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Priya S, Kma L. Identification of novel microRNAs: Biomarkers for pathogenesis of hepatocellular carcinoma in mice model. Biochem Biophys Rep 2025; 41:101896. [PMID: 39881957 PMCID: PMC11774814 DOI: 10.1016/j.bbrep.2024.101896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/26/2024] [Accepted: 12/09/2024] [Indexed: 01/31/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most fatal cancer that has affected both male and female populations globally. With poor diagnosis and patient survival rates, it has become a global need for scientists to come to the aid. The main objective of the study was to profile the miRNAs in the serum of Control and DEN-treated mice at different time intervals (4 Weeks, 8 Weeks, 12 Weeks, and 16 Weeks) and identify HCC-associated miRNA as putative early biomarkers along with the miRNA regulated candidate gene which may be involved in HCC. Our study group involves 4,8,12, & 16 weeks 16-week-old treated male mice. Each group was sacrificed and analyzed for the stages of HCC. We employed in silico techniques for the small RNA-Seq and bioinformatics pipeline for further analysis. Our analysis revealed over 400 differentially expressed miRNAs in each treated sample and 10 novel miRNAs. The downstream analysis of these differentially expressed miRNAs, and their target genes opened an arena of different biological processes and pathways that these miRNAs affect during the development of HCC. The work has a promising role as the miRNAs predicted through this study can be used as biomarkers for early detection of HCC.
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Affiliation(s)
- Shivani Priya
- Department of Chemistry & Biochemistry, Sharda School of Basic Sciences & Research, Sharda University, Noida, UP, India
| | - Lakhon Kma
- Department of Biochemistry, North Eastern Hill University, Shillong, India
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2
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Xu J, Wan J, Huang HY, Chen Y, Huang Y, Huang J, Zhang Z, Su C, Zhou Y, Lin X, Lin YCD, Huang HD. miRStart 2.0: enhancing miRNA regulatory insights through deep learning-based TSS identification. Nucleic Acids Res 2025; 53:D138-D146. [PMID: 39578697 PMCID: PMC11701676 DOI: 10.1093/nar/gkae1086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 10/17/2024] [Accepted: 11/14/2024] [Indexed: 11/24/2024] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding to the 3'-untranslated regions of target mRNAs, influencing various biological processes at the post-transcriptional level. Identifying miRNA transcription start sites (TSSs) and transcription factors' (TFs) regulatory roles is crucial for elucidating miRNA function and transcriptional regulation. miRStart 2.0 integrates over 4500 high-throughput datasets across five data types, utilizing a multi-modal approach to annotate 28 828 putative TSSs for 1745 human and 1181 mouse miRNAs, supported by sequencing-based signals. Over 6 million tissue-specific TF-miRNA interactions, integrated from ChIP-seq data, are supplemented by DNase hypersensitivity and UCSC conservation data, with network visualizations. Our deep learning-based model outperforms existing tools in miRNA TSS prediction, achieving the most overlaps with both cell-specific and non-cell-specific validated TSSs. The user-friendly web interface and visualization tools make miRStart 2.0 easily accessible to researchers, enabling efficient identification of miRNA upstream regulatory elements in relation to their TSSs. This updated database provides systems-level insights into gene regulation and disease mechanisms, offering a valuable resource for translational research, facilitating the discovery of novel therapeutic targets and precision medicine strategies. miRStart 2.0 is now accessible at https://awi.cuhk.edu.cn/∼miRStart2.
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Affiliation(s)
- Jiatong Xu
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Jingting Wan
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Hsi-Yuan Huang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Yigang Chen
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Yixian Huang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Junyang Huang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Ziyue Zhang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Chang Su
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Yuming Zhou
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Xingqiao Lin
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Yang-Chi-Dung Lin
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
| | - Hsien-Da Huang
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Guangdong Provincial Key Laboratory of Digital Biology and Drug Development, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Boulevard, Longgang District, Shenzhen, Guangdong 518172, P.R. China
- Department of Endocrinology, Key Laboratory of Endocrinology of National Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.9 Dongdansantiao Street, Dongcheng District, Beijing 100730, P.R. China
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3
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Park B, Choi ME, Ryu KJ, Park C, Choi M, Yoon SE, Kim WS, Kim HH, Hong JY, Kim SJ. Exosomal miR-155-5p drives ibrutinib resistance in B-cell lymphoma. Exp Cell Res 2024; 442:114248. [PMID: 39260673 DOI: 10.1016/j.yexcr.2024.114248] [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: 05/20/2024] [Revised: 09/02/2024] [Accepted: 09/07/2024] [Indexed: 09/13/2024]
Abstract
Ibrutinib, a Bruton Tyrosine Kinase (BTK) inhibitor, has shown effectiveness against various B-cell lymphoid malignancies. However, prolonged usage can induce resistance, affecting treatment outcomes. The oncogenic microRNA, miR-155-5p, is associated with poor prognosis in B-cell lymphomas, prompting our investigation into the mechanism of acquired ibrutinib resistance in these cells. We generated ibrutinib-resistant OCI-Ly1 cells (OCI-Ly1-IbtR) through continuous exposure to 1 μM and 2 μM of ibrutinib. We conducted microRNA profiling of OCI-Ly1-IbtR and isolated exosomes via ultracentrifugation. Comparative studies of microRNA levels in cells and exosomes, as well as exploration of targets of up-regulated microRNAs in OCI-Ly1-IbtR, were performed. Target validation involved transfection of candidate microRNAs, and co-culture experiments utilized OCI-Ly1 cells with exosomes from OCI-Ly1-IbtR. Elevated levels of miR-155-5p were observed in OCI-Ly1-IbtR and its exosomes, correlating with AKT and NF-κB activation. Transfection of miR-155-5p induced AKT/NF-κB pathway activation in OCI-Ly1, resulting in ibrutinib resistance, enhanced colony formation, and sustained BTK activity. Primary cell lines from ibrutinib-refractory B-cell lymphoma patients exhibited similar signaling protein activation. Target evaluation identified KDM5B and DEPTOR as miR-155-5p targets, confirmed by downregulation after transfection. We observed KDM5B and DEPTOR enrichment in Ago2 during ibrutinib resistance and miR-155-5p transfection. Co-culture experiments demonstrated exosome-mediated transfer of miR-155-5p, inducing ibrutinib resistance and KDM5B/DEPTOR downregulation in OCI-Ly1. Our findings suggest that miR-155-5p overexpression is associated with AKT and NF-κB pathway activation in ibrutinib-resistant cells, proposing a potential role for acquired miR-155-5p upregulation in B-cell lymphoma ibrutinib resistance.
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Affiliation(s)
- Bon Park
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, South Korea
| | - Myung Eun Choi
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, South Korea
| | - Kyung Ju Ryu
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, South Korea
| | - Chaehwa Park
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, South Korea
| | - Minki Choi
- College of Medicine, Catholic University of Korea, Seoul, South Korea
| | - Sang Eun Yoon
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Won Seog Kim
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, South Korea; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hyeon Ho Kim
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, South Korea
| | - Jung Yong Hong
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - Seok Jin Kim
- Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, South Korea; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
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4
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Wu HH, Leng S, Sergi C, Leng R. How MicroRNAs Command the Battle against Cancer. Int J Mol Sci 2024; 25:5865. [PMID: 38892054 PMCID: PMC11172831 DOI: 10.3390/ijms25115865] [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: 04/24/2024] [Revised: 05/23/2024] [Accepted: 05/26/2024] [Indexed: 06/21/2024] Open
Abstract
MicroRNAs (miRNAs) are small RNA molecules that regulate more than 30% of genes in humans. Recent studies have revealed that miRNAs play a crucial role in tumorigenesis. Large sets of miRNAs in human tumors are under-expressed compared to normal tissues. Furthermore, experiments have shown that interference with miRNA processing enhances tumorigenesis. Multiple studies have documented the causal role of miRNAs in cancer, and miRNA-based anticancer therapies are currently being developed. This review primarily focuses on two key points: (1) miRNAs and their role in human cancer and (2) the regulation of tumor suppressors by miRNAs. The review discusses (a) the regulation of the tumor suppressor p53 by miRNA, (b) the critical role of the miR-144/451 cluster in regulating the Itch-p63-Ago2 pathway, and (c) the regulation of PTEN by miRNAs. Future research and the perspectives of miRNA in cancer are also discussed. Understanding these pathways will open avenues for therapeutic interventions targeting miRNA regulation.
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Affiliation(s)
- Hong Helena Wu
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada;
| | - Sarah Leng
- Department of Laboratory Medicine and Pathology (5B4. 09), University of Alberta, Edmonton, AB T6G 2B7, Canada (C.S.)
| | - Consolato Sergi
- Department of Laboratory Medicine and Pathology (5B4. 09), University of Alberta, Edmonton, AB T6G 2B7, Canada (C.S.)
- Division of Anatomical Pathology, Children’s Hospital of Eastern Ontario (CHEO), University of Ottawa, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada
| | - Roger Leng
- 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada;
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Rath S, Hawsawi YM, Alzahrani F, Khan MI. Epigenetic regulation of inflammation: The metabolomics connection. Semin Cell Dev Biol 2024; 154:355-363. [PMID: 36127262 DOI: 10.1016/j.semcdb.2022.09.008] [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: 07/29/2022] [Revised: 09/12/2022] [Accepted: 09/12/2022] [Indexed: 10/14/2022]
Abstract
Epigenetic factors are considered the regulator of complex machinery behind inflammatory disorders and significantly contributed to the expression of inflammation-associated genes. Epigenetic modifications modulate variation in the expression pattern of target genes without affecting the DNA sequence. The current knowledge of epigenetic research focused on their role in the pathogenesis of various inflammatory diseases that causes morbidity and mortality worldwide. Inflammatory diseases are categorized as acute and chronic based on the disease severity and are regulated by the expression pattern of various genes. Hence, understanding the role of epigenetic modifications during inflammation progression will contribute to the disease outcomes and therapeutic approaches. This review also focuses on the metabolomics approach associated with the study of inflammatory disorders. Inflammatory responses and metabolic regulation are highly integrated and various advanced techniques are adopted to study the metabolic signature molecules. Here we discuss several metabolomics approaches used to link inflammatory disorders and epigenetic changes. We proposed that deciphering the mechanism behind the inflammation-metabolism loop may have immense importance in biomarkers research and may act as a principal component in drug discovery as well as therapeutic applications.
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Affiliation(s)
- Suvasmita Rath
- Center of Environment, Climate Change and Public Health, Utkal University, Vani Vihar, Bhubaneswar 751004, Odisha, India
| | - Yousef M Hawsawi
- Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 40047, Jeddah 21499, Saudi Arabia; College of Medicine, Al-Faisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia.
| | - Faisal Alzahrani
- Department of Biochemistry, King Abdulaziz University (KAU), Jeddah 21577, Saudi Arabia; Embryonic Stem Cells Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mohammad Imran Khan
- Department of Biochemistry, King Abdulaziz University (KAU), Jeddah 21577, Saudi Arabia; Centre of Artificial Intelligence for Precision Medicines, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
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6
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Seyhan AA. Trials and Tribulations of MicroRNA Therapeutics. Int J Mol Sci 2024; 25:1469. [PMID: 38338746 PMCID: PMC10855871 DOI: 10.3390/ijms25031469] [Citation(s) in RCA: 60] [Impact Index Per Article: 60.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 02/12/2024] Open
Abstract
The discovery of the link between microRNAs (miRNAs) and a myriad of human diseases, particularly various cancer types, has generated significant interest in exploring their potential as a novel class of drugs. This has led to substantial investments in interdisciplinary research fields such as biology, chemistry, and medical science for the development of miRNA-based therapies. Furthermore, the recent global success of SARS-CoV-2 mRNA vaccines against the COVID-19 pandemic has further revitalized interest in RNA-based immunotherapies, including miRNA-based approaches to cancer treatment. Consequently, RNA therapeutics have emerged as highly adaptable and modular options for cancer therapy. Moreover, advancements in RNA chemistry and delivery methods have been pivotal in shaping the landscape of RNA-based immunotherapy, including miRNA-based approaches. Consequently, the biotechnology and pharmaceutical industry has witnessed a resurgence of interest in incorporating RNA-based immunotherapies and miRNA therapeutics into their development programs. Despite substantial progress in preclinical research, the field of miRNA-based therapeutics remains in its early stages, with only a few progressing to clinical development, none reaching phase III clinical trials or being approved by the US Food and Drug Administration (FDA), and several facing termination due to toxicity issues. These setbacks highlight existing challenges that must be addressed for the broad clinical application of miRNA-based therapeutics. Key challenges include establishing miRNA sensitivity, specificity, and selectivity towards their intended targets, mitigating immunogenic reactions and off-target effects, developing enhanced methods for targeted delivery, and determining optimal dosing for therapeutic efficacy while minimizing side effects. Additionally, the limited understanding of the precise functions of miRNAs limits their clinical utilization. Moreover, for miRNAs to be viable for cancer treatment, they must be technically and economically feasible for the widespread adoption of RNA therapies. As a result, a thorough risk evaluation of miRNA therapeutics is crucial to minimize off-target effects, prevent overdosing, and address various other issues. Nevertheless, the therapeutic potential of miRNAs for various diseases is evident, and future investigations are essential to determine their applicability in clinical settings.
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Affiliation(s)
- Attila A. Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA;
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI 02912, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
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Karimi B, Mokhtari K, Rozbahani H, Peymani M, Nabavi N, Entezari M, Rashidi M, Taheriazam A, Ghaedi K, Hashemi M. Pathological roles of miRNAs and pseudogene-derived lncRNAs in human cancers, and their comparison as prognosis/diagnosis biomarkers. Pathol Res Pract 2024; 253:155014. [PMID: 38128189 DOI: 10.1016/j.prp.2023.155014] [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: 10/23/2023] [Revised: 12/02/2023] [Accepted: 12/02/2023] [Indexed: 12/23/2023]
Abstract
This review examines and compares the diagnostic and prognostic capabilities of miRNAs and lncRNAs derived from pseudogenes in cancer patients. Additionally, it delves into their roles in cancer pathogenesis. Both miRNAs and pseudogene-derived lncRNAs have undergone thorough investigation as remarkably sensitive and specific cancer biomarkers, offering significant potential for cancer detection and monitoring. . Extensive research is essential to gain a complete understanding of the precise roles these non-coding RNAs play in cancer, allowing the development of novel targeted therapies and biomarkers for improved cancer detection and treatment approaches.
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Affiliation(s)
- Bahareh Karimi
- Department of Cellular and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Khatere Mokhtari
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Hossein Rozbahani
- Department of Psychology, North Tehran Branch, Islamic Azad University, Tehran, Iran; Department of Psychology, West Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H3Z6, Canada
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Pandey C, Tiwari P. Differential microRNAs Expression during Cancer Development, and Chemoprevention by Natural Compounds: A Comprehensive Review. J Environ Pathol Toxicol Oncol 2024; 43:65-80. [PMID: 39016142 DOI: 10.1615/jenvironpatholtoxicoloncol.2024050357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2024] Open
Abstract
MicroRNAs are short non-coding RNAs that inhibit gene expression at the post-transcriptional level. Abnormal microRNA expression has been associated with different human diseases, including cancer. Epigenetic changes, mutation, transcriptional deregulation, DNA copy number abnormalities, and defects in the biogenesis machinery play an important role in abnormal microRNA expression. Modulation of microRNAs by natural agents has emerged to enhance the efficacy of conventional chemotherapy through combinatorial therapeutic approach. This review summarizes the current understanding of abnormal microRNA expression in cancer, the different cellular mechanisms of microRNA, and their prevention by natural compounds. Understanding microRNA expression patterns during cancer development may help to identify stage-specific molecular markers. Natural compounds that exert regulatory effects by modulating microRNAs can be used in better cancer chemopreventive strategies by directly targeting microRNAs or as a way to increase sensitivity to existing chemotherapy regimens.
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Affiliation(s)
- Chhaya Pandey
- School of Environmental Biology, Awadhesh Pratap Singh University, Rewa-486001, Madhya Pradesh, India
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Veryaskina YA, Titov SE, Kovynev IB, Pospelova TI, Fyodorova SS, Shebunyaeva YY, Sumenkova DV, Zhimulev IF. MicroRNA Expression Profile in Bone Marrow and Lymph Nodes in B-Cell Lymphomas. Int J Mol Sci 2023; 24:15082. [PMID: 37894763 PMCID: PMC10606460 DOI: 10.3390/ijms242015082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/29/2023] Open
Abstract
Hodgkin's lymphomas (HL) and the majority of non-Hodgkin's lymphomas (NHL) derive from different stages of B-cell differentiation. MicroRNA (miRNA) expression profiles change during lymphopoiesis. Thus, miRNA expression analysis can be used as a reliable diagnostic tool to differentiate tumors. In addition, the identification of miRNA's role in lymphopoiesis impairment is an important fundamental task. The aim of this study was to analyze unique miRNA expression profiles in different types of B-cell lymphomas. We analyzed the expression levels of miRNA-18a, -20a, -96, -182, -183, -26b, -34a, -148b, -9, -150, -451a, -23b, -141, and -128 in lymph nodes (LNs) in the following cancer samples: HL (n = 41), diffuse large B-cell lymphoma (DLBCL) (n = 51), mantle cell lymphoma (MCL) (n = 15), follicular lymphoma (FL) (n = 12), and lymphadenopathy (LA) (n = 37), as well as bone marrow (BM) samples: HL (n = 11), DLBCL (n = 42), MCL (n = 14), FL (n = 16), and non-cancerous blood diseases (NCBD) (n = 43). The real-time RT-PCR method was used for analysis. An increase in BM expression levels of miRNA-26b, -150, and -141 in MCL (p < 0.01) and a decrease in BM levels of the miR-183-96-182 cluster and miRNA-451a in DLBCL (p < 0.01) were observed in comparison to NCBD. We also obtained data on increased LN levels of the miR-183-96-182 cluster in MCL (p < 0.01) and miRNA-18a, miRNA-96, and miRNA-9 in FL (p < 0.01), as well as decreased LN expression of miRNA-150 in DLBCL (p < 0.01), and miRNA-182, miRNA-150, and miRNA-128 in HL (p < 0.01). We showed that miRNA expression profile differs between BM and LNs depending on the type of B-cell lymphoma. This can be due to the effect of the tumor microenvironment.
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Affiliation(s)
- Yuliya A. Veryaskina
- Department of the Structure and Function of Chromosomes, Laboratory of Molecular Genetics, Institute of Molecular and Cellular Biology, SB RAS, 630090 Novosibirsk, Russia; (S.E.T.); (I.F.Z.)
- Laboratory of Gene Engineering, Institute of Cytology and Genetics, SB RAS, 630090 Novosibirsk, Russia
| | - Sergei E. Titov
- Department of the Structure and Function of Chromosomes, Laboratory of Molecular Genetics, Institute of Molecular and Cellular Biology, SB RAS, 630090 Novosibirsk, Russia; (S.E.T.); (I.F.Z.)
- AO Vector-Best, 630117 Novosibirsk, Russia
| | - Igor B. Kovynev
- Department of Therapy, Hematology and Transfusiology, Novosibirsk State Medical University, 630091 Novosibirsk, Russia; (I.B.K.); (T.I.P.); (S.S.F.); (Y.Y.S.); (D.V.S.)
| | - Tatiana I. Pospelova
- Department of Therapy, Hematology and Transfusiology, Novosibirsk State Medical University, 630091 Novosibirsk, Russia; (I.B.K.); (T.I.P.); (S.S.F.); (Y.Y.S.); (D.V.S.)
| | - Sofya S. Fyodorova
- Department of Therapy, Hematology and Transfusiology, Novosibirsk State Medical University, 630091 Novosibirsk, Russia; (I.B.K.); (T.I.P.); (S.S.F.); (Y.Y.S.); (D.V.S.)
| | - Yana Yu. Shebunyaeva
- Department of Therapy, Hematology and Transfusiology, Novosibirsk State Medical University, 630091 Novosibirsk, Russia; (I.B.K.); (T.I.P.); (S.S.F.); (Y.Y.S.); (D.V.S.)
| | - Dina V. Sumenkova
- Department of Therapy, Hematology and Transfusiology, Novosibirsk State Medical University, 630091 Novosibirsk, Russia; (I.B.K.); (T.I.P.); (S.S.F.); (Y.Y.S.); (D.V.S.)
| | - Igor F. Zhimulev
- Department of the Structure and Function of Chromosomes, Laboratory of Molecular Genetics, Institute of Molecular and Cellular Biology, SB RAS, 630090 Novosibirsk, Russia; (S.E.T.); (I.F.Z.)
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10
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Seyhan AA. Circulating microRNAs as Potential Biomarkers in Pancreatic Cancer-Advances and Challenges. Int J Mol Sci 2023; 24:13340. [PMID: 37686149 PMCID: PMC10488102 DOI: 10.3390/ijms241713340] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
There is an urgent unmet need for robust and reliable biomarkers for early diagnosis, prognosis, and prediction of response to specific treatments of many aggressive and deadly cancers, such as pancreatic cancer, and liquid biopsy-based miRNA profiling has the potential for this. MiRNAs are a subset of non-coding RNAs that regulate the expression of a multitude of genes post-transcriptionally and thus are potential diagnostic, prognostic, and predictive biomarkers and have also emerged as potential therapeutics. Because miRNAs are involved in the post-transcriptional regulation of their target mRNAs via repressing gene expression, defects in miRNA biogenesis pathway and miRNA expression perturb the expression of a multitude of oncogenic or tumor-suppressive genes that are involved in the pathogenesis of various cancers. As such, numerous miRNAs have been identified to be downregulated or upregulated in many cancers, functioning as either oncomes or oncosuppressor miRs. Moreover, dysregulation of miRNA biogenesis pathways can also change miRNA expression and function in cancer. Profiling of dysregulated miRNAs in pancreatic cancer has been shown to correlate with disease diagnosis, indicate optimal treatment options and predict response to a specific therapy. Specific miRNA signatures can track the stages of pancreatic cancer and hold potential as diagnostic, prognostic, and predictive markers, as well as therapeutics such as miRNA mimics and miRNA inhibitors (antagomirs). Furthermore, identified specific miRNAs and genes they regulate in pancreatic cancer along with downstream pathways can be used as potential therapeutic targets. However, a limited understanding and validation of the specific roles of miRNAs, lack of tissue specificity, methodological, technical, or analytical reproducibility, harmonization of miRNA isolation and quantification methods, the use of standard operating procedures, and the availability of automated and standardized assays to improve reproducibility between independent studies limit bench-to-bedside translation of the miRNA biomarkers for clinical applications. Here I review recent findings on miRNAs in pancreatic cancer pathogenesis and their potential as diagnostic, prognostic, and predictive markers.
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Affiliation(s)
- Attila A. Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA;
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI 02912, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
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11
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Autore F, Ramassone A, Stirparo L, Pagotto S, Fresa A, Innocenti I, Visone R, Laurenti L. Role of microRNAs in Chronic Lymphocytic Leukemia. Int J Mol Sci 2023; 24:12471. [PMID: 37569845 PMCID: PMC10419063 DOI: 10.3390/ijms241512471] [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: 07/05/2023] [Revised: 07/29/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
Chronic Lymphocytic Leukemia (CLL) is the most common form of leukemia in adults, with a highly variable clinical course. Improvement in the knowledge of the molecular pathways behind this disease has led to the development of increasingly specific therapies, such as BCR signaling inhibitors and BCL-2 inhibitors. In this context, the emerging role of microRNAs (miRNAs) in CLL pathophysiology and their possible application in therapy is worth noting. MiRNAs are one of the most important regulatory molecules of gene expression. In CLL, they can act both as oncogenes and tumor suppressor genes, and the deregulation of specific miRNAs has been associated with prognosis, progression, and drug resistance. In this review, we describe the role of the miRNAs that primarily impact the disease, and how these miRNAs could be used as therapeutic tools. Certainly, the use of miRNAs in clinical practice is still limited in CLL. Many issues still need to be solved, particularly regarding their biological and safety profile, even if several studies have suggested their efficacy on the disease, alone or in combination with other drugs.
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Affiliation(s)
- Francesco Autore
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
| | - Alice Ramassone
- Center for Advanced Studies and Technology (CAST), G. d’Annunzio University, 66100 Chieti, Italy; (A.R.); (S.P.); (R.V.)
| | - Luca Stirparo
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
| | - Sara Pagotto
- Center for Advanced Studies and Technology (CAST), G. d’Annunzio University, 66100 Chieti, Italy; (A.R.); (S.P.); (R.V.)
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University, 66100 Chieti, Italy
| | - Alberto Fresa
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
| | - Idanna Innocenti
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
| | - Rosa Visone
- Center for Advanced Studies and Technology (CAST), G. d’Annunzio University, 66100 Chieti, Italy; (A.R.); (S.P.); (R.V.)
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University, 66100 Chieti, Italy
| | - Luca Laurenti
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
- Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
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12
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Nagel S, Meyer C, Pommerenke C. Establishment of the lymphoid ETS-code reveals deregulated ETS genes in Hodgkin lymphoma. PLoS One 2023; 18:e0288031. [PMID: 37428779 DOI: 10.1371/journal.pone.0288031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/16/2023] [Indexed: 07/12/2023] Open
Abstract
The human family of ETS transcription factors numbers 28 genes which control multiple aspects of development, notably the differentiation of blood and immune cells. Otherwise, aberrant expression of ETS genes is reportedly involved in forming leukemia and lymphoma. Here, we comprehensively mapped ETS gene activities in early hematopoiesis, lymphopoiesis and all mature types of lymphocytes using public datasets. We have termed the generated gene expression pattern lymphoid ETS-code. This code enabled identification of deregulated ETS genes in patients with lymphoid malignancies, revealing 12 aberrantly expressed members in Hodgkin lymphoma (HL). For one of these, ETS gene ETV3, expression in stem and progenitor cells in addition to that in developing and mature T-cells was mapped together with downregulation in B-cell differentiation. In contrast, subsets of HL patients aberrantly overexpressed ETV3, indicating oncogenic activity in this B-cell malignancy. Analysis of ETV3-overexpressing HL cell line SUP-HD1 demonstrated genomic duplication of the ETV3 locus at 1q23, GATA3 as mutual activator, and suppressed BMP-signalling as mutual downstream effect. Additional examination of the neighboring ETS genes ETS1 and FLI1 revealed physiological activities in B-cell development and aberrant downregulation in HL patient subsets. SUP-HD1 showed genomic loss on chromosome 11, del(11)(q22q25), targeting both ETS1 and FLI1, underlying their downregulation. Furthermore, in the same cell line we identified PBX1-mediated overexpression of RIOK2 which inhibited ETS1 and activated JAK2 expression. Collectively, we codified normal ETS gene activities in lymphopoiesis and identified oncogenic ETS members in HL.
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Affiliation(s)
- Stefan Nagel
- Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
| | - Corinna Meyer
- Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
| | - Claudia Pommerenke
- Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
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13
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Zhao A, Zhou H, Yang J, Li M, Niu T. Epigenetic regulation in hematopoiesis and its implications in the targeted therapy of hematologic malignancies. Signal Transduct Target Ther 2023; 8:71. [PMID: 36797244 PMCID: PMC9935927 DOI: 10.1038/s41392-023-01342-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 01/03/2023] [Accepted: 01/19/2023] [Indexed: 02/18/2023] Open
Abstract
Hematologic malignancies are one of the most common cancers, and the incidence has been rising in recent decades. The clinical and molecular features of hematologic malignancies are highly heterogenous, and some hematologic malignancies are incurable, challenging the treatment, and prognosis of the patients. However, hematopoiesis and oncogenesis of hematologic malignancies are profoundly affected by epigenetic regulation. Studies have found that methylation-related mutations, abnormal methylation profiles of DNA, and abnormal histone deacetylase expression are recurrent in leukemia and lymphoma. Furthermore, the hypomethylating agents and histone deacetylase inhibitors are effective to treat acute myeloid leukemia and T-cell lymphomas, indicating that epigenetic regulation is indispensable to hematologic oncogenesis. Epigenetic regulation mainly includes DNA modifications, histone modifications, and noncoding RNA-mediated targeting, and regulates various DNA-based processes. This review presents the role of writers, readers, and erasers of DNA methylation and histone methylation, and acetylation in hematologic malignancies. In addition, this review provides the influence of microRNAs and long noncoding RNAs on hematologic malignancies. Furthermore, the implication of epigenetic regulation in targeted treatment is discussed. This review comprehensively presents the change and function of each epigenetic regulator in normal and oncogenic hematopoiesis and provides innovative epigenetic-targeted treatment in clinical practice.
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Affiliation(s)
- Ailin Zhao
- Department of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Hui Zhou
- Department of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Jinrong Yang
- Department of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Meng Li
- Department of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Ting Niu
- Department of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China.
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14
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Luo T, Pan Y, Liu Y, Zheng J, Zhuang Z, Ren Z, Zhu J, Gu Y, Zeng Y. LANA regulates miR-155/GATA3 signaling axis by enhancing c-Jun/c-Fos interaction to promote the proliferation and migration of KSHV-infected cells. J Med Virol 2023; 95:e28255. [PMID: 36284455 DOI: 10.1002/jmv.28255] [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: 07/19/2022] [Revised: 10/08/2022] [Accepted: 10/21/2022] [Indexed: 01/11/2023]
Abstract
Kaposi's sarcoma (KS) is the second most common tumor in people infected with human immunodeficiency virus worldwide, but its pathogenesis is still unclear. In this study, we discovered that the expression of GATA-binding protein 3 (GATA3) was lowly expressed in KS tissues and KSHV-infected cells, while microRNA-155 (miR-155) was highly expressed in KS serum and KSHV-infected cells. miR-155 promoted the proliferation, migration and invasion of KSHV infection by targeting GATA3. Further, The KSHV-encoded protein, the Latency associated nuclear antigen (LANA), promotes the proliferation, migration and invasion of KSHV-infected cells by regulating the miR-155/GATA3 axis. Regarding the molecular mechanism, c-Jun and c-Fos interact to form a complex. LANA upregulates the expression of c-Jun and c-Fos and enhances the formation of c-Jun/c-Fos complex. The complex binds to the -95∼-100 bp site of miR-155 promoter and transcriptionally activates miR-155. All in all, LANA enhances the c-Jun/c-Fos interaction, resulting in enhanced transcriptional regulation of miR-155 by the c-Jun/c-Fos complex, thereby downregulating GATA3 and promoting the proliferation, migration and invasion of KSHV-infected cells. The discovery of LANA/c-Jun/c-Fos/miR-155/GATA3 further refines the pathogenesis of KS, potentially opening a new avenue for developing effective drugs against KS.
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Affiliation(s)
- Ting Luo
- Precision Clinical Laboratory, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China.,Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Yangyang Pan
- Precision Clinical Laboratory, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China.,Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Yuhao Liu
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Jun Zheng
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Zhaowei Zhuang
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Zuodong Ren
- Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Jiaojiao Zhu
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Yongqing Gu
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Yan Zeng
- Precision Clinical Laboratory, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, China.,Key Laboratory of Xinjiang Endemic and Ethnic Disease, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
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15
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Proviral ALV-LTR Sequence Is Essential for Continued Proliferation of the ALV-Transformed B Cell Line. Int J Mol Sci 2022; 23:ijms231911263. [PMID: 36232572 PMCID: PMC9569804 DOI: 10.3390/ijms231911263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 08/30/2022] [Accepted: 09/14/2022] [Indexed: 11/25/2022] Open
Abstract
Avian leukosis virus (ALV) induces B-cell lymphomas and other malignancies in chickens through insertional activation of oncogenes, and c-myc activation has been commonly identified in ALV-induced tumors. Using ALV-transformed B-lymphoma-derived HP45 cell line, we applied in situ CRISPR-Cas9 editing of integrated proviral long terminal repeat (LTR) to examine the effects on gene expression and cell proliferation. Targeted deletion of LTR resulted in significant reduction in expression of a number of LTR-regulated genes including c-myc. LTR deletion also induced apoptosis of HP45 cells, affecting their proliferation, demonstrating the significance of LTR-mediated regulation of critical genes. Compared to the global effects on expression and functions of multiple genes in LTR-deleted cells, deletion of c-myc had a major effect on the HP45 cells proliferation with the phenotype similar to the LTR deletion, demonstrating the significance of c-myc expression in ALV-induced lymphomagenesis. Overall, our studies have not only shown the potential of targeted editing of the LTR for the global inhibition of retrovirus-induced transformation, but also have provided insights into the roles of LTR-regulated genes in ALV-induced neoplastic transformation.
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16
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Garrison Z, Hornick N, Cheng J, Kulkarni RP. Circulating biomarkers of response to immunotherapy and immune-related adverse events. Expert Rev Mol Diagn 2022; 22:855-865. [PMID: 36193802 DOI: 10.1080/14737159.2022.2130688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Immune checkpoint blockade has revolutionized cancer treatment. However, response rates vary, and these treatments have a high rate of immune-related side effects, which can be limiting. Thus, tests to predict who will respond and who may experience side effects are of critical importance toward realizing the ultimate goal of precision oncology. AREAS COVERED We review several of the most recent advances in circulating biomarkers that have been reported to be useful in predicting response and immune-related adverse events (irAE) to checkpoint blockade immunotherapies (CBI). We focus on high-quality studies published within the last few years. We highlight significant findings, identify areas for improvement, and provide recommendations on how these biomarkers may be translated into clinical utility. EXPERT OPINION As newer immunotherapies are developed, there is a pressing need to identify circulating biomarkers that can help predict responses and side effects. Current studies are mostly small-scale and retrospective; there is a need for larger-scale and prospective studies to help validate several of the biomarkers detailed here. As oncology focuses more on precision-based approaches, it is likely that a combination of biomarkers, including circulating ones as detailed here, will have critical utility in guiding clinical decisions.
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Affiliation(s)
- Zachary Garrison
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA
| | - Noah Hornick
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA
| | - Jeffrey Cheng
- Department of Dermatology, University of California, San Francisco, CA, USA
| | - Rajan P Kulkarni
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA.,Cancer Early Detection Advanced Research Center (CEDAR), Portland, OR, USA.,Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.,Operative Care Division, U.S. Department of Veterans Affairs Portland Health Care System, Portland, OR, USA
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17
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Downregulation of STAT3 in Epstein-Barr Virus-Positive Hodgkin Lymphoma. Biomedicines 2022; 10:biomedicines10071608. [PMID: 35884913 PMCID: PMC9313380 DOI: 10.3390/biomedicines10071608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 06/30/2022] [Accepted: 07/04/2022] [Indexed: 11/17/2022] Open
Abstract
STAT3 is a transcription factor which is activated via various signaling transduction pathways or Epstein-Barr virus (EBV) infection and plays an oncogenic role in lymphoid malignancies including Hodgkin lymphoma (HL). The tumor cells of HL are derived from germinal center B-cells and transformed by chromosomal rearrangements, aberrant signal transduction, deregulation of developmental transcription factors, and EBV activity. HL cell lines represent useful models to investigate molecular principles and deduced treatment options of this malignancy. Using cell line L-540, we have recently shown that constitutively activated STAT3 drives aberrant expression of hematopoietic NKL homeobox gene HLX. Here, we analyzed HL cell line AM-HLH which is EBV-positive but, nevertheless, HLX-negative. Consistently, AM-HLH expressed decreased levels of STAT3 proteins which were additionally inactivated and located in the cytoplasm. Combined genomic and expression profiling data revealed several amplified and overexpressed gene candidates involved in opposed regulation of STAT3 and EBV. Corresponding knockdown studies demonstrated that IRF4 and NFATC2 inhibited STAT3 expression. MIR155 (activated by STAT3) and SPIB (repressed by HLX) showed reduced and elevated expression levels in AM-HLH, respectively. However, treatment with IL6 or IL27 activated STAT3, elevated expression of HLX and MIR155, and inhibited IRF4. Taken together, this cell line deals with two conflicting oncogenic drivers, namely, JAK2-STAT3 signaling and EBV infection, but is sensitive to switch after cytokine stimulation. Thus, AM-HLH represents a unique cell line model to study the pathogenic roles of STAT3 and EBV and their therapeutic implications in HL.
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18
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Gholami A, Farhadi K, Sayyadipour F, Soleimani M, Saba F. Long noncoding RNAs (lncRNAs) in human lymphomas. Genes Dis 2022; 9:900-914. [PMID: 35685474 PMCID: PMC9170579 DOI: 10.1016/j.gendis.2021.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 01/19/2021] [Accepted: 02/03/2021] [Indexed: 01/17/2023] Open
Abstract
Lymphomas are a diverse group of haematologic malignancies, which occur in infection-fighting cells of the lymphatic system. Long non-coding RNAs (lncRNAs) are non-coding RNAs, which have recently received significant attention as the main mediators of gene expression. In this review, we summarize the current knowledge on lncRNAs involved in lymphomas, their molecular functions, as well as their potential clinical value. Relevant literature was identified by a PubMed search of English language papers using the following terms: Lymphoma, LncRNA, leukemia, proliferation, apoptosis, and prognosis. LncRNAs are imperative for lymphoma carcinogenesis through affecting apoptosis, cell proliferation, invasion, and response to chemotherapy. The expression level of lncRNAs can affect chemotherapy-induced apoptosis. Taken together, lncRNA dysregulation in lymphoma cells is not only an epiphenomenon but also lncRNA transcription is critically related to the initiation and progression of lymphomas. Aberrant expression of lncRNAs can lead to the transformation of normal lymphocytes into lymphoma cells.
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Affiliation(s)
- Ali Gholami
- Clinical Research Development Center, Taleghani and Imam Ali Hospital, Kermanshah University of Medical Sciences, Kermanshah 671568-5420, Iran
| | - Khosro Farhadi
- Clinical Research Development Center, Taleghani and Imam Ali Hospital, Kermanshah University of Medical Sciences, Kermanshah 671568-5420, Iran
| | - Fatemeh Sayyadipour
- Clinical Research Development Center, Taleghani and Imam Ali Hospital, Kermanshah University of Medical Sciences, Kermanshah 671568-5420, Iran
| | - Masoud Soleimani
- Department of Haematology, Tarbiat Modares University, Tehran 146899-5513, Iran
| | - Fakhredin Saba
- Department of Medical Laboratory Science, School of Paramedical, Kermanshah University of Medical Sciences, Kermanshah 671568-5420, Iran
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19
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Krsmanovic P, Mocikova H, Chramostova K, Klanova M, Trnkova M, Pesta M, Laslo P, Pytlik R, Stopka T, Trneny M, Pospisil V. Circulating microRNAs in Cerebrospinal Fluid and Plasma: Sensitive Tool for Detection of Secondary CNS Involvement, Monitoring of Therapy and Prediction of CNS Relapse in Aggressive B-NHL Lymphomas. Cancers (Basel) 2022; 14:cancers14092305. [PMID: 35565434 PMCID: PMC9103209 DOI: 10.3390/cancers14092305] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 04/07/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Lymphoma involving the central nervous system and CNS relapse present diagnostic and predictive challenges. Its diagnosis is based on conventional methods with low sensitivity and/or specificity. More powerful tools for its early detection, response evaluation, and CNS relapse prediction are needed. MicroRNAs are short post-transcriptional gene regulators that are remarkably stable and detectable extracellularly in body fluids. We evaluated the diagnostic and predictive potential of circulating oncogenic microRNAs (oncomiRs) in CSF and plasma for the detection of secondary CNS involvement in aggressive B-NHL lymphomas, as well as for detection and prediction of their CNS relapse. Our findings indicate that the evaluation of oncogenic microRNAs in CSF and plasma potentially provides a sensitive tool for the early detection of secondary CNS lymphoma, the monitoring and estimating of treatment efficacy, and the prediction and early detection of CNS relapse. Abstract Lymphoma with secondary central nervous system (CNS) involvement represents one of the most aggressive malignancies, with poor prognosis and high mortality. New diagnostic tools for its early detection, response evaluation, and CNS relapse prediction are needed. We analyzed circulating microRNAs in the cerebrospinal fluid (CSF) and plasma of 162 patients with aggressive B-cell non-Hodgkin’s lymphomas (B-NHL) and compared their levels in CNS-involving lymphomas versus in systemic lymphomas, at diagnosis and during treatment and CNS relapse. We identified a set of five oncogenic microRNAs (miR-19a, miR-20a, miR-21, miR-92a, and miR-155) in CSF that detect, with high sensitivity, secondary CNS lymphoma involvement in aggressive B-NHL, including DLBCL, MCL, and Burkitt lymphoma. Their combination into an oncomiR index enables the separation of CNS lymphomas from systemic lymphomas or nonmalignant controls with high sensitivity and specificity, and high Receiver Operating Characteristics (DLBCL AUC = 0.96, MCL = 0.93, BL = 1.0). Longitudinal analysis showed that oncomiR levels reflect treatment efficacy and clinical outcomes, allowing their monitoring and prediction. In contrast to conventional methods, CSF oncomiRs enable detection of early and residual CNS involvement, as well as parenchymal involvement. These circulating oncomiRs increase 1–4 months before CNS relapse, allowing its early detection and improving the prediction of CNS relapse risk in DLBCL. Similar effects were detectable, to a lesser extent, in plasma.
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Affiliation(s)
- Pavle Krsmanovic
- Institute of Pathological Physiology, 1st Faculty of Medicine, Charles University, 128 53 Prague, Czech Republic; (P.K.); (K.C.); (M.K.)
| | - Heidi Mocikova
- Department of Haematology, University Hospital Kralovske Vinohrady and 3rd Faculty of Medicine, Charles University, 100 34 Prague, Czech Republic;
| | - Kamila Chramostova
- Institute of Pathological Physiology, 1st Faculty of Medicine, Charles University, 128 53 Prague, Czech Republic; (P.K.); (K.C.); (M.K.)
| | - Magdalena Klanova
- Institute of Pathological Physiology, 1st Faculty of Medicine, Charles University, 128 53 Prague, Czech Republic; (P.K.); (K.C.); (M.K.)
- 1st Department of Medicine, Charles University General Hospital, 128 08 Prague, Czech Republic; (M.T.); (T.S.); (M.T.)
| | - Marie Trnkova
- 1st Department of Medicine, Charles University General Hospital, 128 08 Prague, Czech Republic; (M.T.); (T.S.); (M.T.)
| | - Michal Pesta
- Faculty of Mathematics and Physics, Charles University, 186 75 Prague, Czech Republic;
| | - Peter Laslo
- Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, St James’s University Hospital, University of Leeds, Leeds LS2 9JT, UK;
| | - Robert Pytlik
- Department of Cell Therapy, Institute of Haematology and Blood Transfusion, 128 20 Prague, Czech Republic;
| | - Tomas Stopka
- 1st Department of Medicine, Charles University General Hospital, 128 08 Prague, Czech Republic; (M.T.); (T.S.); (M.T.)
- Biocev, 1st Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic
| | - Marek Trneny
- 1st Department of Medicine, Charles University General Hospital, 128 08 Prague, Czech Republic; (M.T.); (T.S.); (M.T.)
| | - Vit Pospisil
- Institute of Pathological Physiology, 1st Faculty of Medicine, Charles University, 128 53 Prague, Czech Republic; (P.K.); (K.C.); (M.K.)
- Correspondence:
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Abstract
MicroRNAs (miRNAs) are key players in gene regulation that target specific mRNAs for degradation or translational repression. Each miRNA is synthesized as a miRNA duplex comprising two strands (5p and 3p). However, only one of the two strands becomes active and is selectively incorporated into the RNA-induced silencing complex in a process known as miRNA strand selection. Recently, significant progress has been made in understanding the factors and processes involved in strand selection. Here, we explore the selection and functionality of the miRNA star strand (either 5p or 3p), which is generally present in the cell at low levels compared to its partner strand and, historically, has been thought to possess no biological activity. We also highlight the concepts of miRNA arm switching and miRNA isomerism. Finally, we offer insights into the impact of aberrant strand selection on immunity and cancer. Leading us through this journey is miR-155, a well-established regulator of immunity and cancer, and the increasing evidence that its 3p strand plays a role in these arenas. Interestingly, the miR-155-5p/-3p ratio appears to vary dependent on the timing of the immune response, and the 3p strand seems to play a regulatory role upon its partner 5p strand.
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Affiliation(s)
- Owen Dawson
- School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK
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21
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Drandi D, Decruyenaere P, Ferrante M, Offner F, Vandesompele J, Ferrero S. Nucleic Acid Biomarkers in Waldenström Macroglobulinemia and IgM-MGUS: Current Insights and Clinical Relevance. Diagnostics (Basel) 2022; 12:diagnostics12040969. [PMID: 35454017 PMCID: PMC9028641 DOI: 10.3390/diagnostics12040969] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/07/2022] [Accepted: 04/09/2022] [Indexed: 12/13/2022] Open
Abstract
Waldenström Macroglobulinemia (WM) is an indolent lymphoplasmacytic lymphoma, characterized by the production of excess immunoglobulin M monoclonal protein. WM belongs to the spectrum of IgM gammopathies, ranging from asymptomatic IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), through IgM-related disorders and asymptomatic WM to symptomatic WM. In recent years, its complex genomic and transcriptomic landscape has been extensively explored, hereby elucidating the biological mechanisms underlying disease onset, progression and therapy response. An increasing number of mutations, cytogenetic abnormalities, and molecular signatures have been described that have diagnostic, phenotype defining or prognostic implications. Moreover, cell-free nucleic acid biomarkers are increasingly being investigated, benefiting the patient in a minimally invasive way. This review aims to provide an extensive overview of molecular biomarkers in WM and IgM-MGUS, considering current shortcomings, as well as potential future applications in a precision medicine approach.
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Affiliation(s)
- Daniela Drandi
- Department of Molecular Biotechnology and Health Sciences, Hematology Division, University of Torino, 10126 Torino, Italy; (M.F.); (S.F.)
- Correspondence: (D.D.); (P.D.)
| | - Philippe Decruyenaere
- Department of Hematology, Ghent University Hospital, 9000 Ghent, Belgium;
- OncoRNALab, Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium;
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Correspondence: (D.D.); (P.D.)
| | - Martina Ferrante
- Department of Molecular Biotechnology and Health Sciences, Hematology Division, University of Torino, 10126 Torino, Italy; (M.F.); (S.F.)
| | - Fritz Offner
- Department of Hematology, Ghent University Hospital, 9000 Ghent, Belgium;
| | - Jo Vandesompele
- OncoRNALab, Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium;
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
| | - Simone Ferrero
- Department of Molecular Biotechnology and Health Sciences, Hematology Division, University of Torino, 10126 Torino, Italy; (M.F.); (S.F.)
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22
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Malik S, Kumar V, Liu CH, Shih KC, Krueger S, Nieh MP, Bahal R. Head on Comparison of Self- and Nano-assemblies of Gamma Peptide Nucleic Acid Amphiphiles. ADVANCED FUNCTIONAL MATERIALS 2022; 32:2109552. [PMID: 35210986 PMCID: PMC8863176 DOI: 10.1002/adfm.202109552] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Indexed: 05/14/2023]
Abstract
Peptide nucleic acids (PNAs) are nucleic acid analogs with superior hybridization properties and enzymatic stability than deoxyribonucleic acid (DNA). In addition to gene targeting applications, PNAs have garnered significant attention as bio-polymer due to the Watson-Crick -based molecular recognition and flexibility of synthesis. Here, we engineered PNA amphiphiles using chemically modified gamma PNA (8 mer in length) containing hydrophilic diethylene glycol units at the gamma position and covalently conjugated lauric acid (C12) as a hydrophobic moiety. Gamma PNA (γPNA) amphiphiles self-assemble into spherical vesicles. Further, we formulate nano-assemblies using the amphiphilic γPNA as a polymer via ethanol injection-based protocols. We perform comprehensive head-on comparison of the physicochemical and cellular uptake properties of PNA derived self- and nano-assemblies. Small-angle neutron scattering (SANS) and small-angle X-ray scattering (SAXS) analysis reveal ellipsoidal morphology of γPNA nano-assemblies that results in superior cellular delivery compate to the spherical self-assembly. Next, we compare the functional activities of γPNA self-and nano-assemblies in lymphoma cells via multiple endpoints, including gene expression, cell viability, and apoptosis-based assays. Overall, we establish that γPNA amphiphile is a functionally active bio-polymer to formulate nano-assemblies for a wide range of biomedical applications.
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Affiliation(s)
- Shipra Malik
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269, USA
| | - Vikas Kumar
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269, USA
| | - Chung-Hao Liu
- Polymer Program, Institute of Material Sciences, University of Connecticut, 191 Auditorium Road, Storrs, CT, 06269, USA
| | - Kuo-Chih Shih
- Polymer Program, Institute of Material Sciences, University of Connecticut, 191 Auditorium Road, Storrs, CT, 06269, USA
| | - Susan Krueger
- National Institute of Standards and Technology, Gaithersburg, MD 20899-6102, USA
| | - Mu-Ping Nieh
- Polymer Program, Institute of Material Sciences, University of Connecticut, 191 Auditorium Road, Storrs, CT, 06269, USA
| | - Raman Bahal
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269, USA
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23
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Okeke C, Silas U, Nnodu O, Clementina O. HSC and miRNA Regulation with Implication for Foetal Haemoglobin Induction in Beta Haemoglobinopathies. Curr Stem Cell Res Ther 2022; 17:339-347. [PMID: 35189805 DOI: 10.2174/1574888x17666220221104711] [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: 09/02/2021] [Revised: 11/29/2021] [Accepted: 12/08/2021] [Indexed: 11/22/2022]
Abstract
Sickle cell disease (SCD) is one of the most common haemoglobinopathies worldwide, with up to 70 % of global SCD annual births occurring in sub-Saharan Africa. Reports have shown that 50 to 80 % of affected children in these countries die annually. Efforts geared towards understanding and controlling HbF production in SCD patients could lead to strategies for effective control of globin gene expression and therapeutic approaches that could be beneficial to individuals with haemoglobinopathies. Hemopoietic stem cells (HSCs) are characterized by a specific miRNA signature in every state of differentiation. The role of miRNAs has become evident both in the maintenance of the "stemness" and in the early induction of differentiation by modulation of the expression of the master pluripotency genes and during early organogenesis. miRNAs are extra regulatory mechanisms in hematopoietic stem cells (HSCs) via influencing transcription profiles together with transcript stability. miRNAs have been reported to be used to reprogram primary somatic cells toward pluripotency. Their involvement in cell editing holds the potential for therapy for many genetic diseases. This review provides a snapshot of miRNA involvement in cell fate decisions, haemoglobin induction pathway, and their journey as some emerge prime targets for therapy in beta haemoglobinopathies.
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Affiliation(s)
- Chinwe Okeke
- Department of Medical Laboratory Science, Faculty of Health Science and Technology, University of Nigeria, Nsukka, Nigeria
| | - Ufele Silas
- Department of Medical Laboratory Science, Faculty of Health Science and Technology, University of Nigeria, Nsukka, Nigeria
| | - Obiageli Nnodu
- Department of Haematology, College of Medicine, University of Abuja, Abuja Nigeria
| | - Odoh Clementina
- Department of Medical Laboratory Science, Faculty of Health Science and Technology, University of Nigeria, Nsukka, Nigeria
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24
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Sajjadi-Dokht M, Merza Mohamad TA, Rahman HS, Maashi MS, Danshina S, Shomali N, Solali S, Marofi F, Zeinalzadeh E, Akbari M, Adili A, Aslaminabad R, Hagh MF, Jarahian M. MicroRNAs and JAK/STAT3 signaling: A new promising therapeutic axis in blood cancers. Genes Dis 2021; 9:849-867. [PMID: 35685482 PMCID: PMC9170603 DOI: 10.1016/j.gendis.2021.10.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 09/16/2021] [Accepted: 10/22/2021] [Indexed: 11/27/2022] Open
Abstract
Blood disorders include a wide spectrum of blood-associated malignancies resulting from inherited or acquired defects. The ineffectiveness of existing therapies against blood disorders arises from different reasons, one of which is drug resistance, so different types of leukemia may show different responses to treatment. Leukemia occurs for a variety of genetic and acquired reasons, leading to uncontrolled proliferation in one or more cell lines. Regarding the genetic defects, oncogene signal transducer and activator of transcription (STAT) family transcription factor, especially STAT3, play an essential role in hematological disorders onset and progress upon mutations, dysfunction, or hyperactivity. Besides, microRNAs, as biological molecules, has been shown to play a dual role in either tumorigenesis and tumor suppression in various cancers. Besides, a strong association between STAT3 and miRNA has been reported. For example, miRNAs can regulate STAT3 via targeting its upstream mediators such as IL6, IL9, and JAKs or directly binding to the STAT3 gene. On the other hand, STAT3 can regulate miRNAs. In this review study, we aimed to determine the role of either microRNAs and STAT3 along with their effect on one another's activity and function in hematological malignancies.
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25
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Karabon L, Andrzejczak A, Ciszak L, Tomkiewicz A, Szteblich A, Bojarska-Junak A, Roliński J, Wołowiec D, Wróbel T, Kosmaczewska A. BTLA Expression in CLL: Epigenetic Regulation and Impact on CLL B Cell Proliferation and Ability to IL-4 Production. Cells 2021; 10:cells10113009. [PMID: 34831232 PMCID: PMC8616199 DOI: 10.3390/cells10113009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/22/2021] [Accepted: 10/31/2021] [Indexed: 12/13/2022] Open
Abstract
In our previous study, while chronic lymphocytic leukemia (CLL) cases showed higher levels of B and T lymphocyte attenuator (BTLA) mRNA compared to controls, lower BTLA protein expression was observed in cases compared to controls. Hence we hypothesize that micro RNA (miR) 155-5p regulates BTLA expression in CLL. In line with earlier data, expression of BTLA mRNA and miR-155-5p is elevated in CLL (p = 0.034 and p = 0.0006, respectively) as well as in MEC-1 cell line (p = 0.009 and 0.016, respectively). Inhibition of miR-155-5p partially restored BTLA protein expression in CLL patients (p = 0.01) and in MEC-1 cell lines (p = 0.058). Additionally, we aimed to evaluate the significance of BTLA deficiency in CLL cells on proliferation and IL-4 production of B cells. We found that secretion of IL-4 is not dependent on BTLA expression, since fractions of BTLA positive and BTLA negative B cells expressing intracellular IL-4 were similar in CLL patients and controls. We demonstrated that in controls the fraction of proliferating cells is lower in BTLA positive than in BTLA negative B cells (p = 0.059), which was not observed in CLL. However, the frequency of BTLA positive Ki67+ B cells in CLL was higher compared to corresponding cells from controls (p = 0.055) while there were no differences between the examined groups regarding frequency of BTLA negative Ki67+ B cells. Our studies suggest that miR-155-5p is involved in BTLA deficiency, affecting proliferation of CLL B cells, which may be one of the mechanisms responsible for CLL pathogenesis.
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MESH Headings
- Aged
- Base Sequence
- Cell Line, Tumor
- Cell Proliferation/genetics
- Epigenesis, Genetic
- Female
- Gene Expression Regulation, Leukemic
- Humans
- Interleukin-4/biosynthesis
- Ki-67 Antigen/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Male
- MicroRNAs/genetics
- MicroRNAs/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Immunologic/genetics
- Receptors, Immunologic/metabolism
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Affiliation(s)
- Lidia Karabon
- Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland; (A.A.); (A.T.)
- Department and Clinic of Urology and Oncologic Urology, Wroclaw Medical University, Borowska Str. 213, 50-556 Wroclaw, Poland
- Correspondence:
| | - Anna Andrzejczak
- Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland; (A.A.); (A.T.)
| | - Lidia Ciszak
- Laboratory of Immunopathology, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland; (L.C.); (A.S.); (A.K.)
| | - Anna Tomkiewicz
- Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland; (A.A.); (A.T.)
| | - Aleksandra Szteblich
- Laboratory of Immunopathology, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland; (L.C.); (A.S.); (A.K.)
| | - Agnieszka Bojarska-Junak
- Department of Clinical Immunology, Medical University of Lublin, ul. Chodźki 4a, 20-093 Lublin, Poland; (A.B.-J.); (J.R.)
| | - Jacek Roliński
- Department of Clinical Immunology, Medical University of Lublin, ul. Chodźki 4a, 20-093 Lublin, Poland; (A.B.-J.); (J.R.)
| | - Dariusz Wołowiec
- Department and Clinic of Hematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, Wybrzeże Ludwika Pasteura 4, 50-367 Wroclaw, Poland; (D.W.); (T.W.)
| | - Tomasz Wróbel
- Department and Clinic of Hematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, Wybrzeże Ludwika Pasteura 4, 50-367 Wroclaw, Poland; (D.W.); (T.W.)
| | - Agata Kosmaczewska
- Laboratory of Immunopathology, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland; (L.C.); (A.S.); (A.K.)
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26
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Jafarzadeh A, Naseri A, Shojaie L, Nemati M, Jafarzadeh S, Bannazadeh Baghi H, Hamblin MR, Akhlagh SA, Mirzaei H. MicroRNA-155 and antiviral immune responses. Int Immunopharmacol 2021; 101:108188. [PMID: 34626873 DOI: 10.1016/j.intimp.2021.108188] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 02/08/2023]
Abstract
The microRNA, miR-155 regulates both adaptive and innate immune responses. In viral infections, miR-155 can affect both innate immunity (interferon response, natural killer cell activity, and macrophage polarization) and adaptive immunity (including generation of anti-viral antibodies, CD8+ cytotoxic T lymphocytes, Th17, Th2, Th1, Tfh and Treg cells). In many viral infections, the proper and timely regulation of miR-155 expression is critical for the induction of an effective anti-virus immune response and viral clearance without any harmful immunopathologic consequences. MiR-155 may also exert pro-viral effects, mainly through the inhibition of the anti-viral interferon response. Thus, dysregulated expression of miR-155 can result in virus persistence and disruption of the normal response to viral infections. This review provides a thorough discussion of the role of miR-155 in immune responses and immunopathologic reactions during viral infections, and highlights its potential as a therapeutic target.
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Affiliation(s)
- Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Alma Naseri
- Department of Immunology, Islamic Azadi university of Zahedan, Zahedan, Iran
| | - Layla Shojaie
- Research Center for Liver Diseases, Keck School of Medicine, Department of Medicine, University of Southern California, Los angeles, CA, USA
| | - Maryam Nemati
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Hematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Sara Jafarzadeh
- Student Research Committee, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Hossein Bannazadeh Baghi
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | | | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran.
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27
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Wahane A, Malik S, Shih KC, Gaddam RR, Chen C, Liu Y, Nieh MP, Vikram A, Bahal R. Dual-Modality Poly-l-histidine Nanoparticles to Deliver Peptide Nucleic Acids and Paclitaxel for In Vivo Cancer Therapy. ACS APPLIED MATERIALS & INTERFACES 2021; 13:45244-45258. [PMID: 34524806 DOI: 10.1021/acsami.1c11981] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Cationic polymeric nanoformulations have been explored to increase the transfection efficiency of small molecules and nucleic acid-based drugs. However, an excessive positive charge density often leads to severe cell and tissue-based toxicity that restricts the clinical translation of cationic polymeric nanoformulations. Herein, we investigate a series of cationic poly(lactic-co-glycolic acid) (PLGA)-histidine-based nanoformulations for enhanced cytoplasmic delivery with minimal toxicity. PLGA/poly-l-histidine nanoparticles show promising physico-biochemical features and transfection efficiency in a series of in vitro and cell culture-based studies. Further, the use of acetone/dichloromethane as a solvent mixture during the formulation process significantly improves the morphology and size distribution of PLGA/poly-l-histidine nanoparticles. PLGA/poly-l-histidine nanoformulations undergo clathrin-mediated endocytosis. A contrast-matched small-angle neutron scattering experiment confirmed poly-l-histidine's distribution on the PLGA nanoformulations. PLGA/poly-l-histidine formulations containing paclitaxel as a small molecule-based drug and peptide nucleic acids targeting microRNA-155 as nucleic acid analog are efficacious in in vitro and in vivo studies. PLGA/poly-l-histidine NPs significantly decrease tumor growth in PNA-155 (∼6 fold) and paclitaxel (∼6.5 fold) treatment groups in a lymphoma cell line derived xenograft mice model without inducing any toxicity. Hence, PLGA/poly-l-histidine nanoformulations exhibit substantial transfection efficiency and are safe to deliver reagents ranging from small molecules to synthetic nucleic acid analogs and can serve as a novel platform for drug delivery.
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Affiliation(s)
- Aniket Wahane
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Shipra Malik
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Kuo-Chih Shih
- Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Ravinder Reddy Gaddam
- Division of Cardiovascular Medicine, Department of Internal Medicine, The University of Iowa, Iowa City, Iowa 52242, United States
| | - Chaohao Chen
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Yun Liu
- NIST Center for Neutron Research, Gaithersburg, Maryland 20899, United States
| | - Mu-Ping Nieh
- Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, Connecticut 06269, United States
- Polymer Program, Institute of Materials Science, University of Connecticut, 191 Auditorium Road, Storrs, Connecticut 06269, United States
- Department of Biomedical Engineering, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Ajit Vikram
- Division of Cardiovascular Medicine, Department of Internal Medicine, The University of Iowa, Iowa City, Iowa 52242, United States
| | - Raman Bahal
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, United States
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28
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Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma. Cancers (Basel) 2021; 13:cancers13133131. [PMID: 34201504 PMCID: PMC8269295 DOI: 10.3390/cancers13133131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 05/28/2021] [Accepted: 06/14/2021] [Indexed: 11/30/2022] Open
Abstract
Simple Summary The role of transcriptionally deregulated miRNAs (microRNAs) in classical Hodgkin lymphoma (cHL) is still not fully understood. To address this issue, we have performed global miRNA expression profiling of commonly used cHL cell lines and we present a complete cHL miRNome (microRNome). Within this group, we identify miRNAs recurrently deregulated in cHL cell lines, and compare them to non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells. Moreover, we show that several of the recurrently overexpressed miRNAs in cHL cell lines, and also primary microdissected HRS (Hodgkin and Reed-Sternberg) cells, target known B-cell-related transcription factors and NF-κB inhibitors. These findings provide evidence that deregulated miRNAs contribute to the loss of B-cell phenotype and NF-κB activation observed in this lymphoma. Abstract A hallmark of classical Hodgkin lymphoma (cHL) is the attenuation of B-cell transcription factors leading to global transcriptional reprogramming. The role of miRNAs (microRNAs) involved in this process is poorly studied. Therefore, we performed global miRNA expression profiling using RNA-seq on commonly used cHL cell lines, non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells as controls and characterized the cHL miRNome (microRNome). Among the 298 miRNAs expressed in cHL, 56 were significantly overexpressed and 23 downregulated (p < 0.05) compared to the controls. Moreover, we identified five miRNAs (hsa-miR-9-5p, hsa-miR-24-3p, hsa-miR-196a-5p, hsa-miR-21-5p, hsa-miR-155-5p) as especially important in the pathogenesis of this lymphoma. Target genes of the overexpressed miRNAs in cHL were significantly enriched (p < 0.05) in gene ontologies related to transcription factor activity. Therefore, we further focused on selected interactions with the SPI1 and ELF1 transcription factors attenuated in cHL and the NF-ĸB inhibitor TNFAIP3. We confirmed the interactions between hsa-miR-27a-5p:SPI1, hsa-miR-330-3p:ELF-1, hsa-miR-450b-5p:ELF-1 and hsa-miR-23a-3p:TNFAIP3, which suggest that overexpression of these miRNAs contributes to silencing of the respective genes. Moreover, by analyzing microdissected HRS cells, we demonstrated that these miRNAs are also overexpressed in primary tumor cells. Therefore, these miRNAs play a role in silencing the B-cell phenotype in cHL.
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29
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O'Brien G, Cruz-Garcia L, Zyla J, Brown N, Finnon R, Polanska J, Badie C. Kras mutations and PU.1 promoter methylation are new pathways in murine radiation-induced AML. Carcinogenesis 2021; 41:1104-1112. [PMID: 31646336 PMCID: PMC7422620 DOI: 10.1093/carcin/bgz175] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 09/17/2019] [Accepted: 10/21/2019] [Indexed: 12/16/2022] Open
Abstract
Therapy-related and more specifically radiotherapy-associated acute myeloid leukaemia (AML) is a well-recognized potential complication of cytotoxic therapy for the treatment of a primary cancer. The CBA mouse model is used to study radiation leukaemogenesis mechanisms with Sfpi1/PU.1 deletion and point mutation already identified as driving events during AML development. To identify new pathways, we analysed 123 mouse radiation-induced AML (rAML) samples for the presence of mutations identified previously in human AML and found three genes to be mutated; Sfpi1 R235 (68%), Flt3-ITD (4%) and Kras G12 (3%), of which G12R was previously unreported. Importantly, a significant decrease in Sfpi1 gene expression is found almost exclusively in rAML samples without an Sfpi1 R235 mutation and is specifically associated with up-regulation of mir-1983 and mir-582-5p. Moreover, this down-regulation of Sfpi1 mRNA is negatively correlated with DNA methylation levels at specific CpG sites upstream of the Sfpi1 transcriptional start site. The down regulation of Sfpi1/PU.1 has also been reported in human AML cases revealing one common pathway of myeloid disruption between mouse and human AML where dysregulation of Sfpi1/PU.1 is a necessary step in AML development.
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Affiliation(s)
- Gráinne O'Brien
- Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Oxfordshire, UK
| | - Lourdes Cruz-Garcia
- Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Oxfordshire, UK
| | - Joanna Zyla
- Silesian University of Technology, Data Mining Division, Gliwice, Poland
| | - Natalie Brown
- Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Oxfordshire, UK
| | - Rosemary Finnon
- Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Oxfordshire, UK
| | - Joanna Polanska
- Silesian University of Technology, Data Mining Division, Gliwice, Poland
| | - Christophe Badie
- Public Health England, Centre for Radiation, Chemical and Environmental Hazards, Oxfordshire, UK
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30
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Zheng YJ, Liang TS, Wang J, Zhao JY, Zhai SN, Yang DK, Wang LD. MicroRNA-155 acts as a diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2021; 48:977-982. [PMID: 32573268 DOI: 10.1080/21691401.2020.1773479] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
MicroRNA-155 is over-expressed in many human cancers, but researches on its association with malignant oesophageal squamous cell carcinoma (ESCC) are limited. The aim of the present study was to evaluate the potential value of miR-155 as a biomarker for ESCC diagnosis and prognosis. In this study, we found that miR-155 was significantly increased in ESCC tissues compared with the paired adjacent tissues and healthy normal controls (p < .001), according to qRT-PCR, which suggested that miR-155 might act as an oncogene in ESCC. In addition, clinical features such as the depth of tumour invasion, tumour size, and TNM stage were all proved to impact the expression of miR-155 (p < .01). Then, ROC curve analysis, reaching an AUC of 0.870, and a sensitivity and specificity of 83.5% and 77.5%, respectively, revealed that miR-155 was a predictive factor for ESCC. As well, high expression of miR-155 was associated with poor overall survival of the patients (log-rank test, p = .004), according to Kaplan-Meier analysis. MiR-155 might be an independent predictor for overall survival in ESCC patients, manifested by Cox regression analysis (HR = 16.94, 95%CI = 3.33-86.12, p = .001). Taken together, miR-155 could be an independent diagnostic and prognostic biomarker for ESCC.
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Affiliation(s)
- Ying-Juan Zheng
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Tian-Song Liang
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Juan Wang
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jing-Yi Zhao
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Su-Nan Zhai
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dao-Ke Yang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Li-Dong Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Identification of Small Molecule Inhibitors of a Mir155 Transcriptional Reporter in Th17 Cells. Sci Rep 2021; 11:11498. [PMID: 34075120 PMCID: PMC8169650 DOI: 10.1038/s41598-021-90944-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 05/12/2021] [Indexed: 11/09/2022] Open
Abstract
MicroRNA miR-155 is an important regulatory molecule in the immune system and is highly expressed and functional in Th17 cells, a subset of CD4+ T helper cells which are key players in autoimmune diseases. Small molecules that can modulate miR-155 may potentially provide new therapeutic avenues to inhibit Th17 cell-mediated autoimmune diseases. Here, we present a novel high-throughput screening assay using primary T cells from genetically engineered Mir155 reporter mice, and its use to screen libraries of small molecules to identify novel modulators of Th17 cell function. We have discovered a chemical series of (E)-1-(phenylsulfonyl)-2-styryl-1H-benzo[d] imidazoles as novel down-regulators of Mir155 reporter and cytokine expression in Th17 cells. In addition, we found that FDA approved antiparasitic agents belonging to the 'azole' family also down-regulate Mir155 reporter and cytokine expression in Th17 cells, and thus could potentially be repurposed to treat Th17-driven immunopathologies.
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Potential functions of hsa-miR-155-5p and core genes in chronic myeloid leukemia and emerging role in human cancer: A joint bioinformatics analysis. Genomics 2021; 113:1647-1658. [PMID: 33862181 DOI: 10.1016/j.ygeno.2021.04.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 02/07/2021] [Accepted: 04/05/2021] [Indexed: 12/13/2022]
Abstract
Considering the critical roles of hsa-miR-155-5p participated in hematopoietic system, this study aims to clarify the possible pathogenesis of chronic myeloid leukemia (CML) induced by hsa-miR-155-5p.Three different strategies were employed, namely a network-based pipeline, a survival analysis and genetic screening method, and a simulation modeling approach, to assess the oncogenic role of hsa-miR-155-5p in CML. We identified new potential roles of hsa-miR-155-5p in CML, involving the BCR/ABL-mediated leukemogenesis through MAPK signaling. Several promising targets including E2F2, KRAS and FLI1 were screened as candidate diagnostic marker genes. The survival analysis revealed that mRNA expression of E2F2, KRAS and FLI1 was negatively correlated with hsa-miR-155-5p and these targets were significantly associated with poor overall survival. Furthermore, an overlap between CML-related genes and hsa-miR-155-5p target genes was revealed using competing endogenous RNA (ceRNA) networks analysis. Taken together, our results reveal the dynamic regulatory aspect of hsa-miR-155-5p as potential player in CML pathogenesis.
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Rahnama S, Bakhshinejad B, Farzam F, Bitaraf A, Ghazimoradi MH, Babashah S. Identification of dysregulated competing endogenous RNA networks in glioblastoma: A way toward improved therapeutic opportunities. Life Sci 2021; 277:119488. [PMID: 33862117 DOI: 10.1016/j.lfs.2021.119488] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/16/2021] [Accepted: 04/04/2021] [Indexed: 12/17/2022]
Abstract
Glioblastoma is recognized as one of the leading causes of death worldwide. Although there have been considerable advancements in understanding the causative molecular mechanisms of this malignancy, effective therapeutic strategies are still in limited use. It has been revealed that non-coding RNAs (ncRNAs) play critical roles in glioblastoma development, while interactions between the regulatory molecules such as long ncRNAs (lncRNAs), microRNAs (miRNAs), transcribed pseudogenes, and circular RNAs (circRNAs) remain to be fully deciphered. Over the recent years, researchers have discovered a new category of RNA molecules called competing endogenous RNA (ceRNA). This kind of RNA can contribute to molecular interactions in the form of ceRNA networks (ceRNETs). Multiple lines of evidence have demonstrated that dysregulation of various ceRNA networks is involved in glioblastoma development. Therefore, gaining insights into these dysregulations might offer potential for the early diagnosis of glioblastoma patients and identification of efficient therapeutic targets. In this review, we provide an overview of recent discoveries on ceRNA networks and the involvement of dysregulated networks in posing limitations to temozolomide therapy. We also describe signaling pathways relevant to the progression of glioblastoma.
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Affiliation(s)
- Saghar Rahnama
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Babak Bakhshinejad
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Farnoosh Farzam
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amirreza Bitaraf
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
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MicroRNA signature in classical Hodgkin lymphoma. J Appl Genet 2021; 62:281-288. [PMID: 33544339 PMCID: PMC8032569 DOI: 10.1007/s13353-021-00614-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/30/2020] [Accepted: 01/11/2021] [Indexed: 12/11/2022]
Abstract
Classical Hodgkin lymphoma (cHL) is one of the most prevalent lymphomas with a unique cell composition compared to other lymphoma entities. Rare, malignant Hodgkin and Reed-Sternberg (HRS) cells embedded with an extensive but ineffective immune infiltration were previously characterized by a large number of genetic and epigenetic alterations. Recently, microRNA profiling studies highlighted the importance of small non-coding RNA in cHL. This review summarizes available literature data and provides a detailed comparison of four studies where cHL cell lines and microdissected HRS cells were used. Several microRNAs were found to be consistently up- (let-7-f, mir-9, mir-21, mir-23a, mir-27a, mir-155, and mir-196a) or downregulated (mir-138 and mir-150) in cHL. These deregulated microRNAs are involved in the processes crucial for cHL pathogenesis, such as impaired B cell development (mir-9, mir-150, and mir-155), NFκB hyperactivation (mir-155 and mir-196a), and immune evasion (mir-138). Therefore, the deregulation of microRNA expression can be considered a complementary mechanism to genetic alterations promoting lymphomagenesis. Moreover, the expression of let-7f, mir-9 and mir-27a is specific for cHL and can serve as a biomarker to distinguish this lymphoma from other B cell lymphomas. However, additional in-depth and high throughput analysis of microRNA expression in HRS cells is necessary to decipher the complete picture of microRNA in cHL.
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Kim S, Lee ES, Lee EJ, Jung JY, Lee SB, Lee HJ, Kim J, Kim HJ, Lee JW, Son BH, Gong G, Ahn SH, Chang S. Targeted eicosanoids profiling reveals a prostaglandin reprogramming in breast Cancer by microRNA-155. J Exp Clin Cancer Res 2021; 40:43. [PMID: 33494773 PMCID: PMC7831268 DOI: 10.1186/s13046-021-01839-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/11/2021] [Indexed: 11/10/2022] Open
Abstract
Abstract Background Prostaglandin is one of the key metabolites for inflammation-related carcinogenesis. Despite the microRNA-155 is implicated in various types of cancers, it’s function in prostaglandin metabolism is largely unknown. Methods A targeted profiling of eicosanoids including prostaglandin, leukotriene and thromboxanes was performed in miR-155 deficient breast tumors and cancer cells. The molecular mechanism of miR-155-mediated prostaglandin reprogramming was investigated in primary and cancer cell lines, by analyzing key enzymes responsible for the prostaglandin production. Results We found miR-155-deficient breast tumors, plasma of tumor-bearing mouse and cancer cells show altered prostaglandin level, especially for the prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Subsequent analysis in primary cancer cells, 20 triple-negative breast cancer (TNBC) specimens and breast cancer cell lines with miR-155 knockdown consistently showed a positive correlation between miR-155 level and PGE2/PGD2 ratio. Mechanistically, we reveal the miR-155 reprograms the prostaglandin metabolism by up-regulating PGE2-producing enzymes PTGES/PTGES2 while down-regulating PGD2-producing enzyme PTGDS. Further, we show the up-regulation of PTGES2 is driven by miR-155-cMYC axis, whereas PTGES is transactivated by miR-155-KLF4. Thus, miR-155 hires dual-regulatory mode for the metabolic enzyme expression to reprogram the PGE2/PGD2 balance. Lastly, we show the miR-155-driven cellular proliferation is restored by the siRNA of PTGES1/2, of which expression also significantly correlates with breast cancer patients’ survival. Conclusions Considering clinical trials targeting PGE2 production largely have focused on the inhibition of Cox1 or Cox2 that showed cardiac toxicity, our data suggest an alternative way for suppressing PGE2 production via the inhibition of miR-155. As the antagomiR of miR-155 (MRG-106) underwent a phase-1 clinical trial, its effect should be considered and analyzed in prostaglandin metabolism in tumor. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-01839-4.
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Affiliation(s)
- Sinae Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Eun Sung Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Eun Ji Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Jae Yun Jung
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Sae Byul Lee
- Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Hee Jin Lee
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Jisun Kim
- Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Hee Jeong Kim
- Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Jong Won Lee
- Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Byung Ho Son
- Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Gyungyub Gong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Sei-Hyun Ahn
- Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Suhwan Chang
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
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Morales-Martinez M, Vega MI. Participation of different miRNAs in the regulation of YY1: Their role in pathogenesis, chemoresistance, and therapeutic implication in hematologic malignancies. YY1 IN THE CONTROL OF THE PATHOGENESIS AND DRUG RESISTANCE OF CANCER 2021:171-198. [DOI: 10.1016/b978-0-12-821909-6.00010-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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MicroRNA-155 contributes to plexiform neurofibroma growth downstream of MEK. Oncogene 2020; 40:951-963. [PMID: 33293695 PMCID: PMC7867646 DOI: 10.1038/s41388-020-01581-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 11/11/2020] [Accepted: 11/20/2020] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRs) are small non-coding RNAs that can have large impacts on oncogenic pathways. Possible functions of dysregulated miRs have not been studied in neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNFs). In PNFs, Schwann cells (SCs) have biallelic NF1 mutations necessary for tumorigenesis. We analyzed a miR-microarray comparing to normal and PNF SCs and identified differences in miR expression, and we validated in mouse PNFs versus normal mouse SCs by qRT-PCR. Among these, miR-155 was a top overexpressed miR, and its expression was regulated by RAS/MAPK signaling. Overexpression of miR-155 increased mature Nf1−/− mouse SC proliferation. In SC precursors, which model tumor initiating cells, pharmacological and genetic inhibition of miR-155 decreased PNF-derived sphere numbers in vitro and we identified Maf as a miR-155 target. In vivo, global deletion of miR-155 significantly decreased tumor number and volume, increasing mouse survival. Fluorescent nanoparticles entered PNFs, suggesting that an anti-miR might have therapeutic potential. However, treatment of established PNFs using anti-miR-155 peptide nucleic acid-loaded nanoparticles marginally decreased tumor numbers and did not reduce tumor growth. These results suggest that miR-155 plays a functional role in PNF growth and/or SC proliferation, and that targeting neurofibroma miRs is feasible, and might provide novel therapeutic opportunities.
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Kumar S, Gonzalez EA, Rameshwar P, Etchegaray JP. Non-Coding RNAs as Mediators of Epigenetic Changes in Malignancies. Cancers (Basel) 2020; 12:E3657. [PMID: 33291485 PMCID: PMC7762117 DOI: 10.3390/cancers12123657] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/01/2020] [Accepted: 12/03/2020] [Indexed: 12/12/2022] Open
Abstract
Non-coding RNAs (ncRNAs) are untranslated RNA molecules that regulate gene expressions. NcRNAs include small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), circular RNAs (cRNAs) and piwi-interacting RNAs (piRNAs). This review focuses on two types of ncRNAs: microRNAs (miRNAs) or short interfering RNAs (siRNAs) and long non-coding RNAs (lncRNAs). We highlight the mechanisms by which miRNAs and lncRNAs impact the epigenome in the context of cancer. Both miRNAs and lncRNAs have the ability to interact with numerous epigenetic modifiers and transcription factors to influence gene expression. The aberrant expression of these ncRNAs is associated with the development and progression of tumors. The primary reason for their deregulated expression can be attributed to epigenetic alterations. Epigenetic alterations can cause the misregulation of ncRNAs. The experimental evidence indicated that most abnormally expressed ncRNAs impact cellular proliferation and apoptotic pathways, and such changes are cancer-dependent. In vitro and in vivo experiments show that, depending on the cancer type, either the upregulation or downregulation of ncRNAs can prevent the proliferation and progression of cancer. Therefore, a better understanding on how ncRNAs impact tumorigenesis could serve to develop new therapeutic treatments. Here, we review the involvement of ncRNAs in cancer epigenetics and highlight their use in clinical therapy.
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Affiliation(s)
- Subhasree Kumar
- Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA; (S.K.); (E.A.G.)
| | - Edward A. Gonzalez
- Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA; (S.K.); (E.A.G.)
| | - Pranela Rameshwar
- Department of Medicine, Hematology/Oncology, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA
| | - Jean-Pierre Etchegaray
- Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA; (S.K.); (E.A.G.)
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Xiao C, Nemazee D, Gonzalez-Martin A. MicroRNA control of B cell tolerance, autoimmunity and cancer. Semin Cancer Biol 2020; 64:102-107. [PMID: 32522353 DOI: 10.1016/j.semcancer.2019.04.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 04/24/2019] [Indexed: 01/14/2023]
Abstract
Since the discovery of the first microRNA (miRNA) in 1993, thousands of miRNAs have been identified in humans and mice and many of them have been shown to control a large variety of cellular processes in different cell types including those composing the immune system. MicroRNAs regulate virtually all aspects of immune cell development, differentiation and function. Studies have shown that these molecules are involved in the maintenance of lymphocyte tolerance and, when dysregulated, promote the development of autoimmune diseases. In this review, we focus on the current knowledge about the roles of miRNAs in B cell tolerance and their contribution to autoimmunity, highlighting additional roles for some of these miRNAs in T cell tolerance. Finally, we will comment on miRNAs that promote both autoimmunity and lymphoma.
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Affiliation(s)
- Changchun Xiao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005, China
| | - David Nemazee
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA
| | - Alicia Gonzalez-Martin
- Department of Biochemistry, Universidad Autonoma de Madrid (UAM), Instituto de Investigaciones Biomedicas Alberto Sols (CSIC-UAM), 28029, Madrid, Spain.
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40
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Park HJ, Lee SS. Detection of miR‐155 Using Two Types of Electrochemical Approaches. B KOREAN CHEM SOC 2020. [DOI: 10.1002/bkcs.12128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Hyeoun Ji Park
- Department of Pharmaceutical Engineering Soonchunhhyang University Chungnam 31538 South Korea
| | - Soo Suk Lee
- Department of Pharmaceutical Engineering Soonchunhhyang University Chungnam 31538 South Korea
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41
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Poppema S. Lymphocyte predominant Hodgkin lymphoma, antigen-driven after all? J Pathol 2020; 253:1-10. [PMID: 33044742 DOI: 10.1002/path.5567] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/22/2020] [Accepted: 10/06/2020] [Indexed: 01/12/2023]
Abstract
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) was suggested as an entity separate from other types of Hodgkin lymphoma 40 years ago and recognized in the WHO classification in 2001. Based on its relatively benign course with late distant relapses, relation with lymph node hyperplasia with progressively transformed germinal centers, presence of clonal immunoglobulin gene rearrangements with somatic hypermutations and ongoing mutations, and relation with a number of inherited defects affecting the immune system, it has been suspected that NLPHL might be antigen-driven. Recent evidence has shown that cases of IgD-positive NLPHL are associated with infection by Moraxella catarrhalis, a common bacterium in the upper respiratory tract and in lymph nodes. This review summarizes the evidence for NLPHL as a B-cell lymphoma involving follicular T-lymphocytes normally found in germinal centers, its molecular features and relation to inherited immune defects, and its relation and differential diagnosis from similar entities. Finally, it discusses the evidence that in many cases a watch and wait policy might be a viable initial management strategy. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Sibrandes Poppema
- School of Medical and Health Sciences, Sunway University, Bandar Sunway, Malaysia
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42
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Abstract
PURPOSE OF REVIEW MiRNAs are critical regulators for gene expression. Numerous studies have revealed how miRNAs contribute to the pathogenesis of hematologic malignancies. RECENT FINDINGS The identification of novel miRNA regulatory factors and pathways crucial for miRNA dysregulation has been linked to hematologic malignancies. miRNA expression profiling has shown their potential to predict outcomes and treatment responses. Recently, targeting miRNA biogenesis or pathways has become a promising therapeutic strategy with recent miRNA-therapeutics being developed. SUMMARY We provide a comprehensive overview of the role of miRNAs for diagnosis, prognosis, and therapeutic potential in hematologic malignancies.
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Affiliation(s)
- Zhen Han
- Division of Dermatology, City of Hope, Duarte, CA, USA
- Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Steven T. Rosen
- Dept of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA
- Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Christiane Querfeld
- Division of Dermatology, City of Hope, Duarte, CA, USA
- Department of Pathology, City of Hope, Duarte, CA, USA
- Beckman Research Institute, City of Hope, Duarte, CA, USA
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Malik S, Lim J, Slack FJ, Braddock DT, Bahal R. Next generation miRNA inhibition using short anti-seed PNAs encapsulated in PLGA nanoparticles. J Control Release 2020; 327:406-419. [PMID: 32835710 DOI: 10.1016/j.jconrel.2020.08.026] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 08/14/2020] [Accepted: 08/17/2020] [Indexed: 02/07/2023]
Abstract
Selective inhibition of microRNAs (miRNAs) offers a new avenue for cancer therapeutics. While most of the current anti-miRNA (antimiR) reagents target full length miRNAs, here we investigate novel nanoparticle-delivered short PNA probes containing cationic domains targeting the seed region of the miRNA for effective antimiR therapy. For proof of concept, we tested PNAs targeting miRNA-155 and employed poly(lactic-co-glycolic acid) (PLGA)-based nanoparticle formulation for delivery. A comprehensive evaluation of PLGA nanoparticles (NPs) containing short PNA probes showed significantly superior loading, release profile, and uniform size distribution, compared to conventional non-cationic PNA probes. Confocal microscopy and flow cytometry analyses showed efficient transfection efficiency and uniform distribution of PLGA NPs containing short PNA probes in the cytoplasm. Functional analysis also confirmed efficient miRNA-155 inhibition including an effect on its downstream target proteins. Further, reduced tumor growth was observed after systemic delivery of PLGA nanoparticles containing short PNA probes in vivo in a xenograft mouse model following inhibition of miR-155. There was no evidence of acute or chronic toxicity associated with systemic delivery of PLGA NPs containing short PNA probes in the mice. Overall, in this paper we present a novel antimiR strategy based on PLGA nanoparticle delivered short PNA probes for potential cancer therapy.
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Affiliation(s)
- Shipra Malik
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Jihoon Lim
- Department of Pathology, BIDMC Cancer Center, Harvard Medical School, 330, Brookline Ave, Boston, MA 02215, USA
| | - Frank J Slack
- Department of Pathology, BIDMC Cancer Center, Harvard Medical School, 330, Brookline Ave, Boston, MA 02215, USA
| | - Demetrios T Braddock
- Department of Pathology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
| | - Raman Bahal
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
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Liu J, Liu F. The Yin and Yang function of microRNAs in insulin signalling and cancer. RNA Biol 2020; 18:24-32. [PMID: 32746694 DOI: 10.1080/15476286.2020.1804236] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Data accumulated over the past several decades uncover a vital role of microRNAs (miRNAs) in various biological processes. It is well established that, by binding to target mRNAs, miRNAs act as post-transcription suppressors to inhibit mRNA translation and/or to promote mRNA degradation. Very recently, miRNAs have been found to act as positive regulators to promote gene transcription. In this review, we briefly summarize the regulation and functional roles of miRNAs in metabolic diseases and cancer development. We also review recent advances on the mechanisms by which miRNAs regulate gene expression, focusing on their unconventional roles as enhancers to promote gene expression. Given the high potential of miRNAs as biomarkers for risk assessment and as high-value targets for therapy, a better understanding of the Yin-Yang functional feature of miRNAs and their mechanisms of action could have significant clinical implications for the treatment of various diseases such as obesity, type 2 diabetes, and cancer.
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Affiliation(s)
- Juanhong Liu
- National Clinical Research Center for Metabolic Diseases, and Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University , Changsha, China
| | - Feng Liu
- National Clinical Research Center for Metabolic Diseases, and Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University , Changsha, China.,Departments of Pharmacology, University of Texas Health at San Antonio , San Antonio, TX, USA
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Jabłońska E, Białopiotrowicz E, Szydłowski M, Prochorec-Sobieszek M, Juszczyński P, Szumera-Ciećkiewicz A. DEPTOR is a microRNA-155 target regulating migration and cytokine production in diffuse large B-cell lymphoma cells. Exp Hematol 2020; 88:56-67.e2. [PMID: 32702393 DOI: 10.1016/j.exphem.2020.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 06/24/2020] [Accepted: 07/15/2020] [Indexed: 12/24/2022]
Abstract
MicroRNA-155 (MiR-155) is involved in normal B-cell development and lymphomagenesis, affecting cell differentiation, motility, and intracellular signaling. In this study, we searched for new targets of MiR-155 potentially involved in deregulation of the B-cell receptor pathway (BCR) in diffuse large B-cell lymphoma (DLBCL). We report that MiR-155 represses DEPTOR (an mTOR phosphatase) and c-CBL (SYK ubiquitin E3 ligase) through direct 3'-untranslated region interactions. In primary DLBCLs, MiR-155 exhibits a reciprocal expression pattern with DEPTOR and c-CBL. Inhibition of MiR-155 decreased expression of NFκB target genes and sensitized DLBCL cells to ibrutinib, confirming the role of MiR-155 in the modulation of BCR signaling. As the function of DEPTOR in DLBCLs has never been addressed, we first evaluated its expression in a series of 76 newly diagnosed DLBCL patients. DEPTOR protein expression was markedly lower in more aggressive nongerminal center-like (non-GCB) DLBCLs than in GCB tumors. In cell line models, inhibition of DEPTOR expression favored the migration of DLBCL cells toward the CXCL12 gradient. Finally, loss or gain of DEPTOR modulated the expression of specific pro-inflammatory cytokines and chemokines. We thus identified DEPTOR as a new MiR-155 target that is differentially expressed between GCB- and non-GCB-type DLBCLs and modulates cell migration and cytokine expression in DLBCL cells.
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Affiliation(s)
- Ewa Jabłońska
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Emilia Białopiotrowicz
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Maciej Szydłowski
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | | | - Przemysław Juszczyński
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
| | - Anna Szumera-Ciećkiewicz
- Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
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46
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Drees EEE, Pegtel DM. Circulating miRNAs as Biomarkers in Aggressive B Cell Lymphomas. Trends Cancer 2020; 6:910-923. [PMID: 32660885 DOI: 10.1016/j.trecan.2020.06.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 04/23/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023]
Abstract
B cell lymphomas are heterogeneous malignancies of hematological origin with vastly different biology and clinical outcomes. Histopathology of tissue biopsies and image-based assessment guide clinical decisions. Given that tissue biopsies cannot be frequently repeated and will not inform on systemic responses to the treatment, more accessible biomarkers, such as circulating miRNAs, are considered. Aberrant miRNA expression in lymphoma tissues and ongoing immune reactions may lead to miRNA alterations in circulation. miRNAs bound to extracellular vesicles (EVs) are of interest because of their role in intercellular communication and organ crosstalk. Herein, we highlight the role of miRNAs and EVs in B cell lymphomagenesis and explain how circulating miRNAs may be turned into robust liquid biopsy tests for aggressive B cell lymphoma.
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Affiliation(s)
- Esther E E Drees
- Amsterdam UMC, Vrije Universiteit Amsterdam, Exosomes Research Group, Department of Pathology, Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
| | - D Michiel Pegtel
- Amsterdam UMC, Vrije Universiteit Amsterdam, Exosomes Research Group, Department of Pathology, Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
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47
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Heydari Z, Rahaie M, Alizadeh AM, Agah S, Khalighfard S, Bahmani S. Effects of Lactobacillus acidophilus and Bifidobacterium bifidum Probiotics on the Expression of MicroRNAs 135b, 26b, 18a and 155, and Their Involving Genes in Mice Colon Cancer. Probiotics Antimicrob Proteins 2020; 11:1155-1162. [PMID: 30311185 DOI: 10.1007/s12602-018-9478-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
A wide range of sources supports that the link between diet and colorectal cancer may be due to an imbalance of the intestinal microflora. In this case, it seems that the probiotics may have a possible molecular mechanism via microRNAs (miRNAs). The present study is aimed to evaluate the effects of Lactobacillus acidophilus and Bifidobacterium bifidum probiotics on the expression of miRNAs 135b, 26b, 18a, and 155 and their target genes, including APC, PTEN, KRAS, and PU.1 in mouse azoxymethane (AOM)-induced colon cancer. Thirty-eight male BALB/c mice were randomly divided into four groups: the control, AOM, Lactobacillus acidophilus, and Bifidobacterium bifidum to deliberate the effects of the probiotics on the miRNAs and their target genes. Except for the control group, the rest groups were weekly given AOM (15 mg/kg, s.c) in three consecutive weeks to induce mouse colon cancer. The animals were given 1.5 g powders of L. acidophilus (1 × 109 cfu/g) and B. bifidum (1 × 109 cfu/g) in 30 cc drinking water in the related groups for 5 months. At the end of the study, the animals were sacrificed and their blood and colon samples were removed for the molecular analyses. The results showed that the expression of the miR-135b, miR-155, and KRAS was increased in the AOM group compared to the control group in both the plasma and the colon tissue samples, and the consumption of the probiotics decreased their expression. Moreover, the miR-26b, miR-18a, APC, PU.1, and PTEN expressions were decreased in the AOM group compared to the control group and the consumption of the probiotics increased their expressions. It seems that Lactobacillus acidophilus and Bifidobacterium bifidum though increasing the expression of the tumor suppressor miRNAs and their target genes and decreasing the oncogenes can improve colon cancer treatment.
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Affiliation(s)
- Zahra Heydari
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | - Mahdi Rahaie
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | - Ali Mohammad Alizadeh
- Cancer Research Center, Tehran University of Medical Sciences, Tehran, 1419733141, Iran.
- Cancer Biology Research Center, Tehran University of Medical Science, Tehran, Iran.
| | - Shahram Agah
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Solmaz Khalighfard
- Cancer Research Center, Tehran University of Medical Sciences, Tehran, 1419733141, Iran
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Sahar Bahmani
- Research and Development Department, Zist Takhmir Company, Tehran, Iran
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48
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Szczepanek J. Role of microRNA dysregulation in childhood acute leukemias: Diagnostics, monitoring and therapeutics: A comprehensive review. World J Clin Oncol 2020; 11:348-369. [PMID: 32855905 PMCID: PMC7426929 DOI: 10.5306/wjco.v11.i6.348] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/18/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are short noncoding RNAs that regulate the expression of genes by sequence-specific binding to mRNA to either promote or block its translation; they can also act as tumor suppressors (e.g., let-7b, miR-29a, miR-99, mir-100, miR-155, and miR-181) and/or oncogenes (e.g., miR-29a, miR-125b, miR-143-p3, mir-155, miR-181, miR-183, miR-196b, and miR-223) in childhood acute leukemia (AL). Differentially expressed miRNAs are important factors associated with the initiation and progression of AL. As shown in many studies, they can be used as noninvasive diagnostic and prognostic biomarkers, which are useful in monitoring early stages of AL development or during therapy (e.g., miR-125b, miR-146b, miR-181c, and miR-4786), accurate classification of different cellular or molecular AL subgroups (e.g., let-7b, miR-98, miR-100, miR-128b, and miR-223), and identification and development of new therapeutic agents (e.g., mir-10, miR-125b, miR-203, miR-210, miR-335). Specific miRNA patterns have also been described for commonly used AL therapy drugs (e.g., miR-125b and miR-223 for doxorubicin, miR-335 and miR-1208 for prednisolone, and miR-203 for imatinib), uncovering miRNAs that are associated with treatment response. In the current review, the role of miRNAs in the development, progression, and therapy monitoring of pediatric ALs will be presented and discussed.
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Affiliation(s)
- Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Toruń 87100, Poland
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49
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Kiel C, Berber P, Karlstetter M, Aslanidis A, Strunz T, Langmann T, Grassmann F, Weber BH. A Circulating MicroRNA Profile in a Laser-Induced Mouse Model of Choroidal Neovascularization. Int J Mol Sci 2020; 21:E2689. [PMID: 32294914 PMCID: PMC7216141 DOI: 10.3390/ijms21082689] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/09/2020] [Accepted: 04/10/2020] [Indexed: 12/15/2022] Open
Abstract
Choroidal neovascularization (CNV) is a pathological process in which aberrant blood vessels invade the subretinal space of the mammalian eye. It is a characteristic feature of the prevalent neovascular age-related macular degeneration (nAMD). Circulating microRNAs (cmiRNAs) are regarded as potentially valuable biomarkers for various age-related diseases, including nAMD. Here, we investigated cmiRNA expression in an established laser-induced CNV mouse model. Upon CNV induction in C57Bl/6 mice, blood-derived cmiRNAs were initially determined globally by RNA next generation sequencing, and the most strongly dysregulated cmiRNAs were independently replicated by quantitative reverse transcription PCR (RT-qPCR) in blood, retinal, and retinal pigment epithelium (RPE)/choroidal tissue. Our findings suggest that two miRNAs, mmu-mir-486a-5p and mmur-mir-92a-3p, are consistently dysregulated during CNV formation. Furthermore, in functional in vitro assays, a significant impact of mmu-mir-486a-5p and mmu-mir-92a-3p on murine microglial cell viability was observed, while mmu-mir-92a-3p also showed an impact on microglial mobility. Taken together, we report a robust dysregulation of two miRNAs in blood and RPE/choroid after laser-induced initiation of CNV lesions in mice, highlighting their potential role in pathology and eventual therapy of CNV-associated complications.
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Affiliation(s)
- Christina Kiel
- Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany; (C.K.); (P.B.); (T.S.); (F.G.)
| | - Patricia Berber
- Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany; (C.K.); (P.B.); (T.S.); (F.G.)
| | - Marcus Karlstetter
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital of Cologne, 50931 Cologne, Germany; (M.K.); (A.A.); (T.L.)
| | - Alexander Aslanidis
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital of Cologne, 50931 Cologne, Germany; (M.K.); (A.A.); (T.L.)
| | - Tobias Strunz
- Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany; (C.K.); (P.B.); (T.S.); (F.G.)
| | - Thomas Langmann
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital of Cologne, 50931 Cologne, Germany; (M.K.); (A.A.); (T.L.)
| | - Felix Grassmann
- Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany; (C.K.); (P.B.); (T.S.); (F.G.)
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 171 77 Stockholm, Sweden
| | - Bernhard H.F. Weber
- Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany; (C.K.); (P.B.); (T.S.); (F.G.)
- Institute of Clinical Human Genetics, University Clinics Regensburg, 93053 Regensburg, Germany
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50
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Wang L, You Z, Wang M, Yuan Y, Liu C, Yang N, Zhang H, Lian L. Genome-wide analysis of circular RNAs involved in Marek's disease tumourigenesis in chickens. RNA Biol 2020; 17:517-527. [PMID: 31948317 PMCID: PMC7237138 DOI: 10.1080/15476286.2020.1713538] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 01/02/2020] [Accepted: 01/04/2020] [Indexed: 01/01/2023] Open
Abstract
Marek's disease (MD), induced by Marek's disease virus (MDV), is a lymphotropic neoplastic disease and causes huge economic losses to the poultry industry. Non-coding RNAs (ncRNAs) play important regulatory roles in disease pathogenesis. To investigate host circular RNA (circRNA) and microRNA (miRNA) expression profile, RNA sequencing was performed in tumourous spleens (TS), spleens from the survivors (SS) without any lesion after MDV infection, and non-infected chicken spleens (NS). A total of 2,169 circRNAs were identified and more than 80% of circRNAs were derived from exon. The flanking introns of 1,744 exonic circRNAs possessed 579 reverse complementary matches (RCMs), which mainly overlapped with chicken repeat 1 family (CR1F). It suggested that CR1F mediated the cyclization of exons by intron pairing. Out of 2,169 circRNAs, 113 were differentially expressed circRNAs (DECs). The Q-PCR and Rnase R digestion experiments showed circRNA possessed high stability compared with their linear RNAs. Integrated with previous transcriptome data, we profiled regulatory networks of circRNA/long non-coding RNA (lncRNA)-miRNA-mRNA. Extensive competing endogenous RNA (ceRNA) networks were predicted to be involved in MD tumourigenesis. Interestingly, circZMYM3, an intronic circRNA, interacted with seven miRNAs which targeted some immune genes, such as SWAP70 and CCL4. Gga-miR-155 not only interacted with circGTDC1 and circMYO1B, but also targeted immune-related genes, such as GATA4, which indicated the roles of non-coding RNAs played to mediate immune responsive genes. Collectively, this is the first study that integrated RNA expression profiles in MD model. Our results provided comprehensive interactions of ncRNAs and mRNA in MD tumourigenesis.
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Affiliation(s)
- Lulu Wang
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Zhen You
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Mingyue Wang
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Yiming Yuan
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Changjun Liu
- Division of Avian Infectious Diseases, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, China
| | - Ning Yang
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Hao Zhang
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Ling Lian
- Department of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
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