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1
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Lauzon-Young C, Silva A, Sadikovic B. Epigenomic insights and computational advances in hematologic malignancies. Mol Cytogenet 2025; 18:9. [PMID: 40221777 PMCID: PMC11993968 DOI: 10.1186/s13039-025-00712-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 04/04/2025] [Indexed: 04/14/2025] Open
Abstract
Hematologic malignancies (HMs) encompass a diverse spectrum of cancers originating from the blood, bone marrow, and lymphatic systems, with myeloid malignancies representing a significant and complex subset. This review provides a focused analysis of their classification, prevalence, and incidence, highlighting the persistent challenges posed by their intricate genetic and epigenetic landscapes in clinical diagnostics and therapeutics. The genetic basis of myeloid malignancies, including chromosomal translocations, somatic mutations, and copy number variations, is examined in detail, alongside epigenetic modifications with a specific emphasis on DNA methylation. We explore the dynamic interplay between genetic and epigenetic factors, demonstrating how these mechanisms collectively shape disease progression, therapeutic resistance, and clinical outcomes. Advances in diagnostic modalities, particularly those integrating epigenomic insights, are revolutionizing the precision diagnosis of HMs. Key approaches such as nano-based contrast agents, optical imaging, flow cytometry, circulating tumor DNA analysis, and somatic mutation testing are discussed, with particular attention to the transformative role of machine learning in epigenetic data analysis. DNA methylation episignatures have emerged as a pivotal tool, enabling the development of highly sensitive and specific diagnostic and prognostic assays that are now being adopted in clinical practice. We also review the impact of computational advancements and data integration in refining diagnostic and therapeutic strategies. By combining genomic and epigenomic profiling techniques, these innovations are accelerating biomarker discovery and clinical translation, with applications in precision oncology becoming increasingly evident. Comprehensive genomic datasets, coupled with artificial intelligence, are driving actionable insights into the biology of myeloid malignancies and facilitating the optimization of patient management strategies. Finally, this review emphasizes the translational potential of these advancements, focusing on their tangible benefits for patient care and outcomes. By synthesizing current knowledge and recent innovations, we underscore the critical role of precision medicine and epigenomic research in transforming the diagnosis and treatment of myeloid malignancies, setting the stage for ongoing advancements and broader clinical implementation.
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Affiliation(s)
- Carolyn Lauzon-Young
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada
- Pathology and Laboratory Medicine, Western University, London, ON, Canada
| | - Ananilia Silva
- Pathology and Laboratory Medicine, Western University, London, ON, Canada
| | - Bekim Sadikovic
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.
- Pathology and Laboratory Medicine, Western University, London, ON, Canada.
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2
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Tang J, Amin MA, Campian JL. Glioblastoma Stem Cells at the Nexus of Tumor Heterogeneity, Immune Evasion, and Therapeutic Resistance. Cells 2025; 14:562. [PMID: 40277888 PMCID: PMC12025403 DOI: 10.3390/cells14080562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 04/26/2025] Open
Abstract
Glioblastoma (GBM) is an exceedingly aggressive primary brain tumor defined by rapid growth, extensive infiltration, and resistance to standard therapies. A central factor driving these malignancies is the subpopulation of glioblastoma stem cells (GSCs), which possess self-renewal capacity, multipotency, and the ability to regenerate tumor heterogeneity. GSCs contribute to key hallmarks of GBM pathobiology, including relentless progression, resistance to chemotherapy and radiotherapy, and inevitable recurrence. GSCs exhibit distinct molecular signatures, enhanced DNA repair, and metabolic adaptations that protect them against conventional treatments. Moreover, they reside within specialized niches-such as perivascular or hypoxic microenvironments-that sustain stemness, promote immunosuppression, and facilitate angiogenesis. Recent discoveries highlight signaling pathways like Notch, Wnt/β-catenin, Hedgehog, STAT3-PARN, and factors such as TFPI2 and HML-2 as critical regulators of GSC maintenance, plasticity, and immune evasion. These findings underscore the complexity of GSC biology and their pivotal role in driving GBM heterogeneity and therapeutic failure. Emerging therapeutic strategies aim to target GSCs through multiple avenues, including surface markers, immunotherapeutics (e.g., CAR T cells), metabolic vulnerabilities, and combination regimens. Advances in patient-derived organoids, single-cell omics, and 3D co-culture models enable more accurate representation of the tumor ecosystem and personalized therapeutic approaches. Ultimately, improved understanding of GSC-specific targets and the tumor microenvironment promises more effective interventions, paving the way toward better clinical outcomes for GBM patients.
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Affiliation(s)
- Justin Tang
- Department of Biomedical Science, University of Guelph, Guelph, ON N1G 2W1, Canada
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (M.A.A.); (J.L.C.)
| | - Md Al Amin
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (M.A.A.); (J.L.C.)
| | - Jian L. Campian
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (M.A.A.); (J.L.C.)
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3
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Zhao WJ, Wang ML, Zhao YF, Zhao WP, Huang QH, Lu ZW, Jia F, Shi JJ, Liu BS, Han WH, Lu HW, Zhang BC, Wang ZX. Pan-cancer analysis reveals SMARCAL1 expression is associated with immune cell infiltration and poor prognosis in various cancers. Sci Rep 2025; 15:6591. [PMID: 39994264 PMCID: PMC11850860 DOI: 10.1038/s41598-025-88955-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 02/03/2025] [Indexed: 02/26/2025] Open
Abstract
Although immune checkpoint inhibition in particular has shown promise in cancer immunotherapy, it is not always efficient. Recent studies suggest that SMARCAL1 may play a role in tumor immune evasion, yet its pan-cancer role is unclear. We conducted a comprehensive analysis of SMARCAL1 using TCGA, GTEx, and CCLE databases, evaluating its expression, genetic alterations, epigenetic modifications, and their clinical correlations across 33 cancer types. Our findings indicate that SMARCAL1 is overexpressed in several cancers, such as Glioma, LUAD, KIRC, and LIHC, impacting prognosis. Elevated SMARCAL1 is linked to poor outcomes in Glioma, LUAD, and LIHC but correlates with better survival in KIRC. We also found significant associations between SMARCAL1 expression and DNA methylation in 13 cancers. Furthermore, SMARCAL1 expression correlates with immune infiltration, suggesting it as a potential therapeutic target in cancer immunotherapy. This study underscores the need for further research on SMARCAL1 to enhance immunotherapeutic strategies.
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Affiliation(s)
- Wu-Jie Zhao
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Meng-Lei Wang
- Department of Digestive Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Yun-Fang Zhao
- Jitang College of North China University of Science and Technology, Tangshan, 063000, Hebei, China
| | - Wen-Peng Zhao
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Qiong-Hui Huang
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, 350108, Fujian, China
| | - Zhen-Wei Lu
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, 350108, Fujian, China
| | - Fang Jia
- Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
| | - Jin-Jin Shi
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Bo-Sen Liu
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Wan-Hong Han
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Han-Wen Lu
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
| | - Bing-Chang Zhang
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China.
| | - Zhan-Xiang Wang
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China.
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4
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Jaiswal A, Shrivastav S, Kushwaha HR, Chaturvedi R, Singh RP. Oncogenic potential of SARS-CoV-2-targeting hallmarks of cancer pathways. Cell Commun Signal 2024; 22:447. [PMID: 39327555 PMCID: PMC11426004 DOI: 10.1186/s12964-024-01818-0] [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: 07/01/2024] [Accepted: 09/04/2024] [Indexed: 09/28/2024] Open
Abstract
The 2019 outbreak of SARS-CoV-2 has caused a major worldwide health crisis with high rates of morbidity and death. Interestingly, it has also been linked to cancer, which begs the issue of whether it plays a role in carcinogenesis. Recent studies have revealed various mechanisms by which SARS-CoV-2 can influence oncogenic pathways, potentially promoting cancer development. The virus encodes several proteins that alter key signaling pathways associated with cancer hallmarks. Unlike classical oncogenic viruses, which transform cells through viral oncogenes or by activating host oncogenes, SARS-CoV-2 appears to promote tumorigenesis by inhibiting tumor suppressor genes and pathways while activating survival, proliferation, and inflammation-associated signaling cascades. Bioinformatic analyses and experimental studies have identified numerous interactions between SARS-CoV-2 proteins and cellular components involved in cancer-related processes. This review explores the intricate relationship between SARS-CoV-2 infection and cancer, focusing on the regulation of key hallmarks driving initiation, promotion and progression of cancer by viral proteins. By elucidating the underlying mechanisms driving cellular transformation, the potential of SARS-CoV-2 as an oncovirus is highlighted. Comprehending these interplays is essential to enhance our understanding of COVID-19 and cancer biology and further formulating strategies to alleviate SARS-CoV-2 influence on cancer consequences.
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Affiliation(s)
- Aishwarya Jaiswal
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Sanah Shrivastav
- SRM Institute of Science and Technology, Delhi-NCR Campus, Ghaziabad, Uttar Pradesh, India
| | - Hemant R Kushwaha
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
- Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India
| | - Rupesh Chaturvedi
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
- Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India
| | - Rana P Singh
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
- Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India.
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
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5
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Harithpriya K, Ganesan K, Ramkumar KM. Pterostilbene Reverses Epigenetic Silencing of Nrf2 and Enhances Antioxidant Response in Endothelial Cells in Hyperglycemic Microenvironment. Nutrients 2024; 16:2045. [PMID: 38999793 PMCID: PMC11242982 DOI: 10.3390/nu16132045] [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: 05/25/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/14/2024] Open
Abstract
The epigenetic regulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal redox transcription factor, plays a crucial role in maintaining cellular homeostasis. Recent research has underscored the significance of epigenetic modifications of Nrf2 in the pathogenesis of diabetic foot ulcers (DFUs). This study investigates the epigenetic reversal of Nrf2 by pterostilbene (PTS) in human endothelial cells in a hyperglycemic microenvironment (HGM). The activation potential of PTS on Nrf2 was evaluated through ARE-Luciferase reporter assays and nuclear translocation studies. Following 72 h of exposure to an HGM, mRNA expression and protein levels of Nrf2 and its downstream targets NAD(P)H quinone oxidoreductase 1 (NQO1), heme-oxygenase 1(HO-1), superoxide dismutase (SOD), and catalase (CAT) exhibited a decrease, which was mitigated in PTS-pretreated endothelial cells. Epigenetic markers, including histone deacetylases (HDACs class I-IV) and DNA methyltransferases (DNMTs 1/3A and 3B), were found to be downregulated under diabetic conditions. Specifically, Nrf2-associated HDACs, including HDAC1, HDAC2, HDAC3, and HDAC4, were upregulated in HGM-induced endothelial cells. This upregulation was reversed in PTS-pretreated cells, except for HDAC2, which exhibited elevated expression in endothelial cells treated with PTS in a hyperglycemic microenvironment. Additionally, PTS was observed to reverse the activity of the methyltransferase enzyme DNMT. Furthermore, CpG islands in the Nrf2 promoter were hypermethylated in cells exposed to an HGM, a phenomenon potentially counteracted by PTS pretreatment, as shown by methyl-sensitive restriction enzyme PCR (MSRE-qPCR) analysis. Collectively, our findings highlight the ability of PTS to epigenetically regulate Nrf2 expression under hyperglycemic conditions, suggesting its therapeutic potential in managing diabetic complications.
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Affiliation(s)
- Kannan Harithpriya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, India;
| | - Kumar Ganesan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong 999077, China
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, India;
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6
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Chehelgerdi M, Behdarvand Dehkordi F, Chehelgerdi M, Kabiri H, Salehian-Dehkordi H, Abdolvand M, Salmanizadeh S, Rashidi M, Niazmand A, Ahmadi S, Feizbakhshan S, Kabiri S, Vatandoost N, Ranjbarnejad T. Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy. Mol Cancer 2023; 22:189. [PMID: 38017433 PMCID: PMC10683363 DOI: 10.1186/s12943-023-01873-0] [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: 07/04/2023] [Accepted: 09/27/2023] [Indexed: 11/30/2023] Open
Abstract
The advent of iPSCs has brought about a significant transformation in stem cell research, opening up promising avenues for advancing cancer treatment. The formation of cancer is a multifaceted process influenced by genetic, epigenetic, and environmental factors. iPSCs offer a distinctive platform for investigating the origin of cancer, paving the way for novel approaches to cancer treatment, drug testing, and tailored medical interventions. This review article will provide an overview of the science behind iPSCs, the current limitations and challenges in iPSC-based cancer therapy, the ethical and social implications, and the comparative analysis with other stem cell types for cancer treatment. The article will also discuss the applications of iPSCs in tumorigenesis, the future of iPSCs in tumorigenesis research, and highlight successful case studies utilizing iPSCs in tumorigenesis research. The conclusion will summarize the advancements made in iPSC-based tumorigenesis research and the importance of continued investment in iPSC research to unlock the full potential of these cells.
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Affiliation(s)
- Matin Chehelgerdi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Fereshteh Behdarvand Dehkordi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Mohammad Chehelgerdi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran.
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Hamidreza Kabiri
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | | | - Mohammad Abdolvand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Sharareh Salmanizadeh
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar-Jereeb Street, Isfahan, 81746-73441, 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
| | - Anoosha Niazmand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Saba Ahmadi
- Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi, Georgia
| | - Sara Feizbakhshan
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Saber Kabiri
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Nasimeh Vatandoost
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Tayebeh Ranjbarnejad
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
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7
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Zhuang Q, Yang H, Mao Y. The Oncogenesis of Glial Cells in Diffuse Gliomas and Clinical Opportunities. Neurosci Bull 2022; 39:393-408. [PMID: 36229714 PMCID: PMC10043159 DOI: 10.1007/s12264-022-00953-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 06/06/2022] [Indexed: 11/25/2022] Open
Abstract
Glioma is the most common and lethal intrinsic primary tumor of the brain. Its controversial origins may contribute to its heterogeneity, creating challenges and difficulties in the development of therapies. Among the components constituting tumors, glioma stem cells are highly plastic subpopulations that are thought to be the site of tumor initiation. Neural stem cells/progenitor cells and oligodendrocyte progenitor cells are possible lineage groups populating the bulk of the tumor, in which gene mutations related to cell-cycle or metabolic enzymes dramatically affect this transformation. Novel approaches have revealed the tumor-promoting properties of distinct tumor cell states, glial, neural, and immune cell populations in the tumor microenvironment. Communication between tumor cells and other normal cells manipulate tumor progression and influence sensitivity to therapy. Here, we discuss the heterogeneity and relevant functions of tumor cell state, microglia, monocyte-derived macrophages, and neurons in glioma, highlighting their bilateral effects on tumors. Finally, we describe potential therapeutic approaches and targets beyond standard treatments.
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Affiliation(s)
- Qiyuan Zhuang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Hui Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- Institute for Translational Brain Research, Fudan University, Shanghai, 200032, China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
- Neurosurgical Institute of Fudan University, Shanghai, 200032, China.
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8
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Yang K, Liang X, Wen K. Long non‑coding RNAs interact with RNA‑binding proteins to regulate genomic instability in cancer cells (Review). Oncol Rep 2022; 48:175. [PMID: 36004472 PMCID: PMC9478986 DOI: 10.3892/or.2022.8390] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/27/2022] [Indexed: 11/05/2022] Open
Abstract
Genomic instability, a feature of most cancers, contributes to malignant cell transformation and cancer progression due to the accumulation of genetic alterations. Genomic instability is reflected at numerous levels, from single nucleotide to the chromosome levels. However, the exact molecular mechanisms and regulators of genomic instability in cancer remain unclear. Growing evidence indicates that the binding of long non-coding RNAs (lncRNAs) to protein chaperones confers a variety of regulatory functions, including managing of genomic instability. The aim of the present review was to examine the roles of mitosis, telomeres, DNA repair, and epigenetics in genomic instability, and the mechanisms by which lncRNAs regulate them by binding proteins in cancer cells. This review contributes to our understanding of the role of lncRNAs and genomic instability in cancer and can potentially provide entry points and molecular targets for cancer therapies.
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Affiliation(s)
- Kai Yang
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Xiaoxiang Liang
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Kunming Wen
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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Hussain S, Tulsyan S, Dar SA, Sisodiya S, Abiha U, Kumar R, Mishra BN, Haque S. Role of epigenetics in carcinogenesis: Recent advancements in anticancer therapy. Semin Cancer Biol 2022; 83:441-451. [PMID: 34182144 DOI: 10.1016/j.semcancer.2021.06.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 04/29/2021] [Accepted: 06/23/2021] [Indexed: 02/08/2023]
Abstract
The role of epigenetics in the etiology of cancer progression is being emphasized for the past two decades to check the impact of chromatin modifiers and remodelers. Histone modifications, DNA methylation, chromatin remodeling, nucleosome positioning, regulation by non-coding RNAs and precisely microRNAs are influential epigenetic marks in the field of progressive cancer sub-types. Furthermore, constant epigenetic changes due to hyper or hypomethylation could efficiently serve as effective biomarkers of cancer diagnosis and therapeutic development. Ongoing research in the field of epigenetics has resulted in the resolutory role of various epigenetic markers and their inhibition using specific inhibitors to arrest their key cellular functions in in-vitro and pre-clinical studies. Although, the mechanism of epigenetics in cancer largely remains unexplored. Nevertheless, various advancements in the field of epigenetics have been made through transcriptome analysis and in-vitro genome targeting technologies to unravel the applicability of epigenetic markers for future cancer therapeutics and management. Therefore, this review emphasizes on recent advances in epigenetic landscapes that could be targeted/explored using novel approaches as personalized treatment modalities for cancer containment.
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Affiliation(s)
- Showket Hussain
- Division of Molecular Oncology & Molecular Diagnostics, ICMR-National Institute of Cancer Prevention and Research, Noida, India
| | - Sonam Tulsyan
- Division of Molecular Oncology & Molecular Diagnostics, ICMR-National Institute of Cancer Prevention and Research, Noida, India
| | - Sajad Ahmad Dar
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Sandeep Sisodiya
- Division of Molecular Oncology & Molecular Diagnostics, ICMR-National Institute of Cancer Prevention and Research, Noida, India; Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Umme Abiha
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida, India
| | - Rakesh Kumar
- Dr. B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Bhartendu Nath Mishra
- Department of Biotechnology, Institute of Engineering and Technology, Lucknow, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia; Bursa Uludağ University Faculty of Medicine, Görükle Campus, Nilüfer, Bursa, Turkey.
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10
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CBX3 accelerates the malignant progression of glioblastoma multiforme by stabilizing EGFR expression. Oncogene 2022; 41:3051-3063. [PMID: 35459780 DOI: 10.1038/s41388-022-02296-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 03/17/2022] [Accepted: 03/23/2022] [Indexed: 12/13/2022]
Abstract
CBX3, also known as HP1γ, is a major isoform of heterochromatin protein 1, whose deregulation has been reported to promote the development of human cancers. However, the molecular mechanism of CBX3 in glioblastoma multiforme (GBM) are unclear. Our study reported the identification of CBX3 as a potential therapeutic target for GBM. Briefly, we found that, CBX3 is significantly upregulated in GBM and reduces patient survival. In addition, functional assays demonstrated that CBX3 significantly promote the proliferation, invasion and tumorigenesis of GBM cells in vitro and in vivo. Mechanistically, Erlotinib, a small molecule targeting epidermal growth factor receptor (EGFR) tyrosine kinase, was used to demonstrate that CBX3 direct the malignant progression of GBM are EGFR dependent. Previous studies have shown that PARK2(Parkin) and STUB1(Carboxy Terminus of Hsp70-Interacting Protein) are EGFR-specific E3 ligases. Notably, we verified that CBX3 directly suppressed PARK2 and STUB1 at the transcriptional level through its CD domain to reduce the ubiquitination of EGFR. Moreover, the CSD domain of CBX3 interacted with PARK2 and regulated its ubiquitination to further reduce its protein level. Collectively, these results revealed an unknown mechanism underlying the pathogenesis of GBM and confirmed that CBX3 is a promising therapeutic target.
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11
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The association of long non-coding RNA in the prognosis of oral squamous cell carcinoma. Genes Genomics 2022; 44:327-342. [PMID: 35023067 DOI: 10.1007/s13258-021-01194-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 11/17/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Oral cancer is considered one of the most prevalent cancers in India. This is mainly because India suffers from high usage of tobacco, which is one of the main causative agents of oral cancer, and lacks proper health and sexual hygiene in rural areas. DISCUSSION Non-coding RNAs are reported to be involved in the various mechanism and causality of cancer. Numerous reports have identified viable prospects connecting non-coding RNA (ncRNA) with cancer. Specific ncRNAs like long non-coding RNA or lncRNAs are recently being prioritized as potential associations in the cause of cancer. CONCLUSION This review aims at presenting a concise perspective on the basics and the recent advancements of the lncRNA research pertaining specifically to oral cancer, its recurrence, and the future possibilities of knowledge it might possess.
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12
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Hemmati-Dinarvand M, Ahmadvand H, Seghatoleslam A. Nitazoxanide and Cancer Drug Resistance: Targeting Wnt/β-catenin Signaling Pathway. Arch Med Res 2021; 53:263-270. [DOI: 10.1016/j.arcmed.2021.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 11/24/2021] [Accepted: 12/07/2021] [Indexed: 11/02/2022]
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13
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Kuijpers TJM, Kleinjans JCS, Jennen DGJ. From multi-omics integration towards novel genomic interaction networks to identify key cancer cell line characteristics. Sci Rep 2021; 11:10542. [PMID: 34006939 PMCID: PMC8131752 DOI: 10.1038/s41598-021-90047-3] [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: 11/23/2020] [Accepted: 04/26/2021] [Indexed: 11/09/2022] Open
Abstract
Cancer is a complex disease where cancer cells express epigenetic and transcriptomic mechanisms to promote tumor initiation, progression, and survival. To extract relevant features from the 2019 Cancer Cell Line Encyclopedia (CCLE), a multi-layer nonnegative matrix factorization approach is used. We used relevant feature genes and DNA promoter regions to construct genomic interaction network to study gene-gene and gene-DNA promoter methylation relationships. Here, we identified a set of gene transcripts and methylated DNA promoter regions for different clusters, including one homogeneous lymphoid neoplasms cluster. In this cluster, we found different methylated transcription factors that affect transcriptional activation of EGFR and downstream interactions. Furthermore, the hippo-signaling pathway might not function properly because of DNA hypermethylation and low gene expression of both LATS2 and YAP1. Finally, we could identify a potential dysregulation of the CD28-CD86-CTLA4 axis. Characterizing the interaction of the epigenome and the transcriptome is vital for our understanding of cancer cell line behavior, not only for deepening insights into cancer-related processes but also for future disease treatment and drug development. Here we have identified potential candidates that characterize cancer cell lines, which give insight into the development and progression of cancers.
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Affiliation(s)
- T J M Kuijpers
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, the Netherlands.
| | - J C S Kleinjans
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, the Netherlands
| | - D G J Jennen
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, the Netherlands
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14
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Dushanan R, Weerasinghe S, Dissanayake DP, Senthilinithy R. Cracking a cancer code histone deacetylation in epigenetic: the implication from molecular dynamics simulations on efficacy assessment of histone deacetylase inhibitors. J Biomol Struct Dyn 2020; 40:2352-2368. [PMID: 33131428 DOI: 10.1080/07391102.2020.1838328] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Epigenetic changes, histone acetylation and deacetylation in chromatin have been intensively studied due to their significance in regulating the gene expression. According to the type of tumor, the levels of histone deacetylases (HDAC) are varied. HDAC inhibitors are a new promising class of compounds that inhibit the proliferation of tumor cells. In this study, the inhibitory efficacy of some HDAC inhibitors such as vorinostat, panobinostat, abexinostat, belinostat, resminostat, dacinostat and pracinostat was studied using molecular dynamics simulation. The inhibitory efficacy was estimated by computing the enzyme's stability, positional stability of the individual amino acids and interaction energies of HDLP-inhibitor complexes. It is hoped that this investigation may improve our understanding of the atomic-level description of the inhibitor binding site and how the HDAC inhibitors change the environment of the enzyme's active site. The results obtained from the root-mean-square deviation, the radius of gyration, solvent-accessible surface area, root-mean-square fluctuation, stride server and Ramachandran plot have revealed that the stability of HDLP enzyme with vorinostat, panobinostat and abexinostat is higher than the other studied complexes. According to the calculated values for MM-PBSA, LIE, semi-LIE binding free energies and interaction energies, the stability of the HDLP enzyme varies as panobinostat > abexinostat > vorinostat where resminostat complex showed relatively low stability. The ligandability and drugability values also give the same trend as above. The findings revealed that the panobinostat and abexinostat are potential lead compounds as reference inhibitor vorinostat. Therefore, it is possible to use these drugs as HDAC inhibitors in clinical practices. Also, the outcomes of this study could be utilized to identify new inhibitors for clinical research.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Ramachandren Dushanan
- Department of Chemistry, Faculty of Natural Sciences, The Open University of Sri Lanka, Nugegoda, Sri Lanka
| | - Samantha Weerasinghe
- Department of Chemistry, Faculty of Science, University of Colombo, Colombo, Sri Lanka
| | | | - Rajendram Senthilinithy
- Department of Chemistry, Faculty of Natural Sciences, The Open University of Sri Lanka, Nugegoda, Sri Lanka
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15
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Karimzadeh MR, Pourdavoud P, Ehtesham N, Qadbeigi M, Asl MM, Alani B, Mosallaei M, Pakzad B. Regulation of DNA methylation machinery by epi-miRNAs in human cancer: emerging new targets in cancer therapy. Cancer Gene Ther 2020; 28:157-174. [PMID: 32773776 DOI: 10.1038/s41417-020-00210-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 07/24/2020] [Accepted: 07/29/2020] [Indexed: 12/13/2022]
Abstract
Disruption in DNA methylation processes can lead to alteration in gene expression and function that would ultimately result in malignant transformation. In this way, studies have shown that, in cancers, methylation-associated silencing inactivates tumor suppressor genes, as effectively as mutations. DNA methylation machinery is composed of several genes, including those with DNA methyltransferases activity, proteins that bind to methylated cytosine in the promoter region, and enzymes with demethylase activity. Based on a prominent body of evidence, DNA methylation machinery could be regulated by microRNAs (miRNAs) called epi-miRNAs. Numerous studies demonstrated that dysregulation in DNA methylation regulators like upstream epi-miRNAs is indispensable for carcinogenesis; consequently, the malignant capacity of these cells could be reversed by restoring of this regulatory system in cancer. Conceivably, recognition of these epi-miRNAs in cancer cells could not only reveal novel molecular entities in carcinogenesis, but also render promising targets for cancer therapy. In this review, at first, we have an overview of the methylation alteration in cancers, and the effect of this phenomenon in miRNAs expression and after that, we conduct an in-depth discussion about the regulation of DNA methylation regulators by epi-miRNAs in cancer cells.
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Affiliation(s)
- Mohammad Reza Karimzadeh
- Department of medical Genetics, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | | | - Naeim Ehtesham
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Masood Movahedi Asl
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Behrang Alani
- Department of Applied Cell Sciences, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Meysam Mosallaei
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Bahram Pakzad
- Department of Internal Medicine, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran.
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16
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Renzi A, Morandi L, Lenzi J, Rigillo A, Bettini G, Bellei E, Giacomini A, Tinto D, Sabattini S. Analysis of DNA methylation and TP53 mutational status for differentiating feline oral squamous cell carcinoma from non-neoplastic mucosa: A preliminary study. Vet Comp Oncol 2020; 18:825-837. [PMID: 32506786 DOI: 10.1111/vco.12624] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/13/2020] [Accepted: 06/02/2020] [Indexed: 12/14/2022]
Abstract
Feline oral squamous cell carcinoma (FOSCC) is characterized by high local invasiveness and early bone lysis. The late diagnosis largely limits the efficacy of therapy and increases treatment-related morbidity. The aim of this exploratory study was to assess the methylation pattern of 10 candidate genes and TP53 mutational status in histologic samples of FOSCC. Results were compared with normal oral mucosa and oral inflammatory lesions, in order to establish a gene panel for FOSCC detection. For 10 cats, the above analyses were also performed on oral brushing samples, in order to explore the utility of these methods for screening purposes. Thirty-one FOSCC, 25 chronic inflammatory lesions and 12 controls were included. TP53 mutations were significantly more frequent in the FOSCC (68%) than in the non-neoplastic oral mucosa (3%; P <.001). Based on lasso regression analysis, a step-wise algorithm including TP53, FLI1, MiR124-1, KIF1A and MAGEC2 was proposed. The algorithm allowed to differentiate FOSCC with 94% sensitivity and 100% specificity (accuracy, 97%). When applying the proposed algorithm on 10 brushing samples, accuracy decreased to 80%. These results indicate that the altered DNA methylation of specific genes is present in FOSCC, together with a significant proportion of TP53 mutations. Such alterations are infrequent in normal oral mucosa and chronic stomatitis in cats, suggesting their involvement in feline oral carcinogenesis and their utility as diagnostic biomarkers. Further studies on a high number of brushing samples will be needed to assess the utility of a screening test for the early detection of FOSCC.
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Affiliation(s)
- Andrea Renzi
- Department of Veterinary Medical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Luca Morandi
- Department of Biomedical and Neuromotor Sciences, Functional MR Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Jacopo Lenzi
- Department of Biomedical and Neuromotor Sciences, Section of Hygiene, Public Health and Medical Statistics, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Antonella Rigillo
- Department of Veterinary Medical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Giuliano Bettini
- Department of Veterinary Medical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Emma Bellei
- Department of Veterinary Medical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Alessandra Giacomini
- Department of Veterinary Medical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Debora Tinto
- Department of Veterinary Medical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Silvia Sabattini
- Department of Veterinary Medical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
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17
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Rezaei S, Hosseinpourfeizi MA, Moaddab Y, Safaralizadeh R. Contribution of DNA methylation and EZH2 in SRBC down-regulation in gastric cancer. Mol Biol Rep 2020; 47:5721-5727. [PMID: 32676814 DOI: 10.1007/s11033-020-05619-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 06/22/2020] [Indexed: 12/16/2022]
Abstract
Gastric cancer (GC), a high mortality malignancy, is induced by genetic and epigenetic factors. DNA and histone methylation play critical roles in tumor suppressor genes inactivation. SRBC (serum deprivation response factor-related gene product that binds to the c-kinase), suggested as a tumor suppressor gene, participates in apoptosis, tumor chemoresistance and DNA damage response and is repressed in various cancers. Inspecting the mechanisms underlying SRBC suppression is important for cancer treatments. We investigated SRBC promoter DNA methylation status and expression of SRBC and EZH2 histone methyltrasferase in gastric cancer. Also, we surveyed SRBC expression after 5-azacitidine and UNC1999 treatments of AGS cell line. In current work, we used gastric adenocarcinoma tissues, marginal samples and normal gastric biopsies. DNA methylation was detected by Methylation- Specific PCR and mRNA expression was measured by Real-Time PCR. SRBC promoter methylation analysis, showed fully and partial methylated versions that were associated with patient's age (p = 0.001). SRBC expression significantly decreased in GC compare with marginal and normal samples (p-value < 0.001). EZH2 showed remarkable up-regulation in GC than controls and demonstrated a strong inverse correlation with SRBC expression (r = - 0.69). Restoration of SRBC expression was observed after 5-azacitidine and UNC1999 applications with a remarkable increase by combinational treatment. We showed that EZH2 plays role in SRBC silencing in addition to DNA methylation. Our study, suggests that DNA methylation and EZH2 are involved in SRBC silencing and their inhibitors can be considered in cancer treatment investigations to overcome chemoresistance induced by SRBC inactivation.
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Affiliation(s)
- Shiva Rezaei
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | - Yaghoub Moaddab
- Liver and Gastroenterology Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
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18
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Eshghifar N, Badrlou E, Pouresmaeili F. The roles of miRNAs' clinical efficiencies in the colorectal cancer pathobiology: A review article. Hum Antibodies 2020; 28:273-285. [PMID: 32623393 DOI: 10.3233/hab-200417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
MiRNAs (microRNAs) are defined as micro directors and regulators of gene expression. Since altered miRNA expression is signified in the pathobiology of diverse cancers such as colorectal cancers (CRCs), these molecules are described as therapeutic targets, either. Manipulation of miRNAs could lead to further therapy for chemo and radio-resistant CRCs. The usage of microRNAs has indicated prominent promise in the prognosis and diagnosis of CRC, because of their unique expression pattern associated with cancer types and malignancies. Nowadays, many researchers are analyzing the correlation between miRNA polymorphisms and cancer risk. With continuous incompatibility in colorectal cancer (CRC) miRNAs expression data, it is critical to move toward the content of a "pre-laboratory" analysis to speed up efficient accuracy medicine and translational study. Pathway study for the highest expressed miRNAs- regulated target genes resulted in the identification of a considerable number of genes associated with CRC pathway including PI3K, TGFβ, and APC. In this review, we aimed to collect fruitful information about miRNAs and their potential roles in CRC, and provide a meta-analysis of the most frequently studied miRNAs in association with the disease.
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Affiliation(s)
- Nahal Eshghifar
- Department of Molecular and Cellular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elham Badrlou
- Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farkhondeh Pouresmaeili
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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19
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Ashrafizadeh M, Rafiei H, Mohammadinejad R, Farkhondeh T, Samarghandian S. Wnt-regulating microRNAs role in gastric cancer malignancy. Life Sci 2020; 250:117547. [PMID: 32173311 DOI: 10.1016/j.lfs.2020.117547] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 03/06/2020] [Accepted: 03/11/2020] [Indexed: 02/06/2023]
Abstract
Gastric cancer (GC) is responsible for high morbidity and mortality worldwide. This cancer claims fifth place among other cancers. There are a number of factors associated with GC development such as alcohol consumption and tobacco smoking. It seems that genetic factors play significant role in GC malignancy and progression. MicroRNAs (miRs) are short non-coding RNA molecules with negative impact on the expression of target genes. A variety of studies have elucidated the potential role of miRs in GC growth. Investigation of molecular pathways has revealed that miRs function as upstream modulators of Wnt signaling pathway. This signaling pathway involves in important biological processes such as cell proliferation and differentiation, and its dysregulation is associated with GC invasion. At the present review, we demonstrate that how miRs regulate Wnt signaling pathway in GC malignancy.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Hossein Rafiei
- Department of Biology, Faculty of Sciences, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Reza Mohammadinejad
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Tahereh Farkhondeh
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Saeed Samarghandian
- Healthy Ageing Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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20
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Dzobo K. Epigenomics-Guided Drug Development: Recent Advances in Solving the Cancer Treatment "jigsaw puzzle". OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2020; 23:70-85. [PMID: 30767728 DOI: 10.1089/omi.2018.0206] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The human epigenome plays a key role in determining cellular identity and eventually function. Drug discovery undertakings have focused mainly on the role of genomics in carcinogenesis, with the focus turning to the epigenome recently. Drugs targeting DNA and histone modifications are under development with some such as 5-azacytidine, decitabine, vorinostat, and panobinostat already approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This expert review offers a critical analysis of the epigenomics-guided drug discovery and development and the opportunities and challenges for the next decade. Importantly, the coupling of epigenetic editing techniques, such as clustered regularly interspersed short palindromic repeat (CRISPR)-CRISPR-associated protein-9 (Cas9) and APOBEC-coupled epigenetic sequencing (ACE-seq) with epigenetic drug screens, will allow the identification of small-molecule inhibitors or drugs able to reverse epigenetic changes responsible for many diseases. In addition, concrete and sustainable innovation in cancer treatment ought to integrate epigenome targeting drugs with classic therapies such as chemotherapy and immunotherapy.
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Affiliation(s)
- Kevin Dzobo
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.,2 Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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21
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Gorokhova E, Martella G, Motwani NH, Tretyakova NY, Sundelin B, Motwani HV. DNA epigenetic marks are linked to embryo aberrations in amphipods. Sci Rep 2020; 10:655. [PMID: 31959811 PMCID: PMC6971077 DOI: 10.1038/s41598-020-57465-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 12/26/2019] [Indexed: 11/22/2022] Open
Abstract
Linking exposure to environmental stress factors with diseases is crucial for proposing preventive and regulatory actions. Upon exposure to anthropogenic chemicals, covalent modifications on the genome can drive developmental and reproductive disorders in wild populations, with subsequent effects on the population persistence. Hence, screening of chemical modifications on DNA can be used to provide information on the probability of such disorders in populations of concern. Using a high-resolution mass spectrometry methodology, we identified DNA nucleoside adducts in gravid females of the Baltic amphipods Monoporeia affinis, and linked the adduct profiles to the frequency of embryo malformations in the broods. Twenty-three putative nucleoside adducts were detected in the females and their embryos, and eight modifications were structurally identified using high-resolution accurate mass data. To identify which adducts were significantly associated with embryo malformations, partial least squares regression (PLSR) modelling was applied. The PLSR model yielded three adducts as the key predictors: methylation at two different positions of the DNA (5-methyl-2'-deoxycytidine and N6-methyl-2'-deoxyadenosine) representing epigenetic marks, and a structurally unidentified nucleoside adduct. These adducts predicted the elevated frequency of the malformations with a high classification accuracy (84%). To the best of our knowledge, this is the first application of DNA adductomics for identification of contaminant-induced malformations in field-collected animals. The method can be adapted for a broad range of species and evolve as a new omics tool in environmental health assessment.
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Affiliation(s)
- Elena Gorokhova
- Department of Environmental Science and Analytical Chemistry, Stockholm University, Stockholm, SE, 10691, Sweden
| | - Giulia Martella
- Department of Environmental Science and Analytical Chemistry, Stockholm University, Stockholm, SE, 10691, Sweden
| | - Nisha H Motwani
- Department of Environmental Science and Analytical Chemistry, Stockholm University, Stockholm, SE, 10691, Sweden
| | - Natalia Y Tretyakova
- Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, United States
| | - Brita Sundelin
- Department of Environmental Science and Analytical Chemistry, Stockholm University, Stockholm, SE, 10691, Sweden
| | - Hitesh V Motwani
- Department of Environmental Science and Analytical Chemistry, Stockholm University, Stockholm, SE, 10691, Sweden.
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22
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Tsagiopoulou M, Papakonstantinou N, Moysiadis T, Mansouri L, Ljungström V, Duran-Ferrer M, Malousi A, Queirós AC, Plevova K, Bhoi S, Kollia P, Oscier D, Anagnostopoulos A, Trentin L, Ritgen M, Pospisilova S, Stavroyianni N, Ghia P, Martin-Subero JI, Pott C, Rosenquist R, Stamatopoulos K. DNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy. Clin Epigenetics 2019; 11:177. [PMID: 31791414 PMCID: PMC6889736 DOI: 10.1186/s13148-019-0783-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 11/19/2019] [Indexed: 01/01/2023] Open
Abstract
Background In order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen. Results The extent of identified changes in CLL cells versus memory B cells from healthy donors was termed “epigenetic burden” (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed “relapse changes” (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology. Conclusions Overall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features.
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Affiliation(s)
- Maria Tsagiopoulou
- Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece.,Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikos Papakonstantinou
- Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece
| | - Theodoros Moysiadis
- Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece.,Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Larry Mansouri
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Viktor Ljungström
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Martí Duran-Ferrer
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain
| | - Andigoni Malousi
- Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ana C Queirós
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain
| | - Karla Plevova
- Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Medical Faculty of Masaryk University, Brno, Czech Republic.,Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Sujata Bhoi
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Panagoula Kollia
- Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - David Oscier
- Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK
| | | | - Livio Trentin
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy
| | - Matthias Ritgen
- Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Sarka Pospisilova
- Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Medical Faculty of Masaryk University, Brno, Czech Republic.,Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Niki Stavroyianni
- Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
| | - Paolo Ghia
- Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy
| | - Jose I Martin-Subero
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Fundamentos Clínicos, Universitat de Barcelona, Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Christiane Pott
- Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Richard Rosenquist
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Kostas Stamatopoulos
- Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece. .,Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
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23
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Begolli R, Sideris N, Giakountis A. LncRNAs as Chromatin Regulators in Cancer: From Molecular Function to Clinical Potential. Cancers (Basel) 2019; 11:E1524. [PMID: 31658672 PMCID: PMC6826483 DOI: 10.3390/cancers11101524] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 09/28/2019] [Accepted: 10/06/2019] [Indexed: 12/15/2022] Open
Abstract
During the last decade, high-throughput sequencing efforts in the fields of transcriptomics and epigenomics have shed light on the noncoding part of the transcriptome and its potential role in human disease. Regulatory noncoding RNAs are broadly divided into short and long noncoding transcripts. The latter, also known as lncRNAs, are defined as transcripts longer than 200 nucleotides with low or no protein-coding potential. LncRNAs form a diverse group of transcripts that regulate vital cellular functions through interactions with proteins, chromatin, and even RNA itself. Notably, an important regulatory aspect of these RNA species is their association with the epigenetic machinery and the recruitment of its regulatory apparatus to specific loci, resulting in DNA methylation and/or post-translational modifications of histones. Such epigenetic modifications play a pivotal role in maintaining the active or inactive transcriptional state of chromatin and are crucial regulators of normal cellular development and tissue-specific gene expression. Evidently, aberrant expression of lncRNAs that interact with epigenetic modifiers can cause severe epigenetic disruption and is thus is closely associated with altered gene function, cellular dysregulation, and malignant transformation. Here, we survey the latest breakthroughs concerning the role of lncRNAs interacting with the epigenetic machinery in various forms of cancer.
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Affiliation(s)
- Rodiola Begolli
- Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece.
| | - Nikos Sideris
- Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece.
| | - Antonis Giakountis
- Department of Biochemistry and Biotechnology, University of Thessaly, Biopolis, 41500 Larissa, Greece.
- B.S.R.C "Alexander Fleming", 34 Fleming str, 16672 Vari, Greece.
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24
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Ahn HJ, Hwang SY, Nguyen NH, Lee IJ, Lee EJ, Seong J, Lee JS. Radiation-Induced CXCL12 Upregulation via Histone Modification at the Promoter in the Tumor Microenvironment of Hepatocellular Carcinoma. Mol Cells 2019; 42:530-545. [PMID: 31362469 PMCID: PMC6681868 DOI: 10.14348/molcells.2019.2280] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 05/28/2019] [Accepted: 06/19/2019] [Indexed: 02/07/2023] Open
Abstract
Tumor cells can vary epigenetically during ionizing irradiation (IR) treatment. These epigenetic variegations can influence IR response and shape tumor aggressiveness. However, epigenetic disturbance of histones after IR, implicating in IR responsiveness, has been elusive. Here, we investigate whether altered histone modification after IR can influence radiation responsiveness. The oncogenic CXCL12 mRNA and protein were more highly expressed in residual cancer cells from a hepatoma heterotopic murine tumor microenvironment and coculture of human hepatoma Huh7 and normal IMR90 cells after radiation. H3K4 methylation was also enriched and H3K9 methylation was decreased at its promoter region. Accordingly, invasiveness and the subpopulation of aggressive CD133+/CD24- cells increased after IR. Histone demethylase inhibitor IOX1 attenuated CXCL12 expression and the malignant subpopulation, suggesting that responses to IR can be partially mediated via histone modifications. Taken together, radiation-induced histone alterations at the CXCL12 promoter in hepatoma cells are linked to CXCL12 upregulation and increased aggressiveness in the tumor microenvironment.
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MESH Headings
- Animals
- Benzylamines
- CCAAT-Enhancer-Binding Protein-beta/metabolism
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Cell Survival/drug effects
- Cell Survival/radiation effects
- Chemokine CXCL12/genetics
- Chemokine CXCL12/metabolism
- Cyclams
- Epigenesis, Genetic/radiation effects
- Gene Expression Regulation, Neoplastic/radiation effects
- Heterocyclic Compounds/pharmacology
- Histones/metabolism
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Male
- Mice
- Mice, Nude
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Neoplastic Stem Cells/radiation effects
- Promoter Regions, Genetic
- Protein Processing, Post-Translational/radiation effects
- Receptors, CXCR4/antagonists & inhibitors
- Receptors, CXCR4/metabolism
- Recombinant Proteins/pharmacology
- Transcription, Genetic/radiation effects
- Tumor Microenvironment/genetics
- Tumor Microenvironment/radiation effects
- Up-Regulation/genetics
- X-Rays
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Affiliation(s)
- Hak Jun Ahn
- Department of Life Science, College of Natural Sciences, Ajou University, Suwon 16499,
Korea
| | - Soon Young Hwang
- Department of Life Science, College of Natural Sciences, Ajou University, Suwon 16499,
Korea
- Functional Cellunomics Institute, Ajou University, Suwon 16499,
Korea
| | - Ngoc Hoan Nguyen
- Department of Life Science, College of Natural Sciences, Ajou University, Suwon 16499,
Korea
| | - Ik Jae Lee
- Department of Radiation Oncology, Yonsei University Medical College, Yonsei University Health System, Seoul 03722,
Korea
| | - Eun Jeong Lee
- Department of Radiation Oncology, Yonsei University Medical College, Yonsei University Health System, Seoul 03722,
Korea
| | - Jinsil Seong
- Department of Radiation Oncology, Yonsei University Medical College, Yonsei University Health System, Seoul 03722,
Korea
| | - Jong-Soo Lee
- Department of Life Science, College of Natural Sciences, Ajou University, Suwon 16499,
Korea
- Functional Cellunomics Institute, Ajou University, Suwon 16499,
Korea
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25
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Prognostic Role of miR-221 and miR-222 Expression in Cancer Patients: A Systematic Review and Meta-Analysis. Cancers (Basel) 2019; 11:cancers11070970. [PMID: 31336701 PMCID: PMC6678869 DOI: 10.3390/cancers11070970] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 07/08/2019] [Indexed: 12/13/2022] Open
Abstract
Background: A wealth of evidence has shown that microRNAs (miRNAs) can modulate specific genes, increasing our knowledge on the fine-tuning regulation of protein expression. miR-221 and miR-222 have been frequently identified as deregulated across different cancer types; however, their prognostic significance in cancer remains controversial. In view of these considerations, we performed an updated systematic review and meta-analysis of published data investigating the effects of miR-221/222 on overall survival (OS) and other secondary outcomes among cancer patients. A systematic search of PubMed, Web of Knowledge, and Cochrane Library databases was performed. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Results: Fifty studies, analyzing 6086 patients, were included in the systematic review. Twenty-five studies for miR-221 and 17 studies for miR-222 which assessed OS were included in the meta-analysis. High expression of miR-221 and miR-222 significantly predicted poor OS (HR: 1.48, 95% CI: 1.14–1.93, p = 0.003 and HR: 1.90, 95% CI: 1.43–2.54, p < 0.001, respectively). Subgroup analysis revealed that the finding on miR-221 was not as robust as the one on miR-222. Furthermore, high miR-222 expression was also associated with worse progression-free survival and disease-free survival pooled with recurrence-free survival. Conclusions: The meta-analysis demonstrated that high expression of miR-222 is associated with poor prognosis in cancer patients, whereas the significance of miR-221 remains unclear. More work is required to fully elucidate the role of miR-221 and miR-222 in cancer prognosis, particularly in view of the limitations of existing results, including the significant heterogeneity and limited number of studies for some cancers.
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26
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Zhou JW, Wang M, Sun NX, Qing Y, Yin TF, Li C, Wu D. Sulforaphane-induced epigenetic regulation of Nrf2 expression by DNA methyltransferase in human Caco-2 cells. Oncol Lett 2019; 18:2639-2647. [PMID: 31452747 DOI: 10.3892/ol.2019.10569] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 05/24/2019] [Indexed: 12/24/2022] Open
Abstract
The present study aimed to investigate the mechanism underlying sulforaphane-mediated epigenetic regulation of nuclear factor-erythroid derived 2-like 2 (Nrf2) expression in human colon cancer. Proteins were extracted from normal Caco-2 cells using sulforaphane and 5-aza-2'-deoxycytidine (5-Aza) combined with trichostatin A (TSA). The mRNA and protein expression levels and activity of DNA methyltransferase 1 (DNMT1) were determined. Methylation-specific polymerase chain reaction and bisulfite genomic sequencing were also used to measure the methylation levels of CpG sites in the Nrf2 promoter region. Nrf2 expression was measured using reverse transcription-quantitative PCR and western blot analysis. The results demonstrated that sulforaphane did not affect DNMT1 mRNA expression levels. DNMT1 protein expression was inhibited by sulforaphane and 5-Aza co-treatment with TSA. Nrf2 promoter methylation decreased significantly in the sulforaphane group compared with the control group. Nrf2 promoter methylation level in the 5-Aza+TSA group was the lowest among all groups. Nrf2 mRNA levels exhibited significant differences between the sulforaphane-treated and control groups, as well as between the 5-Aza+TSA and control groups, and the sulforaphane-treated and 5-Aza+TSA groups. Nrf2 protein expression was also inhibited by sulforaphane, as well as 5-Aza co-treatment with TSA. The results revealed that sulforaphane may promote demethylation of the Nrf2 promoter region to increase activation of Nrf2, which induces chemoprevention of colon cancer.
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Affiliation(s)
- Jia-Wei Zhou
- Medical School, Qi-Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Min Wang
- Department of of Geriatric Gastroenterology, Qi-Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,Department of General Practice, Qi-Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Nuan-Xin Sun
- Jiangxi Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Ying Qing
- Department of General Practice, Qi-Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Teng-Fei Yin
- Department of General Practice, Qi-Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Cui Li
- Department of General Practice, Qi-Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Dong Wu
- Department of General Surgery, Qi-Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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27
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Condelli V, Crispo F, Pietrafesa M, Lettini G, Matassa DS, Esposito F, Landriscina M, Maddalena F. HSP90 Molecular Chaperones, Metabolic Rewiring, and Epigenetics: Impact on Tumor Progression and Perspective for Anticancer Therapy. Cells 2019; 8:cells8060532. [PMID: 31163702 PMCID: PMC6627532 DOI: 10.3390/cells8060532] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 05/30/2019] [Accepted: 05/31/2019] [Indexed: 12/31/2022] Open
Abstract
Heat shock protein 90 (HSP90) molecular chaperones are a family of ubiquitous proteins participating in several cellular functions through the regulation of folding and/or assembly of large multiprotein complexes and client proteins. Thus, HSP90s chaperones are, directly or indirectly, master regulators of a variety of cellular processes, such as adaptation to stress, cell proliferation, motility, angiogenesis, and signal transduction. In recent years, it has been proposed that HSP90s play a crucial role in carcinogenesis as regulators of genotype-to-phenotype interplay. Indeed, HSP90 chaperones control metabolic rewiring, a hallmark of cancer cells, and influence the transcription of several of the key-genes responsible for tumorigenesis and cancer progression, through either direct binding to chromatin or through the quality control of transcription factors and epigenetic effectors. In this review, we will revise evidence suggesting how this interplay between epigenetics and metabolism may affect oncogenesis. We will examine the effect of metabolic rewiring on the accumulation of specific metabolites, and the changes in the availability of epigenetic co-factors and how this process can be controlled by HSP90 molecular chaperones. Understanding deeply the relationship between epigenetic and metabolism could disclose novel therapeutic scenarios that may lead to improvements in cancer treatment.
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Affiliation(s)
- Valentina Condelli
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy.
| | - Fabiana Crispo
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy.
| | - Michele Pietrafesa
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy.
| | - Giacomo Lettini
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy.
| | - Danilo Swann Matassa
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
| | - Franca Esposito
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
| | - Matteo Landriscina
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy.
- Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy.
| | - Francesca Maddalena
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, Italy.
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28
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Robles Bayón A, Gude Sampedro F. New evidence of the relative protective effects of neurodegenerative diseases and cancer against each other. NEUROLOGÍA (ENGLISH EDITION) 2019. [DOI: 10.1016/j.nrleng.2017.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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29
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Lu QR, Qian L, Zhou X. Developmental origins and oncogenic pathways in malignant brain tumors. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2019; 8:e342. [PMID: 30945456 DOI: 10.1002/wdev.342] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 02/20/2019] [Accepted: 03/08/2019] [Indexed: 12/21/2022]
Abstract
Brain tumors such as adult glioblastomas and pediatric high-grade gliomas or medulloblastomas are among the leading causes of cancer-related deaths, exhibiting poor prognoses with little improvement in outcomes in the past several decades. These tumors are heterogeneous and can be initiated from various neural cell types, contributing to therapy resistance. How such heterogeneity arises is linked to the tumor cell of origin and their genetic alterations. Brain tumorigenesis and progression recapitulate key features associated with normal neurogenesis; however, the underlying mechanisms are quite dysregulated as tumor cells grow and divide in an uncontrolled manner. Recent comprehensive genomic, transcriptomic, and epigenomic studies at single-cell resolution have shed new light onto diverse tumor-driving events, cellular heterogeneity, and cells of origin in different brain tumors. Primary and secondary glioblastomas develop through different genetic alterations and pathways, such as EGFR amplification and IDH1/2 or TP53 mutation, respectively. Mutations such as histone H3K27M impacting epigenetic modifications define a distinct group of pediatric high-grade gliomas such as diffuse intrinsic pontine glioma. The identification of distinct genetic, epigenomic profiles and cellular heterogeneity has led to new classifications of adult and pediatric brain tumor subtypes, affording insights into molecular and lineage-specific vulnerabilities for treatment stratification. This review discusses our current understanding of tumor cells of origin, heterogeneity, recurring genetic and epigenetic alterations, oncogenic drivers and signaling pathways for adult glioblastomas, pediatric high-grade gliomas, and medulloblastomas, the genetically heterogeneous groups of malignant brain tumors. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Signaling Pathways > Cell Fate Signaling.
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Affiliation(s)
- Q Richard Lu
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Lily Qian
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Xianyao Zhou
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, Sichuan University, Chengdu, China.,Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
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30
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Epiphanio TMF, Fernandes NCCDA, de Oliveira TF, Lopes PA, Réssio RA, Gonçalves S, Scattone NV, Tedardi MV, Kulikowski LD, Damasceno J, Loureiro APDM, Dagli MLZ. Global DNA methylation of peripheral blood leukocytes from dogs bearing multicentric non-Hodgkin lymphomas and healthy dogs: A comparative study. PLoS One 2019; 14:e0211898. [PMID: 30908498 PMCID: PMC6433272 DOI: 10.1371/journal.pone.0211898] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 01/22/2019] [Indexed: 12/31/2022] Open
Abstract
Non-Hodgkin lymphomas are among the most common types of tumors in dogs, and they are currently accepted as comparative models of the disease in humans. Aberrant patterns of DNA methylation seem to play a key role in the development of hematopoietic neoplasms in humans, constitute a special mechanism of transcriptional control, and may be influenced by genetic and environmental factors. Blood leukocyte DNA global methylation has been poorly investigated in dogs. The aim of this study is to examine whether peripheral blood global DNA methylation is associated with canine multicentric lymphomas. Peripheral venous blood samples from ten healthy dogs and nine dogs bearing multicentric lymphomas were collected, and the buffy coat was separated. Global DNA methylation was analyzed by High Performance Liquid Chromatography (HPLC) and immunocytochemistry (ICC). In both analyses, leukocytes from dogs with lymphoma presented lower global DNA methylation than in healthy dogs (HPLC: p = 0.027/ 5MeCyt immunoreactivity scores: p = 0.015). Moderate correlation was observed between the results obtained by HPLC and ICC (correlation coefficient = 0.50). For the identification of differently methylated genes between both groups, the Infinium Human Methylation (HM) EPIC BeadChip (850K) was used. Of the 853,307 CpGs investigated in the microarray, there were 34,574 probes hybridized in the canine samples. From this total, significant difference was observed in the methylation level of 8433 regions, and through the homologous and orthologous similarities 525 differently methylated genes were identified between the two groups. This study is pioneer in suggesting that dogs bearing non-Hodgkin lymphoma presented DNA global hypomethylation of circulating leukocytes compared with healthy dogs. Although canine samples were used in an assay developed specifically for human DNA, it was possible to identify differently methylated genes and our results reiterate the importance of the use of peripheral blood leukocytes in cancer research and possible new biomarkers targets.
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Affiliation(s)
| | | | - Tiago Franco de Oliveira
- Department of Pharmacoscience, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Priscila Assis Lopes
- Veterinary Laboratory, Veterinary Image Institute, IVI, São Paulo, São Paulo, Brazil
| | | | - Simone Gonçalves
- Veterinary Hemotherapy Center, Hemovet, São Paulo, São Paulo, Brazil
| | - Náyra Villar Scattone
- Laboratory of Experimental and Comparative Oncology, Department of Pathology, University of São Paulo, São Paulo, São Paulo, Brazil
| | - Marcello Vannucci Tedardi
- Laboratory of Experimental and Comparative Oncology, Department of Pathology, University of São Paulo, São Paulo, São Paulo, Brazil
| | | | - Jullian Damasceno
- Cytogenomic Laboratory, Department of Pathology, University of São Paulo, São Paulo, São Paulo, Brazil
| | - Ana Paula de Melo Loureiro
- Department of Clinical and Toxicological Analysis, University of São Paulo, São Paulo, São Paulo, Brazil
| | - Maria Lucia Zaidan Dagli
- Laboratory of Experimental and Comparative Oncology, Department of Pathology, University of São Paulo, São Paulo, São Paulo, Brazil
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31
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Kobets T, Iatropoulos MJ, Williams GM. Mechanisms of DNA-reactive and epigenetic chemical carcinogens: applications to carcinogenicity testing and risk assessment. Toxicol Res (Camb) 2019; 8:123-145. [PMID: 30997017 PMCID: PMC6417487 DOI: 10.1039/c8tx00250a] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Accepted: 12/18/2018] [Indexed: 01/03/2023] Open
Abstract
Chemicals with carcinogenic activity in either animals or humans produce increases in neoplasia through diverse mechanisms. One mechanism is reaction with nuclear DNA. Other mechanisms consist of epigenetic effects involving either modifications of regulatory macromolecules or perturbation of cellular regulatory processes. The basis for distinguishing between carcinogens that have either DNA reactivity or an epigenetic activity as their primary mechanism of action is detailed in this review. In addition, important applications of information on these mechanisms of action to carcinogenicity testing and human risk assessment are discussed.
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Affiliation(s)
- Tetyana Kobets
- Department of Pathology , New York Medical College , Valhalla , NY 10595 , USA . ; ; Tel: +1 914-594-3105
| | - Michael J Iatropoulos
- Department of Pathology , New York Medical College , Valhalla , NY 10595 , USA . ; ; Tel: +1 914-594-3105
| | - Gary M Williams
- Department of Pathology , New York Medical College , Valhalla , NY 10595 , USA . ; ; Tel: +1 914-594-3105
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32
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33
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Insights from epigenetic studies on human health and evolution. Curr Opin Genet Dev 2018; 53:36-42. [DOI: 10.1016/j.gde.2018.06.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 06/01/2018] [Accepted: 06/08/2018] [Indexed: 12/28/2022]
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34
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Zhao Y, Dong Q, Li J, Zhang K, Qin J, Zhao J, Sun Q, Wang Z, Wartmann T, Jauch KW, Nelson PJ, Qin L, Bruns C. Targeting cancer stem cells and their niche: perspectives for future therapeutic targets and strategies. Semin Cancer Biol 2018; 53:139-155. [PMID: 30081228 DOI: 10.1016/j.semcancer.2018.08.002] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 07/30/2018] [Accepted: 08/02/2018] [Indexed: 02/07/2023]
Abstract
A small subpopulation of cells within the bulk of tumors share features with somatic stem cells, in that, they are capable of self-renewal, they differentiate, and are highly resistant to conventional therapy. These cells have been referred to as cancer stem cells (CSCs). Recent reports support the central importance of a cancer stem cell-like niche that appears to help foster the generation and maintenance of CSCs. In response to signals provided by this microenvironment, CSCs express the tumorigenic characteristics that can drive tumor metastasis by the induction of epithelial-mesenchymal-transition (EMT) that in turn fosters the migration and recolonization of the cells as secondary tumors within metastatic niches. We summarize here recent advances in cancer stem cell research including the characterization of their genetic and epigenetic features, metabolic specialities, and crosstalk with aging-associated processes. Potential strategies for targeting CSCs, and their niche, by regulating CSCs plasticity, or therapeutic sensitivity is discussed. Finally, it is hoped that new strategies and related therapeutic approaches as outlined here may help prevent the formation of the metastatic niche, as well as counter tumor progression and metastatic growth.
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Affiliation(s)
- Yue Zhao
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany; Department of Surgery, Otto-von-Guericke University, Magdeburg, Germany.
| | - Qiongzhu Dong
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jiahui Li
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Kaili Zhang
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jie Qin
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Jiangang Zhao
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany; Department of General, Visceral und Vascular Surgery, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Qiye Sun
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Zhefang Wang
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Thomas Wartmann
- Department of Surgery, Otto-von-Guericke University, Magdeburg, Germany
| | - Karl Walter Jauch
- Department of General, Visceral und Vascular Surgery, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - Peter J Nelson
- Medizinische Klinik und Poliklinik IV, Ludwig-Maximilian-University (LMU), Munich, Germany
| | - LunXiu Qin
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Christiane Bruns
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany.
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35
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Favero G, Moretti E, Bonomini F, Reiter RJ, Rodella LF, Rezzani R. Promising Antineoplastic Actions of Melatonin. Front Pharmacol 2018; 9:1086. [PMID: 30386235 PMCID: PMC6198052 DOI: 10.3389/fphar.2018.01086] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 09/06/2018] [Indexed: 12/19/2022] Open
Abstract
Melatonin is an endogenous indoleamine with an incredible variety of properties and activities. In recent years, an increasing number of studies have investigated this indoleamine’s interaction with cancerous cells. In particular, it seems that melatonin not only has the ability to improve the efficacy of many drugs used in chemotherapy but also has a direct inhibitory action on neoplastic cells. Many publications underlined the ability of melatonin to suppress the proliferation of various cancer cells or to modulate the expression of membrane receptors on these cells, thereby reducing tumor aggressiveness to metastasize. In addition, while melatonin has antiapoptotic actions in normal cells, in many cancer cells it has proapoptotic effects; these dichotomous actions have gained the interest of researchers. The increasing focus on melatonin in the field of oncology and the growing number of studies on this topic require a deep understanding of what we already know about the antineoplastic actions of melatonin. This information would be of value for potential use of melatonin against neoplastic diseases.
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Affiliation(s)
- Gaia Favero
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Enrico Moretti
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Francesca Bonomini
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.,Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs," University of Brescia, Brescia, Italy
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health Science Center, San Antonio, TX, United States
| | - Luigi Fabrizio Rodella
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.,Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs," University of Brescia, Brescia, Italy
| | - Rita Rezzani
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.,Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs," University of Brescia, Brescia, Italy
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36
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Abbaszadegan MR, Taghehchian N, Li L, Aarabi A, Moghbeli M. Contribution of KCTD12 to esophageal squamous cell carcinoma. BMC Cancer 2018; 18:853. [PMID: 30157793 PMCID: PMC6114029 DOI: 10.1186/s12885-018-4765-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 08/21/2018] [Indexed: 12/30/2022] Open
Abstract
Background It has been shown that the expression of potassium channel tetramerization domain containing 12 (KCTD12) as a regulator of GABAB receptor signaling is reversely associated with gastrointestinal stromal tumors. In present study we examined the probable role of KCTD12 in regulation of several signaling pathways and chromatin remodelers in esophageal squamous cell carcinoma (ESCC). Methods KCTD12 ectopic expression was done in KYSE30 cell line. Comparative quantitative real time PCR was used to assess the expression of stem cell factors and several factors belonging to the WNT/NOTCH and chromatin remodeling in transfected cells in comparison with non-transfected cells. Results We observed that the KCTD12 significantly down regulated expression of NANOG, SOX2, SALL4, KLF4, MAML1, PYGO2, BMI1, BRG1, MSI1, MEIS1, EGFR, DIDO1, ABCC4, ABCG2, and CRIPTO1 in transfected cells in comparison with non-transfected cells. Migration assay showed a significant decrease in cell movement in ectopic expressed cells in comparison with non-transfected cells (p = 0.02). Moreover, KCTD12 significantly decreased the 5FU resistance in transfected cells (p = 0.01). Conclusions KCTD12 may exert its inhibitory role in ESCC through the suppression of WNT /NOTCH, stem cell factors, and chromatin remodelers and can be introduced as an efficient therapeutic marker.
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Affiliation(s)
- Mohammad Reza Abbaszadegan
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Medical Genetics Research Center, Faculty of Medical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Taghehchian
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Medical Genetics Research Center, Faculty of Medical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Liping Li
- Department of Clinical Laboratory, The Third Affiliated Hospital of Nanchang University, Jiangxi, Nanchang, 330008, People's Republic of China
| | - Azadeh Aarabi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Sadeghi MR, Jeddi F, Soozangar N, Somi MH, Shirmohamadi M, Khaze V, Samadi N. Nrf2/P–glycoprotein axis is associated with clinicopathological characteristics in colorectal cancer. Biomed Pharmacother 2018; 104:458-464. [DOI: 10.1016/j.biopha.2018.05.062] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 05/14/2018] [Accepted: 05/14/2018] [Indexed: 12/12/2022] Open
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Mansoori Y, Tabei MB, Askari A, Izadi P, Daraei A, Naghizadeh MM, Zendehbad Z, Bastami M, Nariman-Saleh-Fam Z, Mansoori H, Tavakkoly-Bazzaz J. A link between expression level of long-non-coding RNA ZFAS1 in breast tissue of healthy women and obesity. Int J Biol Markers 2018; 33:500-506. [PMID: 29690801 DOI: 10.1177/1724600818762258] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Epidemiological and experimental literature indicates that the risk of breast cancer incidence is strongly linked to hormone-dependent factors, including reproductive history and obesity. However, the molecular mechanisms underlying the association between these factors and breast cancer risk are poorly understood. The aim of this study, therefore, was to determine whether obesity and reproductive history are associated with expression levels of two breast cancer-related long non-coding RNAs (lncRNAs), namely ZFAS1 and SRA1 in cancer-free breast tissues of women. METHODS In the current research, 145 healthy women were recruited, and the quantitative expression levels of the two lncRNAs were determined through qPCR assay after gathering the mammoplasty breast tissue samples. RESULTS It was found that women with body mass index (BMI)≥30 kg/m2 and BMI 25-29 kg/m2 show a low expression of ZFAS1 compared to the BMI<25 kg/m2 (P=0.031 and P=0.027, respectively). Then, the correlation analysis disclosed a negative correlation of ZFAS1 low expression with increasing BMI (r=-0.194, P=0.019). Interestingly, this analysis demonstrated a negative correlation between low expression of the ZFAS1 and high BMI in women with menarche age below 14 (r=-221; P=0.028). Lastly, it was also revealed that there was a negative association of the low expression level of ZFAS1 with increasing BMI in women through regression models (B=-0.048, P=0.019). CONCLUSIONS These findings suggest interesting clues about the links between high BMI and the expression levels of ZFAS1 in non-diseased breasts that may help us better understand the underlying mechanisms through which obesity contributes to breast carcinogenesis. However, such results need more validations in future research.
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Affiliation(s)
- Yaser Mansoori
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Mohammad Bagher Tabei
- Department of Medical Genetics, School of Medical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Askari
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran.,Bone and Joint Reconstraction Research Center, Shafa Orthopedic Haspital, Iran University of Medical Sciences, Tehran, IR Iran
| | - Pantea Izadi
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdolreza Daraei
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | | | - Zahra Zendehbad
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Milad Bastami
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ziba Nariman-Saleh-Fam
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hosein Mansoori
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran.,Department of Medical Genetics, School of Medical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Javad Tavakkoly-Bazzaz
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Drosophila Histone Demethylase KDM4A Has Enzymatic and Non-enzymatic Roles in Controlling Heterochromatin Integrity. Dev Cell 2017; 42:156-169.e5. [PMID: 28743002 DOI: 10.1016/j.devcel.2017.06.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 03/21/2017] [Accepted: 06/16/2017] [Indexed: 11/23/2022]
Abstract
Eukaryotic genomes are broadly divided between gene-rich euchromatin and the highly repetitive heterochromatin domain, which is enriched for proteins critical for genome stability and transcriptional silencing. This study shows that Drosophila KDM4A (dKDM4A), previously characterized as a euchromatic histone H3 K36 demethylase and transcriptional regulator, predominantly localizes to heterochromatin and regulates heterochromatin position-effect variegation (PEV), organization of repetitive DNAs, and DNA repair. We demonstrate that dKDM4A demethylase activity is dispensable for PEV. In contrast, dKDM4A enzymatic activity is required to relocate heterochromatic double-strand breaks outside the domain, as well as for organismal survival when DNA repair is compromised. Finally, DNA damage triggers dKDM4A-dependent changes in the levels of H3K56me3, suggesting that dKDM4A demethylates this heterochromatic mark to facilitate repair. We conclude that dKDM4A, in addition to its previously characterized role in euchromatin, utilizes both enzymatic and structural mechanisms to regulate heterochromatin organization and functions.
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41
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Li BT, Yu C, Xu Y, Liu SB, Fan HY, Pan WW. TET1 inhibits cell proliferation by inducing RASSF5 expression. Oncotarget 2017; 8:86395-86409. [PMID: 29156803 PMCID: PMC5689693 DOI: 10.18632/oncotarget.21189] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Accepted: 08/23/2017] [Indexed: 02/01/2023] Open
Abstract
Tet methylcytosine dioxygenases (TETs) catalyze the oxidative reactions of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). However, TET1 roles in ovarian cancer cell growth are unknown. Here, we show that ectopic expression of TET1 increased 5hmC levels, and inhibited proliferation and colony formation in ovarian cancer cell lines. Furthermore, in vitro and in vivo functional studies demonstrated that TET1 overexpression is necessary for the suppression of ovarian cancer growth, whereas depletion of TET1 expression had the opposite effect. Furthermore, the results of RNA-seq and qRT-PCR analyses identified a tumor suppressor, Ras association domain family member 5 (RASSF5), as the key downstream target of TET1. TET1 promotes RASSF5 expression by demethylating a CpG site within RASSF5 promoter. Up-regulated RASSF5 expression leads to the suppression of ovarian cancer cells growth. Additionally, we demonstrated that inhibition of CUL4-DDB1 ubiquitin ligase complex decrease 5hmC levels in ovarian cancer cells. These results provide new insights into the understanding of how ovarian cancers develop and grow, and identify TET1 as a key player in this process.
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Affiliation(s)
- Bo-Tai Li
- Life Sciences Institute, Zhejiang University, Hangzhou 301158, China
| | - Chao Yu
- Life Sciences Institute, Zhejiang University, Hangzhou 301158, China
| | - Ying Xu
- Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing 314001, China
| | - Sheng-Bing Liu
- Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing 314001, China
| | - Heng-Yu Fan
- Life Sciences Institute, Zhejiang University, Hangzhou 301158, China
| | - Wei-Wei Pan
- Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing 314001, China
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Balani S, Nguyen LV, Eaves CJ. Modeling the process of human tumorigenesis. Nat Commun 2017; 8:15422. [PMID: 28541307 PMCID: PMC5458507 DOI: 10.1038/ncomms15422] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 03/29/2017] [Indexed: 12/31/2022] Open
Abstract
Modelling the genesis of human cancers is at a scientific turning point. Starting from primary sources of normal human cells, it is now possible to reproducibly generate several types of malignant cell populations. Powerful methods for clonally tracking and manipulating their appearance and progression in serially transplanted immunodeficient mice are also in place. These developments circumvent historic drawbacks inherent in analyses of cancers produced in model organisms, established human malignant cell lines, or highly heterogeneous patient samples. In this review, we survey the advantages, contributions and limitations of current de novo human tumorigenesis strategies and note several exciting prospects on the horizon. A better understanding of the earliest stages of human cancer formation can enable future improvements in early detection, diagnosis and treatment. In this review, the authors summarize the methods enabling de novo tumorigenesis protocols to be applied to human cells and the insights derived from them to date, as well as the exciting and relevant technical developments anticipated to extend even further the utility of these strategies.
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Affiliation(s)
- Sneha Balani
- Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Long V. Nguyen
- Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Connie J. Eaves
- Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
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Yang L, Song X, Zhu J, Li M, Ji Y, Wu F, Chen Y, Cui X, Hu J, Wang L, Cao Y, Wei Y, Zhang W, Li F. Tumor suppressor microRNA-34a inhibits cell migration and invasion by targeting MMP-2/MMP-9/FNDC3B in esophageal squamous cell carcinoma. Int J Oncol 2017; 51:378-388. [PMID: 28534990 DOI: 10.3892/ijo.2017.4015] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 05/12/2017] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs (miRNAs) are a large family of small, non-coding RNAs that play a pivotal role in tumorigenesis. miR‑34a, which is a member of the miR-34 family, is a downstream target of p53. Increasing evidence shows that miR-34a dysregulation may contribute to tumor development and progression in numerous cancers, including esophageal squamous cell carcinoma (ESCC). However, the mechanism of miR-34a in the regulation of ESCC cells need to be further elucidated because of the complex regulative network of miRNAs. The miR-34a expression in ESCC samples has been confirmed using quantitative reverse transcription polymerase chain reaction. The effects of miR-34a on cell migration and invasion were examined in ESCC cell lines using wound healing and Transwell assays, respectively. The effects of miR-34a on matrix metalloproteinase (MMP)-2 and -9 and fibronectin type III domain containing 3B (FNDC3B) expression levels were detected by luciferase reporter assays and western blot analysis. Quantitative polymerase chain reaction revealed that the miR‑34a expression is significantly downregulated in the ESCC tissues compared to that in the adjacent normal tissues. miR-34a overexpression was significantly suppressed migration and invasion in the ESCC cells and simultaneously inhibited the MMP-2, MMP-9 and FNDC3B expression levels by targeting the coding and 3'-untranslated regions, respectively. The findings indicated that microRNA‑34a suppresses cell migration and invasion by targeting MMP-2, MMP-9, and FNDC3B in ESCC.
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Affiliation(s)
- Lan Yang
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Xiaoyue Song
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Jianbo Zhu
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Mei Li
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Yu Ji
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Fei Wu
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Yunzhao Chen
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Xiaobin Cui
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Jianming Hu
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Lianghai Wang
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Yuwen Cao
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Yutao Wei
- The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Wenjie Zhang
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
| | - Feng Li
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, P.R. China
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New evidence of the relative protective effects of neurodegenerative diseases and cancer against each other. Neurologia 2017; 34:283-290. [PMID: 28325559 DOI: 10.1016/j.nrl.2017.01.010] [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: 12/11/2016] [Accepted: 01/08/2017] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Cancer and degenerative diseases share some pathogenic mechanisms which act in opposition to one another to produce either uncontrolled cell proliferation or cell death. According to several studies, patients with Alzheimer disease have a lower risk of neoplasia, and vice versa. This study describes the prevalence of tumours (active or successfully treated) in a series of patients with and without a dementing degenerative disease treated at a cognitive neurology unit. PATIENTS AND METHOD We analysed the frequency and topography of tumours and the presence or absence of a neurodegenerative disease in a group of 1,164 patients. Neurodegenerative diseases were classified in 4 groups: Alzheimer disease, synucleinopathies, Pick complex, and polyglutamine complex. We subsequently compared tumour frequency in patients with and without a degenerative disease, and prevalence of neurodegenerative diseases in patients with and without tumours. RESULTS Tumours were detected in 12.1% of the patients with a neurodegenerative disease and in 17.3% of the remaining patients. Around 14.8% of the patients with a history of neoplasia and 20.8% of the patients with no history of neoplasia were diagnosed with a neurodegenerative disease. Except for these differences and the differences between subgroups (type of degenerative disease and tumour location) were not statistically significant, except when comparing neurodegenerative diseases to central nervous system tumours, and synucleinopathies to neoplasms. CONCLUSION Dementing degenerative diseases and neoplastic disorders are not mutually exclusive. Nevertheless, the rate of co-occurrence is lower than would be expected given the prevalence rate for each group.
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Abstract
Cancer remains one of the leading causes of death around the world. Initially it is recognized as a genetic disease, but now it is known to involve epigenetic abnormalities along with genetic alterations. Epigenetics refers to heritable changes that are not encoded in the DNA sequence itself, but play an important role in the control of gene expression. It includes changes in DNA methylation, histone modifications, and RNA interference. Although it is heritable, environmental factors such as diet could directly influence epigenetic mechanisms in humans. This article will focus on the role of dietary patterns and phytochemicals that have been demonstrated to influence the epigenome and more precisely histone and non-histone proteins modulation by acetylation that helps to induce apoptosis and phosphorylation inhibition, which counteracts with cells proliferation. Recent developments discussed here enhance our understanding of how dietary intervention could be beneficial in preventing or treating cancer and improving health outcomes.
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Affiliation(s)
- Wissam Zam
- a Department of Analytical and Food Chemistry , Faculty of Pharmacy, Al-Andalus University for Medical Sciences, Al-Quadmous , Tartous , Syrian Arab Republic
| | - Aziz Khadour
- b Department of Microbiology , Faculty of Pharmacy, Al-Andalus University for Medical Sciences, Al-Quadmous , Tartous , Syrian Arab Republic
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Costa G, Barra V, Lentini L, Cilluffo D, Di Leonardo A. DNA demethylation caused by 5-Aza-2'-deoxycytidine induces mitotic alterations and aneuploidy. Oncotarget 2016; 7:3726-39. [PMID: 26771138 PMCID: PMC4826165 DOI: 10.18632/oncotarget.6897] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 12/18/2015] [Indexed: 01/19/2023] Open
Abstract
Aneuploidy, the unbalanced number of chromosomes in a cell, is considered a prevalent form of genetic instability and is largely acknowledged as a condition implicated in tumorigenesis. Epigenetic alterations like DNA hypomethylation have been correlated with cancer initiation/progression. Furthermore, a growing body of evidence suggests the involvement of epigenome-wide disruption as a cause of global DNA hypomethylation in aneuploidy generation. Here, we report that the DNA hypomethylating drug 5-aza-2′-deoxycytidine (DAC), affects the correct ploidy of nearly diploid HCT-116 human cells by altering the methylation pattern of the chromosomes. Specifically, we show that a DAC-induced reduction of 5-Methyl Cytosine at the pericentromeric region of chromosomes correlates with aneuploidy and mitotic defects. Our results suggest that DNA hypomethylation leads to aneuploidy by altering the DNA methylation landscape at the centromere that is necessary to ensure proper chromosomes segregation by recruiting the proteins necessary to build up a functional kinetochore.
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Affiliation(s)
- Giuseppe Costa
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Palermo, Italy
| | - Viviana Barra
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Palermo, Italy
| | - Laura Lentini
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Palermo, Italy
| | - Danilo Cilluffo
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Palermo, Italy
| | - Aldo Di Leonardo
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Palermo, Italy.,Centro di OncoBiologia Sperimentale (COBS), Palermo, Italy
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Affiliation(s)
- Connie J. Mulligan
- Department of Anthropology, Genetics Institute, University of Florida, Gainesville, Florida 32610-3610;
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48
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Soini Y. Epigenetic and genetic changes in soft tissue sarcomas: a review. APMIS 2016; 124:925-934. [PMID: 27670825 DOI: 10.1111/apm.12600] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 08/03/2016] [Indexed: 11/26/2022]
Abstract
Soft tissue sarcomas are a versatile group of tumors with a proposed origin from mesenchymal stem cells. During recent years, the molecular biologic mechanisms behind the histogenesis of these tumors have become clearer. In addition to translocations and other genomic changes, epigenetic mechanisms have been shown to be greatly involved in the histogenesis of sarcomas as well as other cancers. Even though the molecular mechanisms behind sarcomas appear to be more complex than previously expected, epigenetic mechanisms bring new opportunities and means for the treatment of these complex diseases.
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Affiliation(s)
- Ylermi Soini
- Department of Pathology and Forensic Medicine, University of Eastern Finland, Kuopio and Cancer Center of Eastern Finland, Kuopio, Finland.
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Lopez-Bertoni H, Lal B, Michelson N, Guerrero-Cázares H, Quiñones-Hinojosa A, Li Y, Laterra J. Epigenetic modulation of a miR-296-5p:HMGA1 axis regulates Sox2 expression and glioblastoma stem cells. Oncogene 2016; 35:4903-13. [PMID: 26898758 PMCID: PMC6151872 DOI: 10.1038/onc.2016.22] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 12/17/2015] [Accepted: 12/18/2015] [Indexed: 12/15/2022]
Abstract
Solid malignancies contain subsets of multipotent cells that grow as spheres and efficiently propagate tumors in xenograft models, reflecting a stem-like, self-renewing and tumor-propagating phenotype. These cancer 'stem cells (SCs)' have been shown to maintain tumor growth, contribute to resistance and drive tumor recurrence. Cancer cell stemness is dynamically influenced by epigenetic mechanisms and differentially regulated coding and noncoding RNAs. How these mechanisms specifically contribute to the generation and/or maintenance of cancer SCs remains unclear. This study identifies a novel epigenetically regulated circuit that integrates microRNA, chromatin remodeling and the reprogramming transcription factor Sox2 to regulate glioblastoma (GBM)-propagating SCs. We show that miR-296-5p expression is repressed in a DNA methylation-dependent manner under conditions that promote GBM cell stemness and that miR-296-5p inhibits GBM cell stemness and their capacity to self-renew as spheres and propagate glioma xenografts in vivo. We show that the chromatin remodeling protein HMGA1 functions as a downstream effector of these biological responses to miR-296-5p and regulates Sox2 expression, a master driver of cell stemness, by modifying chromatin architecture at the Sox2 promoter. These results show for the first time that miR-296-5p inhibits transcriptional mechanisms that support GBM SCs and identify a miR-296-5p:HMGA1:Sox2 axis as a novel regulator of GBM SCs and candidate pathway for targeting therapies directed at depleting tumors of their tumor-propagating stem cell subsets.
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Affiliation(s)
- H Lopez-Bertoni
- Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA
- Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - B Lal
- Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA
- Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - N Michelson
- Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA
| | - H Guerrero-Cázares
- Department of Neurosurgery, The Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - A Quiñones-Hinojosa
- Department of Neurosurgery, The Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Y Li
- Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA
- Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - J Laterra
- Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA
- Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA
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DNA methylation: conducting the orchestra from exposure to phenotype? Clin Epigenetics 2016; 8:92. [PMID: 27602172 PMCID: PMC5012062 DOI: 10.1186/s13148-016-0256-8] [Citation(s) in RCA: 126] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 08/22/2016] [Indexed: 01/02/2023] Open
Abstract
DNA methylation, through 5-methyl- and 5-hydroxymethylcytosine (5mC and 5hmC), is considered to be one of the principal interfaces between the genome and our environment, and it helps explain phenotypic variations in human populations. Initial reports of large differences in methylation level in genomic regulatory regions, coupled with clear gene expression data in both imprinted genes and malignant diseases, provided easily dissected molecular mechanisms for switching genes on or off. However, a more subtle process is becoming evident, where small (<10 %) changes to intermediate methylation levels are associated with complex disease phenotypes. This has resulted in two clear methylation paradigms. The latter “subtle change” paradigm is rapidly becoming the epigenetic hallmark of complex disease phenotypes, although we are currently hampered by a lack of data addressing the true biological significance and meaning of these small differences. Our initial expectation of rapidly identifying mechanisms linking environmental exposure to a disease phenotype led to numerous observational/association studies being performed. Although this expectation remains unmet, there is now a growing body of literature on specific genes, suggesting wide ranging transcriptional and translational consequences of such subtle methylation changes. Data from the glucocorticoid receptor (NR3C1) has shown that a complex interplay between DNA methylation, extensive 5′UTR splicing, and microvariability gives rise to the overall level and relative distribution of total and N-terminal protein isoforms generated. Additionally, the presence of multiple AUG translation initiation codons throughout the complete, processed mRNA enables translation variability, hereby enhancing the translational isoforms and the resulting protein isoform diversity, providing a clear link between small changes in DNA methylation and significant changes in protein isoforms and cellular locations. Methylation changes in the NR3C1 CpG island alters the NR3C1 transcription and eventually protein isoforms in the tissues, resulting in subtle but visible physiological variability. This review addresses the current pathophysiological and clinical associations of such characteristically small DNA methylation changes, the ever-growing roles of DNA methylation and the evidence available, particularly from the glucocorticoid receptor of the cascade of events initiated by such subtle methylation changes, as well as addressing the underlying question as to what represents a genuine biologically significant difference in methylation.
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