstract
Tumors of the lacrimal gland comprise a wide spectrum, of which the most common demonstrate epithelial and lymphoid differentiation. The diagnosis of lacrimal gland tumors depends primarily on histological evaluation, as do the choice of treatment and prognosis. For some lacrimal gland neoplasms, such as adenoid cystic carcinoma, the outlook is grave. Optimal treatment for several lacrimal gland tumors is also a matter of controversy. However, recent progress has been made in the molecular and genetic understanding of tumorigenesis for such lesions. This article presents an overview of the histopathology of lacrimal gland tumors, together with their epidemiological features, clinical characteristics, and treatment strategies.
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Affiliation(s)
- Sarah Linea von Holstein
- Eye Pathology Section, Department of Neuroscience and Pharmacology, University of Copenhagen, Frederik V׳s Vej 11, 1, DK-2100 Copenhagen, Denmark; Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
| | - Peter Kristian Rasmussen
- Eye Pathology Section, Department of Neuroscience and Pharmacology, University of Copenhagen, Frederik V׳s Vej 11, 1, DK-2100 Copenhagen, Denmark; Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
| | - Steffen Heegaard
- Eye Pathology Section, Department of Neuroscience and Pharmacology, University of Copenhagen, Frederik V׳s Vej 11, 1, DK-2100 Copenhagen, Denmark; Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Department of Pathology, Rigshospitalet, University of Copenhagen, Frederiks V's Vej, DK-2100 Copenhagen, Denmark.
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Molecular cytogenetics of pediatric adipocytic tumors. Cancer Genet 2015; 208:469-81. [DOI: 10.1016/j.cancergen.2015.06.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 06/16/2015] [Accepted: 06/23/2015] [Indexed: 12/20/2022]
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A novel cell line derived from pleomorphic adenoma expresses MMP2, MMP9, TIMP1, TIMP2, and shows numeric chromosomal anomalies. PLoS One 2014; 9:e105231. [PMID: 25137137 PMCID: PMC4138172 DOI: 10.1371/journal.pone.0105231] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Accepted: 07/23/2014] [Indexed: 01/25/2023] Open
Abstract
Pleomorphic adenoma is the most common salivary gland neoplasm, and it can be locally invasive, despite its slow growth. This study aimed to establish a novel cell line (AP-1) derived from a human pleomorphic adenoma sample to better understand local invasiveness of this tumor. AP-1 cell line was characterized by cell growth analysis, expression of epithelial and myoepithelial markers by immunofluorescence, electron microscopy, 3D cell culture assays, cytogenetic features and transcriptomic study. Expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) was also analyzed by immunofluorescence and zymography. Furthermore, epithelial and myoepithelial markers, MMPs and TIMPs were studied in the tumor that originated the cell line. AP-1 cells showed neoplastic epithelial and myoepithelial markers, such as cytokeratins, vimentin, S100 protein and smooth-muscle actin. These molecules were also found in vivo, in the tumor that originated the cell line. MMPs and TIMPs were observed in vivo and in AP-1 cells. Growth curve showed that AP-1 exhibited a doubling time of 3.342 days. AP-1 cells grown inside Matrigel recapitulated tumor architecture. Different numerical and structural chromosomal anomalies were visualized in cytogenetic analysis. Transcriptomic analysis addressed expression of 7 target genes (VIM, TIMP2, MMP2, MMP9, TIMP1, ACTA2 e PLAG1). Results were compared to transcriptomic profile of non-neoplastic salivary gland cells (HSG). Only MMP9 was not expressed in both libraries, and VIM was expressed solely in AP-1 library. The major difference regarding gene expression level between AP-1 and HSG samples occurred for MMP2. This gene was 184 times more expressed in AP-1 cells. Our findings suggest that AP-1 cell line could be a useful model for further studies on pleomorphic adenoma biology.
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Shah AA, Wenig BM, LeGallo RD, Mills SE, Stelow EB. Morphology in conjunction with immunohistochemistry is sufficient for the diagnosis of mammary analogue secretory carcinoma. Head Neck Pathol 2014; 9:85-95. [PMID: 25078757 PMCID: PMC4382490 DOI: 10.1007/s12105-014-0557-1] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 07/02/2014] [Indexed: 10/25/2022]
Abstract
The recently described mammary analogue secretory carcinoma (MASC) is a low-grade salivary gland malignancy that harbors the recurrent cytogenetic abnormality t(12;15) (p13;q25) ETV6-NTRK3. Confirmation of this is currently considered the gold standard for diagnosis. Some have postulated that morphology together with supporting immunohistochemistry is sufficient to diagnose MASC. In this study we retrospectively review a series of 19 MASCs diagnosed based on histology in conjunction with immunohistochemistry; subsequently we performed in situ hybridization using an ETV6 break-apart probe. Immunohistochemistry for S100 protein and mammaglobin as well as fluorescence in situ hybridization using the Vysis ETV6 Dual Color Break-Apart FISH Probe Kit were performed on all cases. The 19 cases were from 12 females and 7 males with ages ranging from 16 to 76 years (mean = 45 years). Sixteen cases were from the parotid gland, 1 case was from a periparotid lymph node and 2 cases were from the submandibular gland. All 19 cases demonstrated moderate to strong expression of S100 protein. Eighteen cases demonstrated strong, diffuse expression of mammaglobin, while one case had only rare tumor cells that strongly expressed mammaglobin. Eighteen of 19 cases (95 %) demonstrated the ETV6 rearrangement by fluorescence in situ hybridization. Given that morphology together with immunohistochemistry is highly correlated with the ETV6 gene rearrangement, we conclude that molecular confirmation is not required to diagnose MASC.
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Affiliation(s)
- Akeesha A. Shah
| | - Bruce M. Wenig
| | - Robin D. LeGallo
| | - Stacey E. Mills
| | - Edward B. Stelow
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Iglesias-Platas I, Martin-Trujillo A, Petazzi P, Guillaumet-Adkins A, Esteller M, Monk D. Altered expression of the imprinted transcription factor PLAGL1 deregulates a network of genes in the human IUGR placenta. Hum Mol Genet 2014; 23:6275-85. [PMID: 24993786 DOI: 10.1093/hmg/ddu347] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Genomic imprinting is the epigenetic process that results in monoallelic expression of genes depending on parental origin. These genes are known to be critical for placental development and fetal growth in mammals. Aberrant epigenetic profiles at imprinted loci, such as DNA methylation defects, are surprisingly rare in pregnancies with compromised fetal growth, while variations in transcriptional output from the expressed alleles of imprinted genes are more commonly reported in pregnancies complicated with intrauterine growth restriction (IUGR). To determine if PLAGL1 and HYMAI, two imprinted transcripts deregulated in Transient Neonatal Diabetes Mellitus, are involved in non-syndromic IUGR we compared the expression and DNA methylation levels in a large cohort of placental biopsies from IUGR and uneventful pregnancies. This revealed that despite appropriate maternal methylation at the shared PLAGL1/HYMAI promoter, there was a loss of correlation between PLAGL1 and HYMAI expression in IUGR. This incongruity was due to higher HYMAI expression in IUGR gestations, coupled with PLAGL1 down-regulation in placentas from IUGR girls, but not boys. The PLAGL1 protein is a zinc-finger transcription factor that has been shown to be a master coordinator of a genetic growth network in mice. We observe PLAGL1 binding to the H19/IGF2 shared enhancers in placentae, with significant correlations between PLAGL1 levels with H19 and IGF2 expression levels. In addition, PLAGL1 binding and expression also correlate with expression levels of metabolic regulator genes SLC2A4, TCF4 and PPARγ1. Our results strongly suggest that fetal growth can be influenced by altered expression of the PLAGL1 gene network in human placenta.
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Affiliation(s)
- Isabel Iglesias-Platas
- Servicio de Neonatología, Hospital Sant Joan de Déu, Fundació Sant Joan de Déu, Barcelona 08950, Spain,
| | | | - Paolo Petazzi
- Cancer Epigenetics Group, Cancer Epigenetic and Biology Program, Institut D'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona 08907, Spain
| | - Amy Guillaumet-Adkins
- Servicio de Neonatología, Hospital Sant Joan de Déu, Fundació Sant Joan de Déu, Barcelona 08950, Spain, Imprinting and Cancer Group
| | - Manel Esteller
- Cancer Epigenetics Group, Cancer Epigenetic and Biology Program, Institut D'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona 08907, Spain, Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona 08097, Spain and Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia 08010, Spain
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Sekiya R, Maeda M, Yuan H, Asano E, Hyodo T, Hasegawa H, Ito S, Shibata K, Hamaguchi M, Kikkawa F, Kajiyama H, Senga T. PLAGL2 regulates actin cytoskeletal architecture and cell migration. Carcinogenesis 2014; 35:1993-2001. [DOI: 10.1093/carcin/bgu081] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Klemke M, Müller MH, Wosniok W, Markowski DN, Nimzyk R, Helmke BM, Bullerdiek J. Correlated expression of HMGA2 and PLAG1 in thyroid tumors, uterine leiomyomas and experimental models. PLoS One 2014; 9:e88126. [PMID: 24516594 PMCID: PMC3917869 DOI: 10.1371/journal.pone.0088126] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Accepted: 01/06/2014] [Indexed: 12/13/2022] Open
Abstract
In pleomorphic adenomas of the salivary glands (PASG) recurrent chromosomal rearrangements affecting either 8q12 or 12q14∼15 lead to an overexpression of the genes of the genuine transcription factor PLAG1 or the architectural transcription factor HMGA2, respectively. Both genes are also affected by recurrent chromosomal rearrangements in benign adipocytic tumors as e. g. lipomas and lipoblastomas. Herein, we observed a strong correlation between the expression of HMGA2 and PLAG1 in 14 benign and 23 malignant thyroid tumors. To address the question if PLAG1 can be activated by HMGA2, the expression of both genes was quantified in 32 uterine leiomyomas 17 of which exhibited an overexpression of HMGA2. All leiomyomas with HMGA2 overexpression also revealed an activation of PLAG1 in the absence of detectable chromosome 8 abnormalities affecting the PLAG1 locus. To further investigate if the overexpression of PLAG1 is inducible by HMGA2 alone, HMGA2 was transiently overexpressed in MCF-7 cells. An increased PLAG1 expression was observed 24 and 48 h after transfection. Likewise, stimulation of HMGA2 by FGF1 in adipose tissue-derived stem cells led to a simultaneous increase of PLAG1 mRNA. Altogether, these data suggest that HMGA2 is an upstream activator of PLAG1. Accordingly, this may explain the formation of tumors as similar as lipomas and lipoblastomas resulting from an activation of either of both genes by chromosomal rearrangements.
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Affiliation(s)
- Markus Klemke
- Center for Human Genetics, University of Bremen, Bremen, Germany
| | | | - Werner Wosniok
- Institute of Statistics, University of Bremen, Bremen, Germany
| | | | - Rolf Nimzyk
- Center for Human Genetics, University of Bremen, Bremen, Germany
| | | | - Jörn Bullerdiek
- Center for Human Genetics, University of Bremen, Bremen, Germany
- Institute for Medical Genetics, University of Rostock, University Medicine, Rostock, Germany
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Omer A, Yadav NK, Singh P, Singh RK. Hematological malignancies: role of miRNAs and theirin silicoaspects. Expert Rev Anticancer Ther 2014; 13:1121-33. [DOI: 10.1586/14737140.2013.833683] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Mendoza PR, Jakobiec FA, Krane JF. Immunohistochemical features of lacrimal gland epithelial tumors. Am J Ophthalmol 2013; 156:1147-1158.e1. [PMID: 23972314 DOI: 10.1016/j.ajo.2013.06.034] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 06/23/2013] [Accepted: 06/24/2013] [Indexed: 11/19/2022]
Abstract
PURPOSE To investigate the immunohistochemical features of ocular adnexal pleomorphic adenoma and adenoid cystic carcinoma. DESIGN Retrospective clinicopathologic study. METHODS Clinical records and microscopic slides of 7 cases of each tumor type were reviewed. Immunohistochemical probes for Ki-67 and p53, and newer nuclear markers MYB for adenoid cystic carcinoma and PLAG1 for pleomorphic adenoma, were employed. RESULTS Pleomorphic adenomas were asymptomatic, whereas adenoid cystic carcinomas were painful. No pleomorphic adenomas recurred; 4 adenoid cystic carcinomas recurred, resulting in 3 deaths. Unusual histopathologic variants for which immunohistochemistry proved useful included a myoepithelioma, an atypical pleomorphic adenoma, tubular and solid/basaloid variants of adenoid cystic carcinoma, and a morphologically heterogeneous adenoid cystic carcinoma of a Wolfring gland. For the pleomorphic adenomas, the average Ki-67 proliferation index was 3.8%; p53 was weakly staining, with an average positivity of 18.5%; PLAG1 was strongly positive in all cases; MYB was negative in 5 cases and weakly focally positive in 2 cases. For the adenoid cystic carcinomas, the average Ki-67 proliferation index was 29.1%; p53 stained positively and strongly with an average of 39%; none stained positively for PLAG1; and 6 out of 7 were MYB positive. CONCLUSIONS Between pleomorphic adenoma and adenoid cystic carcinoma, there was no overlap in Ki-67 positivity. Positivity for p53 showed overlap in only one lesion of each type. PLAG1 and MYB positivity were highly discriminating between pleomorphic adenoma and adenoid cystic carcinoma. Immunohistochemical analysis should be investigated further for its role in the evaluation of pleomorphic adenoma and adenoid cystic carcinoma.
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Affiliation(s)
- Pia R Mendoza
- David G. Cogan Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts
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