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Thankan RS, Thomas E, Weldemariam MM, Purushottamachar P, Huang W, Kane MA, Zhang Y, Ambulos N, Wang BD, Weber D, Njar VCO. Thermal proteome profiling and proteome analysis using high-definition mass spectrometry demonstrate modulation of cholesterol biosynthesis by next-generation galeterone analog VNPP433-3β in castration-resistant prostate cancer. Mol Oncol 2025. [PMID: 40007440 DOI: 10.1002/1878-0261.70009] [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: 07/16/2024] [Revised: 02/03/2025] [Accepted: 02/17/2025] [Indexed: 02/27/2025] Open
Abstract
Cholesterol (CHOL) homeostasis is significantly modulated in prostate cancer (PCa) suggesting an active role in PCa development and progression. Several studies indicate a strong correlation between elevated CHOL levels and increased PCa risk and severity. Inhibition of CHOL biosynthesis at different steps, including lanosterol synthase (LSS), has shown significant efficacy against both hormone-dependent and castration-resistant PCa. Earlier, we reported proteasomal degradation of androgen receptor (AR)/AR-Vs and Mnk1/2 as the primary mechanisms of action of VNPP433-3β in inhibiting PCa cell proliferation and tumor growth. Through thermal proteome profiling, comparative proteomics and cellular thermal shift assay, we identified VNPP433-3β's ancillary effect of lowering CHOL by binding to LSS and lanosterol 14-alpha demethylase, potentially inhibiting CHOL biosynthesis in PCa cells and tumors. Additionally, in conjunction with our previously reported transcriptome analysis, proteomics reveals that VNPP433-3β modulated upstream regulators and pathways critical for PCa stem cell maintenance and recurrence. The inhibition of CHOL biosynthesis by VNPP433-3β reinforces its multifaceted effects in PCa across all stages, highlighting its potential as a single-agent therapy. Achieving reduced CHOL levels aligns with better treatment outcomes, further substantiating VNPP433-3β's therapeutic potential.
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Affiliation(s)
- Retheesh S Thankan
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA
- Isoprene Pharmaceuticals, Inc., University of Maryland Baltimore BioPark, Baltimore, MD, USA
| | - Elizabeth Thomas
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA
- The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Mehari M Weldemariam
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA
| | - Puranik Purushottamachar
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA
- The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Weiliang Huang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA
| | - Maureen A Kane
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA
| | - Yuji Zhang
- Division of Biostatistics and Bioinformatics, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Nicholas Ambulos
- Department of Microbiology and Immunology, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Bi-Dar Wang
- Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, MD, USA
| | - David Weber
- The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Vincent C O Njar
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA
- Isoprene Pharmaceuticals, Inc., University of Maryland Baltimore BioPark, Baltimore, MD, USA
- The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
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2
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Azizan A, Farhadi E, Faezi ST, Jamshidi A, Alikhani M, Mahmoudi M. Role of miRNAs in Apoptosis Pathways of Immune Cells in Systemic Lupus Erythematosus. Immun Inflamm Dis 2025; 13:e70124. [PMID: 39912562 PMCID: PMC11800236 DOI: 10.1002/iid3.70124] [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: 09/01/2024] [Revised: 12/24/2024] [Accepted: 01/01/2025] [Indexed: 02/07/2025] Open
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by dysregulated immune responses and multi-organ involvement. Dysregulation of apoptosis, a key process for maintaining immune homeostasis, plays a critical role in the pathogenesis of SLE. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as important modulators of apoptosis in immune cells, influencing the balance between immune tolerance and autoimmunity. OBJECTIVES This review aims to comprehensively summarize recent advancements in understanding the roles of miRNAs in apoptosis regulation within immune cells in SLE, highlighting their therapeutic potential for restoring immune balance and mitigating disease progression. RESULTS Aberrant expression of specific miRNAs contributes to the dysregulation of apoptosis in SLE immune cells. Pro-apoptotic miRNAs, such as miR-125b and miR-150, are often downregulated, leading to enhanced survival of autoreactive immune cells. Conversely, anti-apoptotic miRNAs, including miR-21, are upregulated, further disrupting the delicate balance of immune cell apoptosis. Dual-function miRNAs, such as miR-155, exhibit context-dependent roles based on cellular environments and target gene interactions. This dysregulation promotes the persistence of autoreactive immune cells and the development of autoimmunity. CONCLUSIONS miRNAs play critical roles in modulating apoptosis pathways, making them promising therapeutic targets for SLE. Restoring the balance of pro-apoptotic and anti-apoptotic miRNAs could help reinstate immune tolerance and reduce tissue damage. Future research should focus on elucidating miRNA targetomes, improving delivery systems, and addressing off-target effects to fully harness their therapeutic potential.
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Affiliation(s)
- Amin Azizan
- Rheumatology Research CenterTehran University of Medical SciencesTehranIran
- Research Center for Chronic Inflammatory DiseasesTehran University of Medical SciencesTehranIran
| | - Elham Farhadi
- Rheumatology Research CenterTehran University of Medical SciencesTehranIran
- Research Center for Chronic Inflammatory DiseasesTehran University of Medical SciencesTehranIran
| | | | - Ahmadreza Jamshidi
- Rheumatology Research CenterTehran University of Medical SciencesTehranIran
| | - Majid Alikhani
- Rheumatology Research CenterTehran University of Medical SciencesTehranIran
| | - Mahdi Mahmoudi
- Rheumatology Research CenterTehran University of Medical SciencesTehranIran
- Research Center for Chronic Inflammatory DiseasesTehran University of Medical SciencesTehranIran
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Khalili-Tanha G, Khalili-Tanha N, Rouzbahani AK, Mahdieh R, Jasemi K, Ghaderi R, Leylakoohi FK, Ghorbani E, Khazaei M, Hassanian SM, Gataa IS, Ferns GA, Nazari E, Avan A. Diagnostic, prognostic, and predictive biomarkers in gastric cancer: from conventional to novel biomarkers. Transl Res 2024; 274:35-48. [PMID: 39260559 DOI: 10.1016/j.trsl.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 08/12/2024] [Accepted: 09/04/2024] [Indexed: 09/13/2024]
Abstract
Gastric cancer is a major health concern worldwide. The survival rate of Gastric cancer greatly depends on the stage at which it is diagnosed. Early diagnosis is critical for improving survival outcomes. To improve the chances of early diagnosis, regular screening tests, such as an upper endoscopy or barium swallow, are recommended for individuals at a higher risk due to factors like family history or a previous diagnosis of gastric conditions. Biomarkers can be detected and measured using non-invasive methods such as blood tests, urine tests, breath analysis, or imaging techniques. These non-invasive approaches offer many advantages, including convenience, safety, and cost-effectiveness, making them valuable tools for disease diagnosis, monitoring, and research. Biomarker-based tests have emerged as a useful tool for identifying gastric cancer early, monitoring treatment response, assessing the recurrence risk, and personalizing treatment plans. In this current review, we have explored both classical and novel biomarkers for gastric cancer. We have centralized their potential clinical application and discussed the challenges in Gastric cancer research.
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Affiliation(s)
- Ghazaleh Khalili-Tanha
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Khalili-Tanha
- Department of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK S7N 5B4, Canada
| | | | - Ramisa Mahdieh
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kimia Jasemi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rosa Ghaderi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Elnaz Ghorbani
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Gordon A Ferns
- Brighton & Sussex Medical School, Department of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Elham Nazari
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia.
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4
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Baek S, Mairinger FD, Borchert S, Zhao Y, Ratiu D, Mallmann PK, Pilch H, Noh KW. Comparative Analysis of Digital Transcriptomics Between Pre- and Post-Treatment Samples of Patients with Locally Advanced Cervical Cancer: A Preliminary Study. Curr Issues Mol Biol 2024; 46:12075-12087. [PMID: 39590310 PMCID: PMC11592615 DOI: 10.3390/cimb46110716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 11/28/2024] Open
Abstract
Cervical cancer remains a leading cause of cancer-related deaths in women worldwide, with limited treatment options for advanced stages and therapy-resistant cases. Despite advances in treatment, the variability in the patient response to standard therapies underscores the need for molecular biomarkers to guide personalized treatment strategies. This study aimed to explore the transcriptomic changes associated with the therapeutic response in locally advanced cervical cancer, focusing on 770 immune-related genes. We employed a digital multiplexed gene expression analysis, comparing gene expression profiles between matching pre- and post-treatment samples. The results revealed the significant upregulation of C7 and EGR2 in the post-treatment samples, suggesting that enhanced immune activity is a key factor in therapeutic success. Conversely, IL17RB, S100A7, and SAA1 were upregulated in the pre-treatment samples, potentially indicating resistance mechanisms. Pathway enrichment analysis highlighted that the immune response and apoptosis pathways are crucial to post-treatment changes. These findings suggest that C7, EGR2, and IL17RB may serve as biomarkers for predicting therapeutic outcomes and could inform the development of more effective, individualized treatment strategies for cervical cancer. This study provides new insights into the molecular mechanisms underlying treatment response and resistance.
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Affiliation(s)
- Sunhwa Baek
- Department of Obstetrics and Gynecology, University Hospital Cologne and Medical Faculty, 50937 Cologne, Germany
| | | | - Sabrina Borchert
- Institute for Pathology, University Hospital Essen, 45147 Essen, Germany; (F.D.M.); (S.B.)
| | - Yue Zhao
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital Cologne and Medical Faculty, 50937 Cologne, Germany;
| | - Dominik Ratiu
- Department of Obstetrics and Gynecology, University Hospital Cologne and Medical Faculty, 50937 Cologne, Germany
| | - Peter Konrad Mallmann
- Department of Obstetrics and Gynecology, University Hospital Cologne and Medical Faculty, 50937 Cologne, Germany
| | - Henryk Pilch
- Department of Obstetrics and Gynecology, University Hospital Cologne and Medical Faculty, 50937 Cologne, Germany
| | - Ka-Won Noh
- Institute for Pathology, University Hospital Cologne and Medical Faculty, 50937 Cologne, Germany
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5
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Yang H, Wang H, He Y, Yang Y, Thompson EW, Xia D, Burke LJ, Cao L, Hooper JD, Roberts MS, Crawford DHG, Liang X. Identification and characterization of TM4SF1 + tumor self-seeded cells. Cell Rep 2024; 43:114512. [PMID: 39003738 DOI: 10.1016/j.celrep.2024.114512] [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: 09/11/2023] [Revised: 04/30/2024] [Accepted: 06/30/2024] [Indexed: 07/16/2024] Open
Abstract
Tumor self-seeding is a process whereby circulating tumor cells (CTCs) recolonize the primary tumor, which promotes tumor growth, angiogenesis, and invasion. However, the detailed nature and functions of tumor self-seeded cells (TSCs) have not been well defined due to challenges in tracking and isolating TSCs. Here, we report an accurate animal model using photoconvertible tagging to recapitulate the spontaneous process of tumor self-seeding and identify TSCs as a subpopulation of primary tumor cells with enhanced invasiveness and survival. We demonstrate transmembrane-4-L-six-family-1 (TM4SF1) as a marker of TSCs, which promotes migration, invasion, and anchorage-independent survival in cancer cells. By analyzing single-cell RNA sequencing datasets, we identify a potential TSC population with a metastatic profile in patients with cancer, which is detectable in early-stage disease and expands during cancer progression. In summary, we establish a framework to study TSCs and identify emerging cell targets with diagnostic, prognostic, or therapeutic potential in cancers.
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Affiliation(s)
- Haotian Yang
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia; Gallipoli Medical Research, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Haolu Wang
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia; Gallipoli Medical Research, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Yaowu He
- Mater Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia
| | - Yang Yang
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia
| | - Erik W Thompson
- School of Biomedical Sciences, Queensland University of Technology and Translational Research Institute, Brisbane, QLD 4000, Australia
| | - Di Xia
- Genome Innovation Hub, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Leslie J Burke
- Gallipoli Medical Research, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Lu Cao
- Gallipoli Medical Research, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - John D Hooper
- Mater Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia
| | - Michael S Roberts
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia
| | - Darrell H G Crawford
- Gallipoli Medical Research, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia; Faculty of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia
| | - Xiaowen Liang
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia; Gallipoli Medical Research, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia.
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6
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Xiang K, Wang E, Mantyh J, Rupprecht G, Negrete M, Sanati G, Hsu C, Randon P, Dohlman A, Kretzschmar K, Bose S, Giroux N, Ding S, Wang L, Balcazar JP, Huang Q, Sundaramoorthy P, Xi R, McCall SJ, Wang Z, Jiang C, Kang Y, Kopetz S, Crawford GE, Lipkin SM, Wang XF, Clevers H, Hsu D, Shen X. Chromatin Remodeling in Patient-Derived Colorectal Cancer Models. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2303379. [PMID: 38380561 DOI: 10.1002/advs.202303379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 11/22/2023] [Indexed: 02/22/2024]
Abstract
Patient-Derived Organoids (PDO) and Xenografts (PDX) are the current gold standards for patient-derived models of cancer (PDMC). Nevertheless, how patient tumor cells evolve in these models and the impact on drug response remains unclear. Herein, the transcriptomic and chromatin accessibility landscapes of matched colorectal cancer (CRC) PDO, PDX, PDO-derived PDX (PDOX), and original patient tumors (PT) are compared. Two major remodeling axes are discovered. The first axis delineates PDMC from PT, and the second axis distinguishes PDX and PDO. PDOX are more similar to PDX than PDO, indicating the growth environment is a driving force for chromatin adaptation. Transcription factors (TF) that differentially bind to open chromatins between matched PDO and PDOX are identified. Among them, KLF14 and EGR2 footprints are enriched in PDOX relative to matched PDO, and silencing of KLF14 or EGR2 promoted tumor growth. Furthermore, EPHA4, a shared downstream target gene of KLF14 and EGR2, altered tumor sensitivity to MEK inhibitor treatment. Altogether, patient-derived CRC cells undergo both common and distinct chromatin remodeling in PDO and PDX/PDOX, driven largely by their respective microenvironments, which results in differences in growth and drug sensitivity and needs to be taken into consideration when interpreting their ability to predict clinical outcome.
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Affiliation(s)
- Kun Xiang
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
| | - Ergang Wang
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
| | - John Mantyh
- Department of Medicine, School of Medicine, Duke University, Durham, NC, 27710, USA
| | - Gabrielle Rupprecht
- Department of Medicine, School of Medicine, Duke University, Durham, NC, 27710, USA
| | - Marcos Negrete
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
| | - Golshid Sanati
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
| | - Carolyn Hsu
- Department of Medicine, School of Medicine, Duke University, Durham, NC, 27710, USA
| | - Peggy Randon
- Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27709, USA
| | - Anders Dohlman
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
| | - Kai Kretzschmar
- Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center (UMC) Utrecht, Uppsalalaan 8, Utrecht, CT, 3584, The Netherlands
- Mildred Scheel Early Career Centre (MSNZ) for Cancer Research Würzburg, University Hospital Würzburg, 97080, Würzburg, Germany
| | - Shree Bose
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
| | - Nicholas Giroux
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
| | - Shengli Ding
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
| | - Lihua Wang
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
| | - Jorge Prado Balcazar
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
| | - Qiang Huang
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
- Terasaki Institute, Los Angeles, CA, 90024, USA
| | | | - Rui Xi
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
| | - Shannon Jones McCall
- Department of Pathology, School of Medicine, Duke University, Durham, NC, 27710, USA
| | - Zhaohui Wang
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
| | | | - Yubin Kang
- Department of Medicine, School of Medicine, Duke University, Durham, NC, 27710, USA
| | - Scott Kopetz
- Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Gregory E Crawford
- Department of Pediatrics, Division of Medical Genetics, School of Medicine, Duke University, Durham, NC, 27710, USA
| | - Steven M Lipkin
- Department of Medicine and Program in Mendelian Genetics, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Xiao-Fan Wang
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA
| | - Hans Clevers
- Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center (UMC) Utrecht, Uppsalalaan 8, Utrecht, CT, 3584, The Netherlands
| | - David Hsu
- Department of Medicine, School of Medicine, Duke University, Durham, NC, 27710, USA
| | - Xiling Shen
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA
- Terasaki Institute, Los Angeles, CA, 90024, USA
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7
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Abdel-Hafiz HA, Kailasam Mani SK, Huang W, Gouin KH, Chang Y, Xiao T, Ma Q, Li Z, Knott SR, Theodorescu D. Single-cell profiling of murine bladder cancer identifies sex-specific transcriptional signatures with prognostic relevance. iScience 2023; 26:107703. [PMID: 37701814 PMCID: PMC10494466 DOI: 10.1016/j.isci.2023.107703] [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: 06/09/2023] [Revised: 07/18/2023] [Accepted: 08/21/2023] [Indexed: 09/14/2023] Open
Abstract
Bladder cancer (BLCA) is more common in men but more aggressive in women. Sex-based differences in cancer biology are commonly studied using a murine model with BLCA generated by N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). While tumors in the BBN model have been profiled, these profiles provide limited information on the tumor microenvironment. Here, we applied single-cell RNA sequencing to characterize cell-type specific transcriptional differences between male and female BBN-induced tumors. We found proportional and gene expression differences in epithelial and non-epithelial subpopulations between male and female tumors. Expression of several genes predicted sex-specific survival in several human BLCA datasets. We identified novel and clinically relevant sex-specific transcriptional signatures including immune cells in the tumor microenvironment and it validated the relevance of the BBN model for studying sex differences in human BLCA. This work highlights the importance of considering sex as a biological variable in the development of new and accurate cancer markers.
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Affiliation(s)
- Hany A. Abdel-Hafiz
- Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA
| | | | - Wesley Huang
- Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kenneth H. Gouin
- Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yuzhou Chang
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center – The James, Columbus, OH 43210, USA
| | - Tong Xiao
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center – The James, Columbus, OH 43210, USA
| | - Qin Ma
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center – The James, Columbus, OH 43210, USA
| | - Zihai Li
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center – The James, Columbus, OH 43210, USA
| | - Simon R.V. Knott
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Dan Theodorescu
- Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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8
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Sarkar A, Paul A, Banerjee T, Maji A, Saha S, Bishayee A, Maity TK. Therapeutic advancements in targeting BCL-2 family proteins by epigenetic regulators, natural, and synthetic agents in cancer. Eur J Pharmacol 2023; 944:175588. [PMID: 36791843 DOI: 10.1016/j.ejphar.2023.175588] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 01/21/2023] [Accepted: 02/08/2023] [Indexed: 02/17/2023]
Abstract
Cancer is amongst the deadliest and most disruptive disorders, having a much higher death rate than other diseases worldwide. Human cancer rates continue to rise, thereby posing the most significant concerns for medical health professionals. In the last two decades, researchers have gone past several milestones in tackling cancer while gaining insight into the role of apoptosis in cancer or targeting various biomarker tools for prognosis and diagnosis. Apoptosis which is still a topic full of complexities, can be controlled considerably by B-cell lymphoma 2 (BCL-2) and its family members. Therefore, targeting proteins of this family to prevent tumorigenesis, is essential to focus on the pharmacological features of the anti-apoptotic and pro-apoptotic members, which will help to develop and manage this disorder. This review deals with the advancements of various epigenetic regulators to target BCL-2 family proteins, including the mechanism of several microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Similarly, a rise in natural and synthetic molecules' research over the last two decades has allowed us to acquire insights into understanding and managing the transcriptional alterations that have led to apoptosis and treating various neoplastic diseases. Furthermore, several inhibitors targeting anti-apoptotic proteins and inducers or activators targeting pro-apoptotic proteins in preclinical and clinical stages have been summarized. Overall, agonistic and antagonistic mechanisms of BCL-2 family proteins conciliated by epigenetic regulators, natural and synthetic agents have proven to be an excellent choice in developing cancer therapeutics.
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Affiliation(s)
- Arnab Sarkar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Abhik Paul
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Tanmoy Banerjee
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Avik Maji
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Sanjukta Saha
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
| | - Tapan Kumar Maity
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, 700032, India.
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9
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Choi EY, Franco D, Stapf CA, Gordin M, Chow A, Cover KK, Chandra R, Lobo MK. Inducible CRISPR Epigenome Systems Mimic Cocaine Induced Bidirectional Regulation of Nab2 and Egr3. J Neurosci 2023; 43:2242-2259. [PMID: 36849419 PMCID: PMC10072301 DOI: 10.1523/jneurosci.1802-22.2022] [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: 09/19/2022] [Revised: 12/06/2022] [Accepted: 12/22/2022] [Indexed: 03/01/2023] Open
Abstract
Substance use disorder is a chronic disease and a leading cause of disability around the world. The NAc is a major brain hub mediating reward behavior. Studies demonstrate exposure to cocaine is associated with molecular and functional imbalance in NAc medium spiny neuron subtypes (MSNs), dopamine receptor 1 and 2 enriched D1-MSNs and D2-MSNs. We previously reported repeated cocaine exposure induced transcription factor early growth response 3 (Egr3) mRNA in NAc D1-MSNs, and reduced it in D2-MSNs. Here, we report our findings of repeated cocaine exposure in male mice inducing MSN subtype-specific bidirectional expression of the Egr3 corepressor NGFI-A-binding protein 2 (Nab2). Using CRISPR activation and interference (CRISPRa and CRISPRi) tools combined with Nab2 or Egr3-targeted sgRNAs, we mimicked these bidirectional changes in Neuro2a cells. Furthermore, we investigated D1-MSN- and D2-MSN-specific expressional changes of histone lysine demethylases Kdm1a, Kdm6a, and Kdm5c in NAc after repeated cocaine exposure in male mice. Since Kdm1a showed bidirectional expression patterns in D1-MSNs and D2-MSNs, like Egr3, we developed a light-inducible Opto-CRISPR-KDM1a system. We were able to downregulate Egr3 and Nab2 transcripts in Neuro2A cells and cause similar bidirectional expression changes we observed in D1-MSNs and D2-MSNs of mouse repeated cocaine exposure model. Contrastingly, our Opto-CRISPR-p300 activation system induced the Egr3 and Nab2 transcripts and caused opposite bidirectional transcription regulations. Our study sheds light on the expression patterns of Nab2 and Egr3 in specific NAc MSNs in cocaine action and uses CRISPR tools to further mimic these expression patterns.SIGNIFICANCE STATEMENT Substance use disorder is a major societal issue. The lack of medication to treat cocaine addiction desperately calls for a treatment development based on precise understanding of molecular mechanisms underlying cocaine addiction. In this study, we show that Egr3 and Nab2 are bidirectionally regulated in mouse NAc D1-MSNs and D2-MSNs after repeated exposure to cocaine. Furthermore, histone lysine demethylations enzymes with putative EGR3 binding sites showed bidirectional regulation in D1- and D2-MSNs after repeated exposure to cocaine. Using Cre- and light-inducible CRISPR tools, we show that we can mimic this bidirectional regulation of Egr3 and Nab2 in Neuro2a cells.
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Affiliation(s)
- Eric Y Choi
- Department of Anatomy and Neurobiology
- Graduate Program in Life Sciences, Biochemistry and Molecular Biology
| | - Daniela Franco
- Department of Anatomy and Neurobiology
- Program in Neuroscience, Graduate Program in Life Sciences
| | - Catherine A Stapf
- Department of Anatomy and Neurobiology
- Program in Neuroscience, Graduate Program in Life Sciences
| | | | | | - Kara K Cover
- Department of Anatomy and Neurobiology
- Program in Neuroscience, Graduate Program in Life Sciences
| | - Ramesh Chandra
- Department of Anatomy and Neurobiology
- Center for Innovative Biomedical Resources, Virus Vector Core, University of Maryland School of Medicine Baltimore, Maryland, 21201
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Eraky AM. Non-coding RNAs as Genetic Biomarkers for the Diagnosis, Prognosis, Radiosensitivity, and Histopathologic Grade of Meningioma. Cureus 2023; 15:e34593. [PMID: 36883085 PMCID: PMC9985895 DOI: 10.7759/cureus.34593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2023] [Indexed: 02/05/2023] Open
Abstract
Meningioma is considered the most common primary benign brain tumor. It originates from the arachnoid cells of the leptomeninges surrounding the brain. The mainstay treatment of meningiomas is microsurgical resection. Meningioma prognosis depends on tumor grade, location, and patient age. Recently, using non-coding RNA as a prognostic and diagnostic biomarker for many tumors became a trend. Herein, we demonstrate the importance of non-coding RNAs, including microRNAs and lncRNAs in meningioma and their potential role in meningioma's early diagnosis, prognosis, histological grade, and radiosensitivity. In this review, many microRNAs were found to be upregulated in radioresistant meningioma cells such as microRNA-221, microRNA-222, microRNA-4286, microRNA-4695-5p, microRNA-6732-5p, microRNA-6855-5p, microRNA-7977, microRNA-6765-3p, and microRNA-6787-5p. Moreover, there are many microRNAs downregulated in radioresistant meningioma cells such as microRNA-1275, microRNA-30c-1-3p, microRNA-4449, microRNA-4539, microRNA-4684-3p, microRNA-6129, and microRNA-6891-5p. Also, we highlight the possible use of non-coding RNAs as serum non-invasive biomarkers and their potential role as therapeutic targets to treat high-grade meningiomas. Recent studies show that microRNA-497, microRNA-195, microRNA-18a, microRNA-197, and microRNA-224 are downregulated in the serum of patients with meningiomas. Additionally, microRNA-106a-5p, microRNA-219-5p, microRNA-375, and microRNA-409-3p are found to be upregulated in the serum of patients with meningioma. We also found that there are many deregulated microRNAs in meningioma cells that can be used as potential biomarkers for meningioma diagnosis, prognosis, and histopathologic grade, such as microRNA-17-5p, microRNA-199a, microRNA-190a, microRNA-186-5p, microRNA155-5p, microRNA-22-3p, microRNA-24-3p, microRNA-26-5p, microRNA-27a-3p, microRNA-27b-3p, microRNA-96-5p, microRNA-146a-5p, microRNA-29c-3p, microRNA-219-5p, microRNA-335, microRNA-200a, microRNA-21, microRNA-107, microRNA-224, microRNA-195, microRNA-34a-3p, and microRNA-let-7d. Of interest, we found fewer studies discussing deregulated long non-coding RNAs (lncRNAs) in meningioma cells. LncRNAs work as competitive endogenous RNA (ceRNA) by binding to oncogenic or anti-oncogenic microRNAs. We found that lncRNA- NUP210, lncRNA-SPIRE2, lncRNA-SLC7A1, lncRNA-DMTN, lncRNA-LINC00702, and lncRNA-LINC00460 are upregulated in meningioma cells. In contrast, lncRNA-MALAT1 was found to be downregulated in meningioma cells.
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Affiliation(s)
- Akram M Eraky
- Neurological Surgery, Medical College of Wisconsin, Milwaukee, USA
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11
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Field JT, Gordon JW. BNIP3 and Nix: Atypical regulators of cell fate. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119325. [PMID: 35863652 DOI: 10.1016/j.bbamcr.2022.119325] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 06/17/2022] [Accepted: 07/05/2022] [Indexed: 11/27/2022]
Abstract
Since their discovery nearly 25 years ago, the BCL-2 family members BNIP3 and BNIP3L (aka Nix) have been labelled 'atypical'. Originally, this was because BNIP3 and Nix have divergent BH3 domains compared to other BCL-2 proteins. In addition, this atypical BH3 domain is dispensable for inducing cell death, which is also unusual for a 'death gene'. Instead, BNIP3 and Nix utilize a transmembrane domain, which allows for dimerization and insertion into and through organelle membranes to elicit cell death. Much has been learned regarding the biological function of these two atypical death genes, including their role in metabolic stress, where BNIP3 is responsive to hypoxia, while Nix responds variably to hypoxia and is also down-stream of PKC signaling and lipotoxic stress. Interestingly, both BNIP3 and Nix respond to signals related to cell atrophy. In addition, our current view of regulated cell death has expanded to include forms of necrosis such as necroptosis, pyroptosis, ferroptosis, and permeability transition-mediated cell death where BNIP3 and Nix have been shown to play context- and cell-type specific roles. Perhaps the most intriguing discoveries in recent years are the results demonstrating roles for BNIP3 and Nix outside of the purview of death genes, such as regulation of proliferation, differentiation/maturation, mitochondrial dynamics, macro- and selective-autophagy. We provide a historical and unbiased overview of these 'death genes', including new information related to alternative splicing and post-translational modification. In addition, we propose to redefine these two atypical members of the BCL-2 family as versatile regulators of cell fate.
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Affiliation(s)
- Jared T Field
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Canada; The Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme of the Children's Hospital Research Institute of Manitoba, Winnipeg, Canada
| | - Joseph W Gordon
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Canada; College of Nursing, Rady Faculty of Health Science, University of Manitoba, Canada; The Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme of the Children's Hospital Research Institute of Manitoba, Winnipeg, Canada.
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12
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Bo Z, Huang S, Li L, Chen L, Chen P, Luo X, Shi F, Zhu B, Shen L. EGR2 is a hub-gene in myocardial infarction and aggravates inflammation and apoptosis in hypoxia-induced cardiomyocytes. BMC Cardiovasc Disord 2022; 22:373. [PMID: 35971091 PMCID: PMC9377070 DOI: 10.1186/s12872-022-02814-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 08/06/2022] [Indexed: 11/25/2022] Open
Abstract
Background Myocardial infarction (MI) is characterized by coronary artery occlusion, ischemia and hypoxia of myocardial cells, leading to irreversible myocardial damage. Therefore, it is urgent to explore the potential mechanism of myocardial injury during the MI process to develop effective therapies for myocardial cell rescue. Methods We downloaded the GSE71906 dataset from GEO DataSets, and the R software was used to identify the differentially expressed genes (DEGs) in mouse heart tissues of MI and sham controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed to understand the significantly activated signaling pathways in MI. Protein–protein interaction (PPI) network was constructed to highlight the hub genes in DEGs. The Western Blot, qRT-PCR and TUNEL staining were used to explore the function of hub gene in hypoxia-induced cardiomyocytes in vitro. Results A total of 235 DEGs were identified in GSE71906 dataset. Functional enrichment analysis revealed that the upregulated genes were primarily associated with the inflammatory response and apoptosis. 20 hub genes were identified in PPI network, and the early growth response 2 (EGR2) was highlighted. In vitro. We confirmed the EGR2 was upregulated induced by hypoxia and revealed the upregulated EGR2 aggravates pro-inflammation and pro-apoptotic genes expression. In addition, EGR2 knockout mitigates hypoxia-induced inflammation and apoptosis in cardiomyocytes. Conclusion The present study identified the EGR2 was a hub gene in myocardial damage during MI process, the excessive EGR2 aggravates hypoxia-induced myocardial damage by accelerating inflammation and apoptosis in vitro. Therefore, targeting EGR2 offers a potential pharmacological strategy for myocardial cell rescue in MI. Supplementary Information The online version contains supplementary material available at 10.1186/s12872-022-02814-3.
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Affiliation(s)
- Zhixiang Bo
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Chongqing Medical University, #76 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Shuwen Huang
- Research Base of Traditional Chinese Medicine Syndrome, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Li Li
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Chongqing Medical University, #76 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Lin Chen
- Department of Surgery, Wushan County Hospital of Traditional Chinese Medicine, Chongqing, 400010, China
| | - Ping Chen
- Department of Gastroenterology, The Fifth People's Hospital of Chongqing, Chongqing, 400010, China
| | - Xiaoyi Luo
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Chongqing Medical University, #76 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Fang Shi
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Chongqing Medical University, #76 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Bing Zhu
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Chongqing Medical University, #76 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
| | - Lin Shen
- Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Chongqing Medical University, #76 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
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13
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Xu Y, Wang S, Cao X, Yuan Z, Getachew T, Mwacharo JM, Haile A, Lv X, Sun W. The Effect of EGR1 on the Proliferation of Dermal Papilla Cells. Genes (Basel) 2022; 13:genes13071242. [PMID: 35886025 PMCID: PMC9321982 DOI: 10.3390/genes13071242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/04/2022] [Accepted: 07/07/2022] [Indexed: 02/01/2023] Open
Abstract
Early growth response factor 1 (EGR1) is a zinc-finger transcription factor that plays a vital role in the development of hair follicles. According to our previous studies, EGR1 is a transcriptional promoter of the bone morphogenetic protein 7 (BMP7), a candidate gene involved in the proliferation of dermal papilla cells. Since hair follicles are the basis of lambskin pattern formation and dermal papilla cells (DPCs) act on hair follicle growth, in order to elucidate the role of EGR1 and hair follicles, this study aimed to investigate the biological role of EGR1 in DPCs. In our study, the EGR1 coding sequence (CDS) region was firstly cloned by polymerase chain reaction, and bioinformatics analysis was performed. Then, the function of EGR1 was detected by 5-ethynyl-2’-deoxyuridine (EDU) and Cell Counting Kit-8 (CCK8), and Western blot (WB) was conducted to analyze the cellular effect of EGR1 on DPCs. The proliferative effect of EGR1 on DPCs was also further confirmed by detecting its expression by qPCR and WB on marker genes of proliferation, including PCNA and CDK2. The sequence of the EGR1 CDS region of a lamb was successfully cloned, and its nucleic acid sequence was analyzed and found to be highly homologous to Rattus norvegicus, Mus musculus, Bos taurus and Homo sapiens. Predictive analysis of the protein encoded by EGR1 revealed that it is an extra-membrane protein, and not a secretory protein, with subcellular localization in the nucleus and cytoplasm. The proliferative effect of DPCs was significantly stronger (p < 0.01) in EGR1 up-regulated DPCs compared to the controls, while the opposite result was observed in EGR1 down-regulated DPCs. Markers of proliferation including PCNA and CDK2 also appeared to be differentially upregulated in EGR1 gene overexpression compared to the controls, with the opposite result in EGR1 gene downregulation. In summary, our study revealed that EGR1 promotes the proliferation of DPCs, and we speculate that EGR1 may be closely associated with hair follicle growth and development.
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Affiliation(s)
- Yeling Xu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Y.X.); (S.W.)
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, China; (X.C.); (Z.Y.); (T.G.); (J.M.M.); (A.H.)
| | - Shanhe Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Y.X.); (S.W.)
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, China; (X.C.); (Z.Y.); (T.G.); (J.M.M.); (A.H.)
| | - Xiukai Cao
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, China; (X.C.); (Z.Y.); (T.G.); (J.M.M.); (A.H.)
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Zehu Yuan
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, China; (X.C.); (Z.Y.); (T.G.); (J.M.M.); (A.H.)
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Tesfaye Getachew
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, China; (X.C.); (Z.Y.); (T.G.); (J.M.M.); (A.H.)
- International Centre for Agricultural Research in the Dry Areas, Addis Ababa 999047, Ethiopia
| | - Joram M. Mwacharo
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, China; (X.C.); (Z.Y.); (T.G.); (J.M.M.); (A.H.)
- International Centre for Agricultural Research in the Dry Areas, Addis Ababa 999047, Ethiopia
| | - Aynalem Haile
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, China; (X.C.); (Z.Y.); (T.G.); (J.M.M.); (A.H.)
- International Centre for Agricultural Research in the Dry Areas, Addis Ababa 999047, Ethiopia
| | - Xiaoyang Lv
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, China; (X.C.); (Z.Y.); (T.G.); (J.M.M.); (A.H.)
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
- Correspondence: (X.L.); (W.S.)
| | - Wei Sun
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; (Y.X.); (S.W.)
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, China; (X.C.); (Z.Y.); (T.G.); (J.M.M.); (A.H.)
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
- Correspondence: (X.L.); (W.S.)
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An integrated pan-cancer analysis of identifying biomarkers about the EGR family genes in human carcinomas. Comput Biol Med 2022; 148:105889. [DOI: 10.1016/j.compbiomed.2022.105889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/25/2022] [Accepted: 07/16/2022] [Indexed: 12/24/2022]
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15
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Integrative network-based approaches identified systems-level molecular signatures associated with gallbladder cancer pathogenesis from gallstone diseases. J Biosci 2022. [DOI: 10.1007/s12038-022-00267-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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16
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UNOKI M, SASAKI H. The UHRF protein family in epigenetics, development, and carcinogenesis. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2022; 98:401-415. [PMID: 36216533 PMCID: PMC9614205 DOI: 10.2183/pjab.98.021] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 06/14/2022] [Indexed: 05/31/2023]
Abstract
The UHRF protein family consists of multidomain regulatory proteins that sense modification status of DNA and/or proteins and catalyze the ubiquitylation of target proteins. Through their functional domains, they interact with other molecules and serve as a hub for regulatory networks of several important biological processes, including maintenance of DNA methylation and DNA damage repair. The UHRF family is conserved in vertebrates and plants but is missing from fungi and many nonvertebrate animals. Mammals commonly have UHRF1 and UHRF2, but, despite their high structural similarity, the two paralogues appear to have distinct functions. Furthermore, UHRF1 and UHRF2 show different expression patterns and different outcomes in gene knockout experiments. In this review, we summarize the current knowledge on the molecular function of the UHRF family in various biological pathways and discuss their roles in epigenetics, development, gametogenesis, and carcinogenesis, with a focus on the mammalian UHRF proteins.
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Affiliation(s)
- Motoko UNOKI
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Department of Human Genetics, School of International Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki SASAKI
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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García-Chávez JN, Vásquez-Garzón VR, López MG, Villa-Treviño S, Montiel R. Integration of chronological omics data reveals mitochondrial regulatory mechanisms during the development of hepatocellular carcinoma. PLoS One 2021; 16:e0256016. [PMID: 34383828 PMCID: PMC8360386 DOI: 10.1371/journal.pone.0256016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 07/28/2021] [Indexed: 12/13/2022] Open
Abstract
Mitochondria participate in multiple functions in eukaryotic cells. Although disruption of mitochondrial function has been associated with energetic deregulation in cancer, the chronological changes in mitochondria during cancer development remain unclear. With the aim to assess the role of mitochondria throughout cancer development, we analyzed samples chronologically obtained from induced hepatocellular carcinoma (HCC) in rats. In our analyses, we integrated mitochondrial proteomic data, mitochondrial metabolomic data and nuclear genome transcriptomic data. We used pathway over-representation and weighted gene co-expression network analysis (WGCNA) to integrate expression profiles of genes, miRNAs, proteins and metabolite levels throughout HCC development. Our results show that mitochondria are dynamic organelles presenting specific modifications in different stages of HCC development. We also found that mitochondrial proteomic profiles from tissues adjacent to nodules or tumor are determined more by the stage of HCC development than by tissue type, and we evaluated two models to predict HCC stage of the samples using proteomic profiles. Finally, we propose an omics integration pipeline to massively identify molecular features that could be further evaluated as key regulators, biomarkers or therapeutic targets. As an example, we show a group of miRNAs and transcription factors as candidates, responsible for mitochondrial metabolic modification in HCC.
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Affiliation(s)
- J. Noé García-Chávez
- Langebio, Unidad de Genómica Avanzada, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Irapuato, Mexico
| | | | - Mercedes G. López
- Departamento de Biotecnología y Bioquímica, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Irapuato, Mexico
| | - Saúl Villa-Treviño
- Department of Cell Biology, Center for Research and Advanced Studies (CINVESTAV-IPN), Ciudad de México, Mexico
| | - Rafael Montiel
- Langebio, Unidad de Genómica Avanzada, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Irapuato, Mexico
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Ozyerli-Goknar E, Bagci-Onder T. Epigenetic Deregulation of Apoptosis in Cancers. Cancers (Basel) 2021; 13:3210. [PMID: 34199020 PMCID: PMC8267644 DOI: 10.3390/cancers13133210] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/09/2021] [Accepted: 06/11/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer cells possess the ability to evade apoptosis. Genetic alterations through mutations in key genes of the apoptotic signaling pathway represent a major adaptive mechanism of apoptosis evasion. In parallel, epigenetic changes via aberrant modifications of DNA and histones to regulate the expression of pro- and antiapoptotic signal mediators represent a major complementary mechanism in apoptosis regulation and therapy response. Most epigenetic changes are governed by the activity of chromatin modifying enzymes that add, remove, or recognize different marks on histones and DNA. Here, we discuss how apoptosis signaling components are deregulated at epigenetic levels, particularly focusing on the roles of chromatin-modifying enzymes in this process. We also review the advances in cancer therapies with epigenetic drugs such as DNMT, HMT, HDAC, and BET inhibitors, as well as their effects on apoptosis modulation in cancer cells. Rewiring the epigenome by drug interventions can provide therapeutic advantage for various cancers by reverting therapy resistance and leading cancer cells to undergo apoptotic cell death.
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Affiliation(s)
- Ezgi Ozyerli-Goknar
- Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey;
- Research Center for Translational Medicine, Koç University, Istanbul 34450, Turkey
| | - Tugba Bagci-Onder
- Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey;
- Research Center for Translational Medicine, Koç University, Istanbul 34450, Turkey
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Geng X, Sun Y, Fu J, Cao L, Li Y. MicroRNA-17-5p inhibits thyroid cancer progression by suppressing Early growth response 2 (EGR2). Bioengineered 2021; 12:2713-2722. [PMID: 34130587 PMCID: PMC8806695 DOI: 10.1080/21655979.2021.1935137] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
miR-17-5p has been proved that play important roles in many kinds of tumors progression. This study aimed at explore the function and mechanism of miR-17-5p in thyroid cancer (TC). RT-qPCR was used to detect miR-17-5p and Early growth response 2 (EGR2) expression in TC tissues and cells. CCK8 and colony formation assay were used to analyze cell proliferation. Cell migration and cell invasion was detected by Wound-healing assay and Transwell assay. Detection of protein expression using Western blot analysis. Dual-Luciferase assay was used to analyze the relationship between miR-17-5p and EGR2. In vivo experiment was performed by establishing Xenograft animal model to observe the function of miR-17-5p. We found that miR-17-5p is significantly increased in thyroid cancer tissues and cells. miR-17-5p inhibition repressed cell proliferation, clonal formation, cell migration, and cell invasion in thyroid carcinoma. Moreover, miR-17-5p inhibition suppressed tumorigenesis in vivo. Dual-Luciferase assay and Western blotting assay further proved that miR-17-5p has a negative regulation to EGR2. EGR2 was decreased in TC tissues and cells. Overexpressed EGR2 inhibited the development of thyroid carcinoma both vivo and in vivo. EGR2 knockdown remarkably decreased the anti-cancer effect of miR-17-5p inhibition. miR-17-5p is a thyroid cancer oncomir by modulation of the EGR2.
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Affiliation(s)
- Xiang Geng
- Department of Thyroid and Breast Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - YangYang Sun
- Department of Pathology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - JinJin Fu
- Department of Gastroenterology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - Liang Cao
- Department of General Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
| | - Yuan Li
- Department of Thyroid and Breast Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
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Hao L, Huang F, Yu X, Xu B, Liu Y, Zhang Y, Zhu Y. The Role of Early Growth Response Family Members 1-4 in Prognostic Value of Breast Cancer. Front Genet 2021; 12:680132. [PMID: 34178038 PMCID: PMC8220134 DOI: 10.3389/fgene.2021.680132] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 04/26/2021] [Indexed: 12/20/2022] Open
Abstract
Early growth response family members (EGRs), EGR1–4, have increasingly attracted attention in multiple cancers. However, the exact expression patterns and prognostic values of EGRs in the progress of breast cancer (BRCA) remain largely unknown. The mRNA expression and prognostic characteristics of EGRs were examined by the Cancer Genome Atlas (TCGA), Oncomine, and Kaplan-Meier plotter. Enrichment analyses were conducted based on protein-protein interaction (PPI) network. The Tumor Immune Estimation Resource (TIMER) database and MethSurv were further explored. The protein expression of EGR1 in BRCA was measured by western blotting and immunohistochemistry. The migration of mammary epithelial cells was determined by Boyden chamber assay. The transcriptional levels of EGR1/2/3 displayed significantly low expression in BRCA compared with that in normal tissues, while EGR4 was shown adverse expression pattern. Survival analysis revealed upregulated EGR1–4 were remarkably associated with favorable relapse-free survival (RFS). A close correlation with specific tumor-infiltrating immune cells (TIICs) and several CpG sites of EGRs were exhibited. Immunohistochemistry assays showed that the protein expression of EGR1 was remarkably downregulated in BRCA compared with that in paracancerous tissues. The migration of MCF10A mammary epithelial cells was increased after the silence of EGR1 by siRNA transfection. This study provides a novel insight to the role of EGRs in the prognostic value of BRCA.
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Affiliation(s)
- Leiyu Hao
- Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Fengru Huang
- Research Division of Clinical Pharmacology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinqian Yu
- Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Bujie Xu
- Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Yan Liu
- Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Yan Zhang
- Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Yichao Zhu
- Department of Physiology, Nanjing Medical University, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
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21
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Guo H, Zhang L. EGR1/2 Inhibits Papillary Thyroid Carcinoma Cell Growth by Suppressing the Expression of PTEN and BAX. Biochem Genet 2021; 59:1544-1557. [PMID: 33973090 DOI: 10.1007/s10528-021-10075-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 04/22/2021] [Indexed: 12/14/2022]
Abstract
Early growth response (EGR) proteins have been reported to be involved in cell growth and apoptosis in a variety of cancer types and could inhibit tumor development. However, the role of EGR1/2 in papillary thyroid carcinoma (PTC) has not been elucidated. The expression pattern of EGR1/2 in adjacent tissues and cancer tissues and the clinical prognosis of EGR1/2 were analyzed by using the samples from TCGA database. The cell viability was detected by MTT assay. Luciferase reporter assay was used to demonstrate the binding of EGR1/2 to the target gene promotor region. Our results showed that EGR1/2 was significantly downregulated in tumor tissues and correlated with poor prognosis. Overexpression of EGR1/2 inhibited proliferation of IHH-4 and BCPAP cells, and knockdown of EGR1/2 showed a reverse effect. Overexpression of EGR1 or EGR2 promoted phosphatase and tension homolog (PTEN) or Bcl-2-associated X (BAX) expression, and EGR1 or EGR2 was able to directly bind to the promoter region of PTEN or BAX. In conclusion, we found that the altered expression of EGR1/2 affected the proliferation of PTC cells and regulated the expression of PTEN and BAX.
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Affiliation(s)
- Hao Guo
- Department of General Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Linlei Zhang
- Department of General Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China.
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22
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Cao X, Ma Q, Wang B, Qian Q, Liu N, Liu T, Dong X. Silencing long non-coding RNA MIAT ameliorates myocardial dysfunction induced by myocardial infarction via MIAT/miR-10a-5p/EGR2 axis. Aging (Albany NY) 2021; 13:11188-11206. [PMID: 33819189 PMCID: PMC8109106 DOI: 10.18632/aging.202785] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 10/20/2020] [Indexed: 02/07/2023]
Abstract
Long non-coding RNA (lncRNA) myocardial infarction-associated transcript (MIAT) has been widely-demonstrated to function as diagnostic markers for acute myocardial infarction (MI). This study was designed to explore the modulatory role of MIAT and its underlying molecular mechanism in MI. Firstly, MI mouse model was developed via ligation of the descending branch of the left coronary artery, and cell model was established through exposure to hypoxic conditions. Online prediction indicated that MIAT could bind to microRNA-10a-5p (miR-10a-5p), while miR-10a-5p was highlighted to bind to early growth response gene-2 (EGR2). MIAT and EGR2 were subsequently determined to be highly-expressed, whereas miR-10a-5p was found to be poorly-expressed in cardiomyocytes exposed to hypoxia as well as in MI mice using RT-qPCR and Western blot assay. The binding relationships between MIAT and miR-10a-5p, and between miR-10a-5p and EGR2 were further confirmed by dual-luciferase reporter and RNA immunoprecipitation assays. The results of in vitro and in vivo experimentation also suggested that overexpression of miR-10a-5p or silencing of MIAT and EGR2 reduced cardiomyocyte apoptosis and increased ATP content, thus alleviating the impairment of cardiac function following MI. In a word, inhibition of MIAT protects against cardiac dysfunction induced by MI through the crosstalk with miR-10a-5p/EGR2.
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Affiliation(s)
- Xiangke Cao
- School of Life Sciences, North China University of Science and Technology, Tangshan 063210, P.R. China
| | - Qinghua Ma
- Department of Preventive Health, The Third People's Hospital Of Xiangcheng District In Suzhou, Suzhou 215134, P.R. China
| | - Bin Wang
- Department of Pediatrics, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, P.R. China
| | - Qingqiang Qian
- Department of Neurology, Tangshan Gongren Hospital, Tangshan 063000, P.R. China
| | - Ning Liu
- Department of Cardiovascular Diseases, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, P.R. China
| | - Tiejun Liu
- Department of Anesthesiology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, P.R. China
| | - Xiaoliu Dong
- Department of Neurology, Tangshan People's Hospital, Tangshan 063001, P.R. China
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23
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Zhou X, Zhang FY, Liu Y, Wei DX. A Risk Prediction Model for Breast Cancer Based on Immune Genes Related to Early Growth Response Proteins Family. Front Mol Biosci 2021; 7:616547. [PMID: 33614706 PMCID: PMC7887293 DOI: 10.3389/fmolb.2020.616547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 12/21/2020] [Indexed: 11/19/2022] Open
Abstract
Early growth response proteins (EGRs), a transcriptional regulatory family comprised of EGR1, EGR2, EGR3, and EGR 4, are reportedly involved in a vast array of functions. However, EGRs, as a whole, are rarely studied in breast cancer cases. This research was performed based on public datasets. The results demonstrated that, except EGR4, the other EGRs were differentially expressed genes in breast cancer. Subsequently, this study determined the prognosis significance of the EGR family, higher expression levels of EGRs indicating better overall survival (OS) and disease-free survival (DFS), except EGR4. So we attempted to explore the potential mechanism behind the prognostic value of EGRs. At the DNA level, however, neither DNA methylation status nor genetic alterations of EGRs contributed to the prognosis significance. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that EGRs were involved in several immune-related functions. Afterward, we assessed the correlation between EGRs and the immune system before establishing a risk prediction model with a 14-gene immune signature associated with EGRs, a prognostic nomogram predicting individuals’ 1-, 3-, and 5-year survival probabilities. The risk score was an independent prognosis predictor in the breast cancer cohorts. This study evidenced EGRs’ significance for tumor immunity, demonstrating that the EGR family may be a potential immunotherapeutic target for breast cancer. The 14-gene immune signature is a promising prognostic biomarker in breast cancer.
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Affiliation(s)
- Xin Zhou
- Department of Breast Surgery, Zibo Maternal and Child Health Hospital, Zibo, China
| | - Fang-Yuan Zhang
- Department of Breast Surgery, Zibo Maternal and Child Health Hospital, Zibo, China
| | - Yan Liu
- Department of Breast Surgery, Zibo Maternal and Child Health Hospital, Zibo, China
| | - Dong-Xin Wei
- Department of Breast Surgery, Zibo Maternal and Child Health Hospital, Zibo, China
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24
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Kerr J. Early Growth Response Gene Upregulation in Epstein-Barr Virus (EBV)-Associated Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Biomolecules 2020; 10:biom10111484. [PMID: 33114612 PMCID: PMC7692278 DOI: 10.3390/biom10111484] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem disease exhibiting a variety of symptoms and affecting multiple systems. Psychological stress and virus infection are important. Virus infection may trigger the onset, and psychological stress may reactivate latent viruses, for example, Epstein-Barr virus (EBV). It has recently been reported that EBV induced gene 2 (EBI2) was upregulated in blood in a subset of ME/CFS patients. The purpose of this study was to determine whether the pattern of expression of early growth response (EGR) genes, important in EBV infection and which have also been found to be upregulated in blood of ME/CFS patients, paralleled that of EBI2. EGR gene upregulation was found to be closely associated with that of EBI2 in ME/CFS, providing further evidence in support of ongoing EBV reactivation in a subset of ME/CFS patients. EGR1, EGR2, and EGR3 are part of the cellular immediate early gene response and are important in EBV transcription, reactivation, and B lymphocyte transformation. EGR1 is a regulator of immune function, and is important in vascular homeostasis, psychological stress, connective tissue disease, mitochondrial function, all of which are relevant to ME/CFS. EGR2 and EGR3 are negative regulators of T lymphocytes and are important in systemic autoimmunity.
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Affiliation(s)
- Jonathan Kerr
- Department of Microbiology, Norfolk & Norwich University Hospital (NNUH), Colney Lane, Norwich, Norfolk NR4 7UY, UK
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25
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Mitrea C, Bollig-Fischer A, Voichiţa C, Donato M, Romero R, Drăghici S. Detecting qualitative changes in biological systems. Sci Rep 2020; 10:8146. [PMID: 32424123 PMCID: PMC7235093 DOI: 10.1038/s41598-020-62578-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 03/04/2020] [Indexed: 01/09/2023] Open
Abstract
Currently, most diseases are diagnosed only after significant disease-associated transformations have taken place. Here, we propose an approach able to identify when systemic qualitative changes in biological systems happen, thus opening the possibility for therapeutic interventions before the occurrence of symptoms. The proposed method exploits knowledge from biological networks and longitudinal data using a system impact analysis. The method is validated on eight biological phenomena, three synthetic datasets and five real datasets, for seven organisms. Most importantly, the method accurately detected the transition from the control stage (benign) to the early stage of hepatocellular carcinoma on an eight-stage disease dataset.
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Affiliation(s)
- Cristina Mitrea
- Wayne State University, Department of Computer Science, Detroit, 48202, USA
- Wayne State University, Department of Oncology, Detroit, 48201, USA
| | - Aliccia Bollig-Fischer
- Wayne State University, Department of Oncology, Detroit, 48201, USA
- Karmanos Cancer Institute, Detroit, 48201, USA
| | - Călin Voichiţa
- Wayne State University, Department of Computer Science, Detroit, 48202, USA
| | - Michele Donato
- Stanford University, Institute for Immunity, Transplantation and Infection, Stanford, 94305, USA
| | - Roberto Romero
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Detroit, 48201, USA
- University of Michigan, Department of Obstetrics and Gynecology, Ann Arbor, 48109, USA
- Michigan State University, Department of Epidemiology and Biostatistics, East Lansing, 48824, USA
- Wayne State University, Center for Molecular Medicine and Genetics, Detroit, 48201, USA
| | - Sorin Drăghici
- Wayne State University, Department of Computer Science, Detroit, 48202, USA.
- Wayne State University, Department of Obstetrics and Gynecology, Detroit, 48201, USA.
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26
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Chen QY, Shen S, Sun H, Wu F, Kluz T, Kibriya MG, Chen Y, Ahsan H, Costa M. PBMC gene expression profiles of female Bangladeshi adults chronically exposed to arsenic-contaminated drinking water. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 259:113672. [PMID: 31918125 PMCID: PMC11062206 DOI: 10.1016/j.envpol.2019.113672] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 11/06/2019] [Accepted: 11/22/2019] [Indexed: 06/10/2023]
Abstract
Arsenic, a class I human carcinogen, is ubiquitously found throughout the environment and around the globe, posing a great public health concern. Notably, Bangladesh and regions of West Bengal have been found to have high levels (0.5-4600 μg/L) of arsenic drinking water contamination, and approximately 50 million of the world's 200 million people chronically exposed to arsenic in Bangladesh alone. This study was carried out to examine genome-wide gene expression changes in individuals chronically exposed to arsenic-contaminated drinking water. Our study population includes twenty-nine Bangladeshi female participants with urinary arsenic levels ranging from 22.32 to 1828.12 μg/g creatinine. RNA extracted from peripheral blood mononuclear cells (PBMCs) were evaluated using RNA-Sequencing analysis. Our results indicate that a total of 1,054 genes were significantly associated with increasing urinary arsenic levels (FDR p < 0.05), which include 418 down-regulated and 636 up-regulated genes. Further Ingenuity Pathway Analysis revealed potential target genes (DAPK1, EGR2, APP), microRNAs (miR-155, -338, -210) and pathways (NOTCH signaling pathway) related to arsenic carcinogenesis. The selection of female-only participants provides a homogenous study population since arsenic has significant sex dependent effects, and the wide exposure range provides new insight for key gene expression changes that correlate with increasing urinary arsenic levels.
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Affiliation(s)
- Qiao Yi Chen
- Department of Environmental Medicine, New York University School of Medicine, 10010, New York, NY, USA.
| | - Steven Shen
- Institute of Health Informatics, University of Minnesota, 55455, Minneapolis, MN, USA
| | - Hong Sun
- Department of Environmental Medicine, New York University School of Medicine, 10010, New York, NY, USA
| | - Fen Wu
- Department of Population Health and Environmental Medicine, 10016, New York University School of Medicine, New York, NY, USA
| | - Thomas Kluz
- Department of Environmental Medicine, New York University School of Medicine, 10010, New York, NY, USA
| | - Muhammad G Kibriya
- Institute for Population and Precision Health, Department of Public Health Sciences, The University of Chicago, Chicago, IL, 60637, USA
| | - Yu Chen
- Department of Population Health and Environmental Medicine, 10016, New York University School of Medicine, New York, NY, USA
| | - Habibul Ahsan
- Institute for Population and Precision Health, Department of Public Health Sciences, The University of Chicago, Chicago, IL, 60637, USA
| | - Max Costa
- Department of Environmental Medicine, New York University School of Medicine, 10010, New York, NY, USA.
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27
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Guenzle J, Garrelfs NWC, Goeldner JM, Weyerbrock A. Cyclooxygenase (COX) Inhibition by Acetyl Salicylic Acid (ASA) Enhances Antitumor Effects of Nitric Oxide in Glioblastoma In Vitro. Mol Neurobiol 2019; 56:6046-6055. [DOI: 10.1007/s12035-019-1513-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 01/24/2019] [Indexed: 02/06/2023]
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28
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LaVallee J, Grant T, D'Angelo-Early S, Kletsov S, Berry NA, Abt KM, Bloch CP, Muscedere ML, Adams KW. Refining the nuclear localization signal within the Egr transcriptional coregulator NAB2. FEBS Lett 2018; 593:107-118. [PMID: 30411343 DOI: 10.1002/1873-3468.13288] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 10/29/2018] [Accepted: 11/02/2018] [Indexed: 01/09/2023]
Abstract
NAB1 and 2 are coregulators for early growth response (Egr) transcription factors. The NAB1 nuclear localization signal (NLS) was previously described as a bipartite NLS of sequence R(X2 )K(X11 )KRXK. The sequence is conserved in NAB2 as K(X2 )R(X11 )KKXK; however, whether it functions as the NAB2 NLS has not been tested. We show that the KKXK motif in NAB2 is necessary and sufficient to mediate nuclear localization. Mutation of the KKXK motif to AAXA causes cytoplasmic localization of NAB2, while Lys/Arg-to-Ala mutations of the upstream K(X2 )R motif have no effect. Fusion of the KKXK motif to cytoplasmic protein eIF2Bε causes nuclear localization. Altogether, this study refines our knowledge of the NAB2 NLS, demonstrating that KKXK343-346 is necessary and sufficient for nuclear localization.
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Affiliation(s)
- Jacquelyn LaVallee
- Department of Biological Sciences, Bridgewater State University, Bridgewater, MA, USA
| | - Terrain Grant
- Department of Biological Sciences, Bridgewater State University, Bridgewater, MA, USA
| | | | - Sergey Kletsov
- Department of Biological Sciences, Bridgewater State University, Bridgewater, MA, USA
| | - Nicole A Berry
- Department of Biological Sciences, Bridgewater State University, Bridgewater, MA, USA
| | - Kimberly M Abt
- Department of Biological Sciences, Bridgewater State University, Bridgewater, MA, USA
| | - Christopher P Bloch
- Department of Biological Sciences, Bridgewater State University, Bridgewater, MA, USA
| | | | - Kenneth W Adams
- Department of Biological Sciences, Bridgewater State University, Bridgewater, MA, USA
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29
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Ezh1 Targets Bivalent Genes to Maintain Self-Renewing Stem Cells in Ezh2-Insufficient Myelodysplastic Syndrome. iScience 2018; 9:161-174. [PMID: 30396150 PMCID: PMC6223231 DOI: 10.1016/j.isci.2018.10.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 10/09/2018] [Accepted: 10/09/2018] [Indexed: 11/25/2022] Open
Abstract
Polycomb repressive complex (PRC) 2 represses transcription through histone H3K27 trimethylation (H3K27me3). We previously reported that the hematopoietic-cell-specific deletion of Ezh2, encoding a PRC2 enzyme, induced myelodysplastic syndrome (MDS) in mice, whereas the concurrent Ezh1 deletion depleted hematopoietic stem and progenitor cells (HSPCs). We herein demonstrated that mice with only one Ezh1 allele (Ezh1+/-Ezh2Δ/Δ) maintained HSPCs. A chromatin immunopreciptation sequence analysis revealed that residual PRC2 preferentially targeted genes with high levels of H3K27me3 and H2AK119 monoubiquitination (H2AK119ub1) in HSPCs (designated as Ezh1 core target genes), which were mostly developmental regulators, and maintained H3K27me3 levels in Ezh1+/-Ezh2Δ/Δ HSPCs. Even upon the complete depletion of Ezh1 and Ezh2, H2AK119ub1 levels were largely retained, and only a minimal number of Ezh1 core targets were de-repressed. These results indicate that genes marked with high levels of H3K27me3 and H2AK119ub1 are the core targets of polycomb complexes in HSPCs as well as MDS stem cells.
One allele of Ezh1 is enough to maintain self-renewing HSCs and MDS stem cells Ezh1 core targets are marked with high levels of H3K27me3 and H2AK119ub1 in HSPCs Ezh1 core targets are mostly bivalent developmental regulators and critical for HSCs
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30
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Kumar BNP, Puvvada N, Rajput S, Sarkar S, Mahto MK, Yallapu MM, Pathak A, Emdad L, Das SK, Reis RL, Kundu SC, Fisher PB, Mandal M. Targeting of EGFR, VEGFR2, and Akt by Engineered Dual Drug Encapsulated Mesoporous Silica-Gold Nanoclusters Sensitizes Tamoxifen-Resistant Breast Cancer. Mol Pharm 2018; 15:2698-2713. [PMID: 29787277 DOI: 10.1021/acs.molpharmaceut.8b00218] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Tamoxifen administration enhanced overall disease-free survival and diminished mortality rates in cancer patients. However, patients with breast cancer often fail to respond for tamoxifen therapy due to the development of a drug-resistant phenotype. Functional analysis and molecular studies suggest that protein mutation and dysregulation of survival signaling molecules such as epidermal growth factor receptor, vascular endothelial growth factor receptor 2, and Akt contribute to tamoxifen resistance. Various strategies, including combinatorial therapies, show chemosensitize tamoxifen-resistant cancers. Based on chemotoxicity issues, researchers are actively investigating alternative therapeutic strategies. In the current study, we fabricate a mesoporous silica gold cluster nanodrug delivery system that displays exceptional tumor-targeting capability, thus promoting accretion of drug indices at the tumor site. We employ dual drugs, ZD6474, and epigallocatechin gallate (EGCG) that inhibit EGFR2, VEGFR2, and Akt signaling pathways since changes in these signaling pathways confer tamoxifen resistance in MCF 7 and T-47D cells. Mesoporous silica gold cluster nanodrug delivery of ZD6474 and EGCG sensitize tamoxifen-resistant cells to apoptosis. Western and immune-histochemical analyses confirmed the apoptotic inducing properties of the nanoformulation. Overall, results with these silica gold nanoclusters suggest that they may be a potent nanoformulation against chemoresistant cancers.
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Affiliation(s)
- B N Prashanth Kumar
- Department of Pharmaceutical Sciences and Center for Cancer Research , University of Tennessee Health Science Center , Memphis , Tennessee 38163 , United States
| | - Nagaprasad Puvvada
- Chemical Biology , CSIR-Indian Institute of Chemical Technology , Uppal Road , Hyderabad 500007 , India
| | - Shashi Rajput
- Tumor Initiation and Maintenance , Sanford-Burnham Medical Research Institute , La Jolla , California 92037 , United States
| | - Siddik Sarkar
- Department of Human and Molecular Genetics , VCU Institute of Molecular Genetics, VCU Massey Cancer, Virginia Commonwealth University, School of Medicine , Richmond , Virginia 23298 , United States
| | | | - Murali M Yallapu
- Department of Pharmaceutical Sciences and Center for Cancer Research , University of Tennessee Health Science Center , Memphis , Tennessee 38163 , United States
| | | | - Luni Emdad
- Department of Human and Molecular Genetics , VCU Institute of Molecular Genetics, VCU Massey Cancer, Virginia Commonwealth University, School of Medicine , Richmond , Virginia 23298 , United States
| | - Swadesh K Das
- Department of Human and Molecular Genetics , VCU Institute of Molecular Genetics, VCU Massey Cancer, Virginia Commonwealth University, School of Medicine , Richmond , Virginia 23298 , United States
| | - Rui L Reis
- 3Bs Research Group , Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho , Avepark - 4805-017 , Barco, Guimaraes, Portugal
| | - S C Kundu
- 3Bs Research Group , Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho , Avepark - 4805-017 , Barco, Guimaraes, Portugal
| | - Paul B Fisher
- Department of Human and Molecular Genetics , VCU Institute of Molecular Genetics, VCU Massey Cancer, Virginia Commonwealth University, School of Medicine , Richmond , Virginia 23298 , United States
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31
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Omodho B, Miao T, Symonds ALJ, Singh R, Li S, Wang P. Transcription factors early growth response gene (Egr) 2 and 3 control inflammatory responses of tolerant T cells. IMMUNITY INFLAMMATION AND DISEASE 2018; 6:221-233. [PMID: 29314730 PMCID: PMC5946152 DOI: 10.1002/iid3.210] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 11/17/2017] [Accepted: 11/20/2017] [Indexed: 01/07/2023]
Abstract
Introduction Impaired proliferation and production of IL2 are the hallmarks of experimental T cell tolerance. However, in most autoimmune diseases, auto‐reactive T cells do not display hyper proliferation, but inflammatory phenotypes. Methods We have now demonstrated that the transcription factors Egr2 and 3 are important for the control of inflammatory cytokine production by tolerant T cells, but not for tolerance induction. Results In the absence of Egr2 and 3, T cell tolerance, as measured by impaired proliferation and production of IL2, can still be induced, but tolerant T cells produced high levels of inflammatory cytokines. Egr2 and 3 regulate expression of differentiation repressors and directly inhibit T‐bet function in T cells. Indeed, decreased expression of differentiation repressors, such as Id3 and Tcf1, and increased expression of inflammatory transcription factors, such as RORγt and Bhlhe40 were found in Egr2/3 deficient T cells under tolerogenic conditions. In addition, T‐bet was co‐expressed with Egr2 in tolerant T cells and Egr2/3 defects leads to production of high levels of IFNγ in tolerant T cells. Conclusions Our findings demonstrated that despite impaired proliferation and IL2 production, tolerant T cells can display inflammatory responses in response to antigen stimulation and this is controlled at least partly by Egr2 and 3.
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Affiliation(s)
- Becky Omodho
- The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, UK.,Bioscience, Brunel University London, Kingston Lane, London, UK
| | - Tizong Miao
- The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, UK
| | - Alistair L J Symonds
- The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, UK
| | - Randeep Singh
- Bioscience, Brunel University London, Kingston Lane, London, UK
| | - Suling Li
- Bioscience, Brunel University London, Kingston Lane, London, UK
| | - Ping Wang
- The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, UK
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32
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Early growth response 2 and Egr3 are unique regulators in immune system. Cent Eur J Immunol 2017; 42:205-209. [PMID: 28860938 PMCID: PMC5573894 DOI: 10.5114/ceji.2017.69363] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 06/28/2016] [Indexed: 11/17/2022] Open
Abstract
The immune system is evolved to defend the body against pathogens and is composed of thousands of complicated and intertwined pathways, which are highly controlled by processes such as transcription and repression of cellular genes. Sometimes the immune system malfunctions and a break down in self-tolerance occurs. This lead to the inability to distinguish between self and non-self and cause attacks on host tissues, a condition also known as autoimmunity, which can result in chronic debilitating diseases. Early growth response genes are family of transcription factors comprising of four members, Egr1, Egr2, Egr3 and Egr4. All of which contain three cyc2-His2 zinc fingers. Initially, Egr2 function was identified in the regulation of peripheral nerve myelination, hindbrain segmentation. Egr3, on the other hand, is highly expressed in muscle spindle development. Egr2 and Egr3 are induced due to the antigen stimulation and this signaling is implemented through the B and T cell receptors in the adaptive immunity. T cell receptor signaling plays a key role in Egr 2 and 3 expressions via their interaction with NFAT molecules. Egr 2 and 3 play a crucial role in regulation of the immune system and their involvement in B and T cell activation, anergy induction and preventing the autoimmune disease has been investigated. The deficiency of these transcription factors has been associated to deficient Cbl-b expression, a resistant to anergy phenotype, and expression of effector and activated T cells.
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Ruffalo M, Bar-Joseph Z. Genome wide predictions of miRNA regulation by transcription factors. Bioinformatics 2017; 32:i746-i754. [PMID: 27587697 DOI: 10.1093/bioinformatics/btw452] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
MOTIVATION Reconstructing regulatory networks from expression and interaction data is a major goal of systems biology. While much work has focused on trying to experimentally and computationally determine the set of transcription-factors (TFs) and microRNAs (miRNAs) that regulate genes in these networks, relatively little work has focused on inferring the regulation of miRNAs by TFs. Such regulation can play an important role in several biological processes including development and disease. The main challenge for predicting such interactions is the very small positive training set currently available. Another challenge is the fact that a large fraction of miRNAs are encoded within genes making it hard to determine the specific way in which they are regulated. RESULTS To enable genome wide predictions of TF-miRNA interactions, we extended semi-supervised machine-learning approaches to integrate a large set of different types of data including sequence, expression, ChIP-seq and epigenetic data. As we show, the methods we develop achieve good performance on both a labeled test set, and when analyzing general co-expression networks. We next analyze mRNA and miRNA cancer expression data, demonstrating the advantage of using the predicted set of interactions for identifying more coherent and relevant modules, genes, and miRNAs. The complete set of predictions is available on the supporting website and can be used by any method that combines miRNAs, genes, and TFs. AVAILABILITY AND IMPLEMENTATION Code and full set of predictions are available from the supporting website: http://cs.cmu.edu/~mruffalo/tf-mirna/ CONTACT zivbj@cs.cmu.edu SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Matthew Ruffalo
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA 15213
| | - Ziv Bar-Joseph
- Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA 15213
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Aqmasheh S, Shamsasanjan K, Akbarzadehlaleh P, Pashoutan Sarvar D, Timari H. Effects of Mesenchymal Stem Cell Derivatives on Hematopoiesis and Hematopoietic Stem Cells. Adv Pharm Bull 2017; 7:165-177. [PMID: 28761818 PMCID: PMC5527230 DOI: 10.15171/apb.2017.021] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Revised: 04/08/2017] [Accepted: 04/18/2017] [Indexed: 12/11/2022] Open
Abstract
Hematopoiesis is a balance among quiescence, self-renewal, proliferation, and differentiation, which is believed to be firmly adjusted through interactions between hematopoietic stem and progenitor cells (HSPCs) with the microenvironment. This microenvironment is derived from a common progenitor of mesenchymal origin and its signals should be capable of regulating the cellular memory of transcriptional situation and lead to an exchange of stem cell genes expression. Mesenchymal stem cells (MSCs) have self-renewal and differentiation capacity into tissues of mesodermal origin, and these cells can support hematopoiesis through release various molecules that play a crucial role in migration, homing, self-renewal, proliferation, and differentiation of HSPCs. Studies on the effects of MSCs on HSPC differentiation can develop modern solutions in the treatment of patients with hematologic disorders for more effective Bone Marrow (BM) transplantation in the near future. However, considerable challenges remain on realization of how paracrine mechanisms of MSCs act on the target tissues, and how to design a therapeutic regimen with various paracrine factors in order to achieve optimal results for tissue conservation and regeneration. The aim of this review is to characterize and consider the related aspects of the ability of MSCs secretome in protection of hematopoiesis.
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Affiliation(s)
- Sara Aqmasheh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Shamsasanjan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parvin Akbarzadehlaleh
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Hamze Timari
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Ding X, Liu J, Liu T, Ma Z, Wen D, Zhu J. miR-148b inhibits glycolysis in gastric cancer through targeting SLC2A1. Cancer Med 2017; 6:1301-1310. [PMID: 28440026 PMCID: PMC5463086 DOI: 10.1002/cam4.1008] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 12/03/2016] [Accepted: 12/15/2016] [Indexed: 02/06/2023] Open
Abstract
Although the molecular biology of GC has been well characterized, early diagnostic biomarkers and effective therapeutic options in gastric cancer are still under investigation. Here, we found that miR-148b expression decreased in human gastric cancer tissues compared with matched adjacent nontumor tissues by q-PCR analysis and in situ hybridization. Further investigation revealed that overexpression of miR-148b limited glycolysis including glucose consumption, lactate production in gastric cancer cell lines BGC-823 and MKN45. Bioinformatics prediction uncovered that a dedicated transporters solute carrier family 2 member 1 (SLC2A1), also called GLUT1, was the direct target of miR-148b. The target effects were further confirmed by luciferase assay and western blot analysis. Besides, a reverse correlation was observed between relative SLC2A1 and miR-148b expression in human GC tissues compared with matched adjacent nontumor tissues. Subsequently, SLC2A1 suppression by SLC2A1 siRNA or specific inhibitor restricted the reduced effects of glycolysis mediated by miR-148b while SLC2A1 overexpression abrogated the effect of miR-148b on glycolysis. Our findings provided new evidence of miR-148b in GC development through restraining glycolysis, highlighting the role of miR-148b as a new target for GC treatment.
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Affiliation(s)
- Xiangfu Ding
- Department of Thyroid SurgeryThe Second Hospital of Jilin UniversityChangchun130041China
| | - Jingjing Liu
- Department of Gastrointestinal SurgeryThe Second Hospital of Jilin UniversityChangchun130041China
| | - Tianzhou Liu
- Department of Gastrointestinal SurgeryThe Second Hospital of Jilin UniversityChangchun130041China
| | - Zhiming Ma
- Department of Gastrointestinal SurgeryThe Second Hospital of Jilin UniversityChangchun130041China
| | - Dacheng Wen
- Department of Gastrointestinal SurgeryThe Second Hospital of Jilin UniversityChangchun130041China
| | - Jiaming Zhu
- Department of Gastrointestinal SurgeryThe Second Hospital of Jilin UniversityChangchun130041China
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Sharp JA, Brennan AJ, Polekhina G, Ascher DB, Lefevre C, Nicholas KR. Dimeric but not monomeric α-lactalbumin potentiates apoptosis by up regulation of ATF3 and reduction of histone deacetylase activity in primary and immortalised cells. Cell Signal 2017; 33:86-97. [DOI: 10.1016/j.cellsig.2017.02.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 02/02/2017] [Accepted: 02/06/2017] [Indexed: 11/25/2022]
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De Luca L, Trino S, Laurenzana I, Simeon V, Calice G, Raimondo S, Podestà M, Santodirocco M, Di Mauro L, La Rocca F, Caivano A, Morano A, Frassoni F, Cilloni D, Del Vecchio L, Musto P. MiRNAs and piRNAs from bone marrow mesenchymal stem cell extracellular vesicles induce cell survival and inhibit cell differentiation of cord blood hematopoietic stem cells: a new insight in transplantation. Oncotarget 2017; 7:6676-92. [PMID: 26760763 PMCID: PMC4872742 DOI: 10.18632/oncotarget.6791] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 12/05/2015] [Indexed: 12/18/2022] Open
Abstract
Hematopoietic stem cells (HSC), including umbilical cord blood CD34+ stem cells (UCB-CD34+), are used for the treatment of several diseases. Although different studies suggest that bone marrow mesenchymal stem cells (BM-MSC) support hematopoiesis, the exact mechanism remains unclear. Recently, extracellular vesicles (EVs) have been described as a novel avenue of cell communication, which may mediate BM-MSC effect on HSC. In this work, we studied the interaction between UCB-CD34+ cells and BM-MSC derived EVs. First, by sequencing EV derived miRNAs and piRNAs we found that EVs contain RNAs able to influence UCB-CD34+ cell fate. Accordingly, a gene expression profile of UCB-CD34+ cells treated with EVs, identified about 100 down-regulated genes among those targeted by EV-derived miRNAs and piRNAs (e.g. miR-27b/MPL, miR-21/ANXA1, miR-181/EGR2), indicating that EV content was able to modify gene expression profile of receiving cells. Moreover, we demonstrated that UCB-CD34+ cells, exposed to EVs, significantly changed different biological functions, becoming more viable and less differentiated. UCB-CD34+ gene expression profile also identified 103 up-regulated genes, most of them codifying for chemokines, cytokines and their receptors, involved in chemotaxis of different BM cells, an essential function of hematopoietic reconstitution. Finally, the exposure of UCB-CD34+ cells to EVs caused an increased expression CXCR4, paralleled by an in vivo augmented migration from peripheral blood to BM niche in NSG mice. This study demonstrates the existence of a powerful cross talk between BM-MSC and UCB-CD34+ cells, mediated by EVs, providing new insight in the biology of cord blood transplantation.
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Affiliation(s)
- Luciana De Luca
- Laboratory of Preclinical and Translational Research, IRCCS-Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, 85028 (PZ), Italy
| | - Stefania Trino
- Laboratory of Preclinical and Translational Research, IRCCS-Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, 85028 (PZ), Italy
| | - Ilaria Laurenzana
- Laboratory of Preclinical and Translational Research, IRCCS-Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, 85028 (PZ), Italy
| | - Vittorio Simeon
- Laboratory of Preclinical and Translational Research, IRCCS-Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, 85028 (PZ), Italy
| | - Giovanni Calice
- Laboratory of Preclinical and Translational Research, IRCCS-Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, 85028 (PZ), Italy
| | - Stefania Raimondo
- Department of Clinical and Biological Sciences, University of Turin, Turin 10126, Italy
| | - Marina Podestà
- Stem Cell Center, S. Martino Hospital, Genova 16132, Italy
| | - Michele Santodirocco
- Transfusion Medicine Unit, Puglia Cord Blood Bank, IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 (FG), Italy
| | - Lazzaro Di Mauro
- Transfusion Medicine Unit, Puglia Cord Blood Bank, IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 (FG), Italy
| | - Francesco La Rocca
- Laboratory of Preclinical and Translational Research, IRCCS-Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, 85028 (PZ), Italy
| | - Antonella Caivano
- Laboratory of Preclinical and Translational Research, IRCCS-Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, 85028 (PZ), Italy
| | - Annalisa Morano
- Laboratory of Preclinical and Translational Research, IRCCS-Centro di Riferimento Oncologico della Basilicata (CROB), Rionero in Vulture, 85028 (PZ), Italy
| | - Francesco Frassoni
- Laboratorio Cellule Staminali Post Natali e Terapie Cellulari, Giannina Gaslini Institute, Genova 16148, Italy
| | - Daniela Cilloni
- Department of Clinical and Biological Sciences, University of Turin, Turin 10126, Italy
| | - Luigi Del Vecchio
- CEINGE-Biotecnologie Avanzate S.C.a R.L., Naples, 80145, Italy.,Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples 80131, Italy
| | - Pellegrino Musto
- Scientific Direction, IRCCS-Centro di Riferimento Oncologico Basilicata (CROB), Rionero in Vulture, 85028 (PZ), Italy
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Jin H, Won M, Shin E, Kim HM, Lee K, Bae J. EGR2 is a gonadotropin-induced survival factor that controls the expression of IER3 in ovarian granulosa cells. Biochem Biophys Res Commun 2017; 482:877-882. [PMID: 27890615 DOI: 10.1016/j.bbrc.2016.11.127] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 11/23/2016] [Indexed: 01/14/2023]
Abstract
Pituitary gonadotropins are key hormones that orchestrate the growth and development of ovarian follicles. However, limited information is available on intra-ovarian factors that mediate the actions of gonadotropins. In this study, we identified that the early growth response 2 gene (EGR2) is a gonadotropin-inducible gene in granulosa cells of rats and humans. Analysis of consensus EGR-binding elements (EBEs) showed that the immediate early response 3 gene (IER3) is a novel transcriptional target gene of EGR2 as confirmed by the luciferase assay, electrophoretic mobility-shift assay (EMSA), chromatin immunoprecipitation (ChIP), and western blot analysis. Overexpression of EGR2 promoted survival of KGN human granulosa-derived cells in which IER3 acts as a mediator; knockdown of EGR2 induced death in KGN cells. Additionally, EGR2 was found to regulate the expression of myeloid cell leukemia 1 (MCL-1), which belongs to the BCL-2 family of proteins regulating cell survival. Thus, this study identified a novel signaling axis, comprised of gonadotropins-EGR2-IER3, which is important for the survival of granulosa cells during folliculogenesis.
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Affiliation(s)
- Hanyong Jin
- School of Pharmacy, Chung-Ang University, Seoul 06974, South Korea
| | - Miae Won
- Department of Pharmacy, CHA University, Seongnam 13488, South Korea
| | - Eunkyoung Shin
- School of Pharmacy, Chung-Ang University, Seoul 06974, South Korea
| | - Hong-Man Kim
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Kangseok Lee
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Jeehyeon Bae
- School of Pharmacy, Chung-Ang University, Seoul 06974, South Korea.
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Sakr M, Takino T, Sabit H, Nakada M, Li Z, Sato H. miR-150-5p and miR-133a suppress glioma cell proliferation and migration through targeting membrane-type-1 matrix metalloproteinase. Gene 2016; 587:155-62. [DOI: 10.1016/j.gene.2016.04.058] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 04/18/2016] [Accepted: 04/28/2016] [Indexed: 01/12/2023]
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40
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Boyle SE, Fedele CG, Corbin V, Wybacz E, Szeto P, Lewin J, Young RJ, Wong A, Fuller R, Spillane J, Speakman D, Donahoe S, Pohl M, Gyorki D, Henderson MA, Johnstone RW, Papenfuss AT, Shackleton M. CD271 Expression on Patient Melanoma Cells Is Unstable and Unlinked to Tumorigenicity. Cancer Res 2016; 76:3965-77. [DOI: 10.1158/0008-5472.can-15-2377] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 03/02/2016] [Indexed: 11/16/2022]
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41
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Pastorkova Z, Skarda J, Andel J. The role of microRNA in metastatic processes of non-small cell lung carcinoma. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2016; 160:343-57. [PMID: 27108604 DOI: 10.5507/bp.2016.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 04/08/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND MicroRNAs are small non-coding one-stranded RNA molecules that play an important role in the post-transcriptional regulation of genes. Bioinformatic predictions indicate that each miRNA can regulate hundreds of target genes. MicroRNA expression can be associated with various cellular processes leading to the metastasis of malignant tumours including non-small cell lung carcinoma. This review summarizes current knowledge on the role of microRNAs in NSCLC metastasis to the brain and lymph nodes. METHODS A search of the NCBI/PubMed database for publications on expression levels and the mechanisms of microRNA action in NSCLC metastasis. RESULTS AND CONCLUSION Dysregulation of microRNAs in NSCLC can be associated with brain and lymph node metastasis. There are differences in microRNA expression profiling between NSCLC with and without metastases but it is currently not possible to reliably predict the site of metastasis in NSCLC. Based on data from RNAmicroarrays, bioinformatics analysis is able to predict the target genes of highlighted microRNAs, providing us with complex information about cancer cell features such as enhanced proliferation, migration and invasion. Such microRNAs may then be knocked-down using siRNAs or substituted with miRNA mimics. RNA microarray profiling may thus be a useful tool to select up- or down-regulated microRNAs. A number of authors suggest that microRNAs could serve as biomarkers and therapeutic targets in the treatment of NSCLC metastasis.
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Affiliation(s)
- Zuzana Pastorkova
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - Jozef Skarda
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - Jozef Andel
- Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
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Yao M, Gao W, Tao H, Yang J, Liu G, Huang T. Regulation signature of miR-143 and miR-26 in porcine Salmonella infection identified by binding site enrichment analysis. Mol Genet Genomics 2015; 291:789-99. [PMID: 26589421 DOI: 10.1007/s00438-015-1146-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Accepted: 11/11/2015] [Indexed: 12/21/2022]
Abstract
Salmonella infects many vertebrate species, and pigs colonized with Salmonella are typically Salmonella carriers. Transcriptomic analysis of the response to Salmonella infection in whole blood has been reported for the pig. The objective of this study is to identify the important miRNAs involved in Salmonella infection using binding site enrichment analysis. We predicted porcine microRNA (miRNA) binding sites in the 3' UTR of protein-coding genes for all miRNA families. Based on those predictions, we analyzed miRNA-binding sites for mRNAs expressed in peripheral blood to investigate the functional importance of miRNAs in Salmonella infection in pig. Enrichment analysis revealed that binding sites of five miRNAs (including miR-143, -9839, -26, -2483, and -4335) were significantly over represented for the differentially expressed gene sets. Real-time PCR results indicated that selected members of this miRNA group (miR-143, -26, and -4335) were differentially expressed in whole blood after Salmonella inoculation. The luciferase reporter assay showed that ATP6V1A and IL13RA1 were targets of miR-143 and that miR-26 regulates BINP3L and ARL6IP6. The results strongly suggest that miR-143 and miR-26 play important regulatory roles in the development of Salmonella infection in pig.
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Affiliation(s)
- Min Yao
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China
| | - Weihua Gao
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China
| | - Hengxun Tao
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China
| | - Jun Yang
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China
| | - Guoping Liu
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China.,Black Pig Research Institute, Yangtze University, Jingzhou, 434025, Hubei, China
| | - Tinghua Huang
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China.
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Saad MA, Kuo SZ, Rahimy E, Zou AE, Korrapati A, Rahimy M, Kim E, Zheng H, Yu MA, Wang-Rodriguez J, Ongkeko WM. Alcohol-dysregulated miR-30a and miR-934 in head and neck squamous cell carcinoma. Mol Cancer 2015; 14:181. [PMID: 26472042 PMCID: PMC4608114 DOI: 10.1186/s12943-015-0452-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Accepted: 10/06/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Alcohol consumption is a well-established risk factor for head and neck squamous cell carcinoma (HNSCC); however, the molecular mechanisms by which alcohol promotes HNSCC pathogenesis and progression remain poorly understood. Our study sought to identify microRNAs that are dysregulated in alcohol-associated HNSCC and investigate their contribution to the malignant phenotype. METHOD Using RNA-sequencing data from 136 HNSCC patients, we compared the expression levels of 1,046 microRNAs between drinking and non-drinking cohorts. Dysregulated microRNAs were verified by qRT-PCR in normal oral keratinocytes treated with biologically relevant doses of ethanol and acetaldehyde. The most promising microRNA candidates were investigated for their effects on cellular proliferation and invasion, sensitivity to cisplatin, and expression of cancer stem cell genes. Finally, putative target genes were identified and evaluated in vitro to further establish roles for these miRNAs in alcohol-associated HNSCC. RESULTS From RNA-sequencing analysis we identified 8 miRNAs to be significantly upregulated in alcohol-associated HNSCCs. qRT-PCR experiments determined that among these candidates, miR-30a and miR-934 were the most highly upregulated in vitro by alcohol and acetaldehyde. Overexpression of miR-30a and miR-934 in normal and HNSCC cell lines produced up to a 2-fold increase in cellular proliferation, as well as induction of the anti-apoptotic gene BCL-2. Upon inhibition of these miRNAs, HNSCC cell lines exhibited increased sensitivity to cisplatin and reduced matrigel invasion. miRNA knockdown also indicated direct targeting of several tumor suppressor genes by miR-30a and miR-934. CONCLUSIONS Alcohol induces the dysregulation of miR-30a and miR-934, which may play crucial roles in HNSCC pathogenesis and progression. Future investigation of the alcohol-mediated pathways effecting these transformations will prove valuable for furthering the understanding and treatment of alcohol-associated HNSCC.
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Affiliation(s)
- Maarouf A Saad
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, La Jolla, San Diego, CA, USA.
| | - Selena Z Kuo
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, La Jolla, San Diego, CA, USA.
| | - Elham Rahimy
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, La Jolla, San Diego, CA, USA.
| | - Angela E Zou
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, La Jolla, San Diego, CA, USA.
| | - Avinaash Korrapati
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, La Jolla, San Diego, CA, USA.
| | - Mehran Rahimy
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, La Jolla, San Diego, CA, USA.
| | - Elizabeth Kim
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, La Jolla, San Diego, CA, USA.
| | - Hao Zheng
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, La Jolla, San Diego, CA, USA.
| | - Michael Andrew Yu
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, La Jolla, San Diego, CA, USA.
| | - Jessica Wang-Rodriguez
- Department of Pathology, Veterans Administration Health Care System, San Diego, CA, USA. .,Department of Pathology, University of California, San Diego, CA, USA.
| | - Weg M Ongkeko
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, La Jolla, San Diego, CA, USA.
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Liu X, Shi H, Liu B, Li J, Liu Y, Yu B. miR-330-3p controls cell proliferation by targeting early growth response 2 in non-small-cell lung cancer. Acta Biochim Biophys Sin (Shanghai) 2015; 47:431-40. [PMID: 25935837 DOI: 10.1093/abbs/gmv032] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 02/26/2015] [Indexed: 12/12/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) is one of the most common lung cancers, and microRNAs (miRNAs) have been reported to play essential roles in NSCLC. Recent studies have indicated that miR-330-3p expression is up-regulated in NSCLC samples and in tissues of NSCLC brain metastasis. In this study, up-regulation of miR-330-3p expression was confirmed in NSCLC and 20 NSCLC patient samples. Furthermore, miR-330-3p was over-expressed in NSCLC cell lines A549 and H23, and the promotive function of miR-330-3p was investigated in regulating NSCLC cell proliferation and cell cycle distribution. To identify potential target genes of miR-330-3p in NSCLC, the miRNA target prediction databases were used. Luciferase activity assay and real-time RT-PCR analysis confirmed that miR-330-3p is negatively correlated with the expression of early growth response 2 (EGR2). Moreover, it was also found that EGR2 mRNA contains two potential binding sites for miR-330-3p. Knock-down of EGR2 with siRNA was demonstrated to have a similar effect as the over-expression of miR-330-3p in NSCLC cell lines. Taken together, our results show that EGR2 is a target of miR-330-3p.
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Affiliation(s)
- Xuzhi Liu
- Department of Respiratory Medicine, the Third Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Hanbing Shi
- Department of Respiratory Medicine, the Third Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Bo Liu
- Department of Respiratory Medicine, the Third Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Jianing Li
- Department of Respiratory Medicine, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Yaxin Liu
- Department of Respiratory Medicine, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Baiquan Yu
- Department of Respiratory Medicine, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
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Wang M, Deng X, Ying Q, Jin T, Li M, Liang C. MicroRNA-224 targets ERG2 and contributes to malignant progressions of meningioma. Biochem Biophys Res Commun 2015; 460:354-61. [PMID: 25783051 DOI: 10.1016/j.bbrc.2015.03.038] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 03/08/2015] [Indexed: 12/20/2022]
Abstract
MicroRNA-224 is overexpressed in various malignant tumors with poor prognosis, which plays a critical role in biological processes including cell proliferation, apoptosis and several developmental and physiological progressions. However, the potential association between miR-224 and clinical outcome in patients with meningiomas remains unknown. Here, we investigate miR-224 expression and biological functions in meningiomas. MiR-224 expression was measured by Northern blot analysis and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in meningioma and normal brain tissues. Kaplan-Meier analysis and Cox regression analysis were used to exam its correlation with clinicopathological features and prognostic value. The biological effects of miR-224 on the cell proliferation and apoptosis in meningioma cells were examined by MTT assay and apoptosis assay. We found the expression levels of miR-224 were significantly higher in meningioma tissues than that in normal brain, positively correlated with advanced pathological grade. Kaplan-Meier analysis indicated that meningioma patients with low miR-224 expression exhibited significantly prolonged overall and recurrence-free survival. Furthermore, we demonstrated that ERG2 was an identical candidate target gene of MiR-224 in vitro. Our results indicated that downregulation of miR-224 suppressed cell growth and resulted in the enhancement of cell apoptosis through activation of the ERG2-BAK-induced apoptosis pathway. Our findings imply the miR-224 expression could predict the overall survival and recurrence-free survival of patients with meningioma and it might be a promising therapeutic target for treating malignant meningiomas.
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Affiliation(s)
- Maomao Wang
- The 411 Hospital of PLA, Department of Neurosurgery, 15 Dongjiangwan Road, Shanghai 200081, China
| | - Xiaodong Deng
- The 411 Hospital of PLA, Department of Neurosurgery, 15 Dongjiangwan Road, Shanghai 200081, China
| | - Qi Ying
- The 411 Hospital of PLA, Department of Neurosurgery, 15 Dongjiangwan Road, Shanghai 200081, China
| | - Tingyan Jin
- The 411 Hospital of PLA, Department of Neurosurgery, 15 Dongjiangwan Road, Shanghai 200081, China
| | - Ming Li
- The 81 Hospital of PLA, Department of Neurosurgery, 34 Taiping Road, Nanjing 210002, China
| | - Chong Liang
- The 81 Hospital of PLA, Department of Neurosurgery, 34 Taiping Road, Nanjing 210002, China.
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Abstract
Oncogene-induced senescence (OIS) protects normal cells from transformation by Ras, whereas cells lacking p14/p19(Arf) or other tumor suppressors can be transformed. The transcription factor C/EBPβ is required for OIS in primary fibroblasts but is downregulated by H-Ras(V12) in immortalized NIH 3T3 cells through a mechanism involving p19(Arf) loss. Here, we report that members of the serum-induced early growth response (Egr) protein family are also downregulated in 3T3(Ras) cells and directly and redundantly control Cebpb gene transcription. Egr1, Egr2, and Egr3 recognize three sites in the Cebpb promoter and associate transiently with this region after serum stimulation, coincident with Cebpb induction. Codepletion of all three Egrs prevented Cebpb expression, and serum induction of Egrs was significantly blunted in 3T3(Ras) cells. Egr2 and Egr3 levels were also reduced in Ras(V12)-expressing p19(Arf) null mouse embryonic fibroblasts (MEFs), and overall Egr DNA-binding activity was suppressed in Arf-deficient but not wild-type (WT) MEFs, leading to Cebpb downregulation. Analysis of human cancers revealed a strong correlation between EGR levels and CEBPB expression, regardless of whether CEBPB was increased or decreased in tumors. Moreover, overexpression of Egrs in tumor cell lines induced CEBPB and inhibited proliferation. Thus, our findings identify the Arf-Egr-C/EBPβ axis as an important determinant of cellular responses (senescence or transformation) to oncogenic Ras signaling.
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FENG DAN, YE XIAOFEI, ZHU ZHENXIN, WEI ZIRAN, CAI QINGPING, WANG YAJIE. Comparative transcriptome analysis between metastatic and non-metastatic gastric cancer reveals potential biomarkers. Mol Med Rep 2014; 11:386-92. [DOI: 10.3892/mmr.2014.2709] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 07/04/2014] [Indexed: 11/05/2022] Open
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Liu HS, Xiao HS. MicroRNAs as potential biomarkers for gastric cancer. World J Gastroenterol 2014; 20:12007-12017. [PMID: 25232237 PMCID: PMC4161788 DOI: 10.3748/wjg.v20.i34.12007] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 05/06/2014] [Accepted: 06/13/2014] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer is the fourth most common cancer in the world and the second leading cause of cancer-related death. More than 80% of diagnoses occur at the middle to late stage of the disease, highlighting an urgent need for novel biomarkers detectable at earlier stages. Recently, aberrantly expressed microRNAs (miRNAs) have received a great deal of attention as potential sensitive and accurate biomarkers for cancer diagnosis and prognosis. This review summarizes the current knowledge about potential miRNA biomarkers for gastric cancer that have been reported in the publicly available literature between 2008 and 2013. Available evidence indicates that aberrantly expressed miRNAs in gastric cancer correlate with tumorigenesis, tumor proliferation, distant metastasis and invasion. Furthermore, tissue and cancer types can be classified using miRNA expression profiles and next-generation sequencing. As miRNAs in plasma/serum are well protected from RNases, they remain stable under harsh conditions. Thus, potential functions of these circulating miRNAs can be deduced and may implicate their diagnostic value in cancer detection. Circulating miRNAs, as well as tissue miRNAs, may allow for the detection of gastric cancer at an early stage, prediction of prognosis, and monitoring of recurrence and/or lymph node metastasis. Taken together, the data suggest that the participation of miRNAs in biomarker development will enhance the sensitivity and specificity of diagnostic and prognostic tests for gastric cancer.
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Koppensteiner R, Samartzis EP, Noske A, von Teichman A, Dedes I, Gwerder M, Imesch P, Ikenberg K, Moch H, Fink D, Stucki M, Dedes KJ. Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro. PLoS One 2014; 9:e100041. [PMID: 24927325 PMCID: PMC4057395 DOI: 10.1371/journal.pone.0100041] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2013] [Accepted: 05/21/2014] [Indexed: 01/19/2023] Open
Abstract
AIM OF THE STUDY To evaluate the frequency of MRE11/RAD50/NBS1 (MRN)-complex loss of protein expression in endometrial cancers (EC) and to determine whether loss of MRE11 renders the cancer cells sensitive to Poly(ADP-ribose) polymerase (PARP)-inhibitory treatment. METHODS MRN expression was examined in 521 samples of endometrial carcinomas and in 10 cancer cell lines. A putative mutation hotspot in the form of an intronic poly(T) allele in MRE11 was sequenced in selected cases (n = 26). Sensitivity to the PARP-inhibitor, BMN673 was tested in colony formation assays before and after MRE11 silencing using siRNA. Homologous recombination (HR) DNA repair was evaluated by RAD51-foci formation assay upon irradiation and drug treatment. RESULTS Loss of MRE11 protein was found in 30.7% of EC tumours and significantly associated with loss of RAD50, NBS1 and mismatch repair protein expression. One endometrial cell line showed a markedly reduced MRE11 expression due to a homozygous poly(T) mutation of MRE11, thereby exhibiting an increased sensitivity to BMN673. MRE11 depletion sensitizes MRE11 expressing EC cell lines to the treatment with BMN673. The increased sensitivity to PARP-inhibition correlates with reduced RAD51 foci formation upon ionizing radiation in MRE11-depleted cells. CONCLUSION Loss of the MRE11 protein predicts sensitivity to PARP-inhibitor sensitivity in vitro, defining it as an additional synthetic lethal gene with PARP. The high incidence of MRE11 loss in ECs can be potentially exploited for PARP-inhibitor therapy. Furthermore, MRE11 protein expression using immunohistochemistry could be investigated as a predictive biomarker for PARP-inhibitor treatment.
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Affiliation(s)
| | | | - Aurelia Noske
- Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland
| | - Adriana von Teichman
- Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland
| | - Ioannis Dedes
- Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland
| | - Myriam Gwerder
- Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland
| | - Patrick Imesch
- Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland
| | - Kristian Ikenberg
- Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland
| | - Holger Moch
- Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland
| | - Daniel Fink
- Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland
| | - Manuel Stucki
- Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland
| | - Konstantin J. Dedes
- Division of Gynaecology, University Hospital of Zurich, Zurich, Switzerland
- * E-mail:
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Zysset-Burri DC, Bellac CL, Leib SL, Wittwer M. Vitamin B6 reduces hippocampal apoptosis in experimental pneumococcal meningitis. BMC Infect Dis 2013; 13:393. [PMID: 23977941 PMCID: PMC3765858 DOI: 10.1186/1471-2334-13-393] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Accepted: 08/21/2013] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Bacterial meningitis caused by Streptococcus pneumoniae leads to death in up to 30% of patients and leaves up to half of the survivors with neurological sequelae. The inflammatory host reaction initiates the induction of the kynurenine pathway and contributes to hippocampal apoptosis, a form of brain damage that is associated with learning and memory deficits in experimental paradigms. Vitamin B6 is an enzymatic cofactor in the kynurenine pathway and may thus limit the accumulation of neurotoxic metabolites and preserve the cellular energy status. The aim of this study in a pneumococcal meningitis model was to investigate the effect of vitamin B6 on hippocampal apoptosis by histomorphology, by transcriptomics and by measurement of cellular nicotine amide adenine dinucleotide content. METHODS AND RESULTS Eleven day old Wistar rats were infected with 1x10(6) cfu/ml of S. pneumoniae and randomized for treatment with vitamin B6 or saline as controls. Vitamin B6 led to a significant (p > 0.02) reduction of hippocampal apoptosis. According to functional annotation based clustering, vitamin B6 led to down-regulation of genes involved in processes of inflammatory response, while genes encoding for processes related to circadian rhythm, neuronal signaling and apoptotic cell death were mostly up-regulated. CONCLUSIONS Our results provide evidence that attenuation of apoptosis by vitamin B6 is multi-factorial including down-modulation of inflammation, up-regulation of the neuroprotective brain-derived neurotrophic factor and prevention of the exhaustion of cellular energy stores. The neuroprotective effect identifies vitamin B6 as a potential target for the development of strategies to attenuate brain injury in bacterial meningitis.
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Affiliation(s)
- Denise C Zysset-Burri
- Biology Division, Spiez Laboratory, Federal Office for Civil Protection, Austrasse, CH-3700, Spiez, Switzerland.
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