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Ishikawa M. Perioperative Anesthesia Management: The Role of MicroRNAs. J NIPPON MED SCH 2025; 92:14-21. [PMID: 40058830 DOI: 10.1272/jnms.jnms.2025_92-116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
MicroRNA (miRNA) is a small RNA molecule that does not code for proteins, and organ- and disease-specific miRNAs are being investigated as diagnostic tools and therapeutic targets, particularly for cardiovascular disease and cancer. Much remains unknown about how anesthetics, other drugs, and perioperative management affect miRNAs, but miRNA-targeted drugs might eventually be used perioperatively. This review examines changes in miRNA expression related to anesthesia management. Sevoflurane results in gene expression patterns that differ by organ. The author investigated changes in miRNA expression induced by anesthetics in the brain, lungs, and liver and found that changes in miRNA expression differ by drug and organ. Since miRNA does not have a one-to-one correspondence with its target mRNA and exhibits complex effects within and between cells, as well as remotely, drug- and organ-specific changes in mRNA expression caused by anesthetics likely involve complex alterations. Cardiovascular disease and cancer are related to perioperative management via miRNAs. Inhalational anesthetics may exacerbate or suppress cellular activity, depending on the type of cancer, and the mechanisms of action differ depending on the inhalational anesthetic. These findings suggest that propofol is more likely to contribute to suppression of cancer cells through intercellular communication. The role of miRNA in perioperative management remains unclear. In the future, it is expected that changes in miRNA expression will be considered when selecting and administering anesthetic drugs perioperatively.
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Affiliation(s)
- Masashi Ishikawa
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School
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Singh RR, Mondal I, Janjua T, Popat A, Kulshreshtha R. Engineered smart materials for RNA based molecular therapy to treat Glioblastoma. Bioact Mater 2024; 33:396-423. [PMID: 38059120 PMCID: PMC10696434 DOI: 10.1016/j.bioactmat.2023.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 10/19/2023] [Accepted: 11/14/2023] [Indexed: 12/08/2023] Open
Abstract
Glioblastoma (GBM) is an aggressive malignancy of the central nervous system (CNS) that remains incurable despite the multitude of improvements in cancer therapeutics. The conventional chemo and radiotherapy post-surgery have only been able to improve the prognosis slightly; however, the development of resistance and/or tumor recurrence is almost inevitable. There is a pressing need for adjuvant molecular therapies that can successfully and efficiently block tumor progression. During the last few decades, non-coding RNAs (ncRNAs) have emerged as key players in regulating various hallmarks of cancer including that of GBM. The levels of many ncRNAs are dysregulated in cancer, and ectopic modulation of their levels by delivering antagonists or overexpression constructs could serve as an attractive option for cancer therapy. The therapeutic potential of several types of ncRNAs, including miRNAs, lncRNAs, and circRNAs, has been validated in both in vitro and in vivo models of GBM. However, the delivery of these RNA-based therapeutics is highly challenging, especially to the tumors of the brain as the blood-brain barrier (BBB) poses as a major obstacle, among others. Also, since RNA is extremely fragile in nature, careful considerations must be met while designing a delivery agent. In this review we have shed light on how ncRNA therapy can overcome the limitations of its predecessor conventional therapy with an emphasis on smart nanomaterials that can aide in the safe and targeted delivery of nucleic acids to treat GBM. Additionally, critical gaps that currently exist for successful transition from viral to non-viral vector delivery systems have been identified. Finally, we have provided a perspective on the future directions, potential pathways, and target areas for achieving rapid clinical translation of, RNA-based macromolecular therapy to advance the effective treatment of GBM and other related diseases.
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Affiliation(s)
- Ravi Raj Singh
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
- University of Queensland –IIT Delhi Academy of Research (UQIDAR)
| | - Indranil Mondal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
| | - Taskeen Janjua
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Amirali Popat
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
- Department of Functional Materials and Catalysis, Faculty of Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria
| | - Ritu Kulshreshtha
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
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Jegathesan Y, Stephen PP, Sati ISEE, Narayanan P, Monif M, Kamarudin MNA. MicroRNAs in adult high-grade gliomas: Mechanisms of chemotherapeutic resistance and their clinical relevance. Biomed Pharmacother 2024; 172:116277. [PMID: 38377734 DOI: 10.1016/j.biopha.2024.116277] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 02/11/2024] [Accepted: 02/13/2024] [Indexed: 02/22/2024] Open
Abstract
Notorious for its high mortality rate, the current standard treatment for high-grade gliomas remains a challenge. This is largely due to the complex heterogeneity of the tumour coupled with dysregulated molecular mechanisms leading to the development of drug resistance. In recent years, microRNAs (miRNAs) have been considered to provide important information about the pathogenesis and prognostication of gliomas. miRNAs have been shown to play a specific role in promoting oncogenesis and regulating resistance to anti-glioma therapeutic agents through diverse cellular mechanisms. These include regulation of apoptosis, alterations in drug efflux pathways, enhanced activation of oncogenic signalling pathways, Epithelial-Mesenchymal Transition-like process (EMT-like) and a few others. With this knowledge, upregulation or inhibition of selected miRNAs can be used to directly affect drug resistance in glioma cells. Moreover, the clinical use of miRNAs in glioma management is becoming increasingly valuable. This comprehensive review delves into the role of miRNAs in drug resistance in high-grade gliomas and underscores their clinical significance. Our analysis has identified a distinct cluster of oncogenic miRNAs (miR-9, miR-21, miR-26a, miR-125b, and miR-221/222) and tumour suppressive miRNAs (miR-29, miR-23, miR-34a-5p, miR 181b-5p, miR-16-5p, and miR-20a) that consistently emerge as key players in regulating drug resistance across various studies. These miRNAs have demonstrated significant clinical relevance in the context of resistance to anti-glioma therapies. Additionally, the clinical significance of miRNA analysis is emphasised, including their potential to serve as clinical biomarkers for diagnosing, staging, evaluating prognosis, and assessing treatment response in gliomas.
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Affiliation(s)
- Yugendran Jegathesan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor 47500, Malaysia; Taiping Hospital, Jalan Taming Sari, Perak, Taiping 34000, Malaysia
| | - Pashaun Paveen Stephen
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor 47500, Malaysia; Coffs Harbour Health Campus, Coffs Harbour, NSW 2450, Australia
| | - Isra Saif Eldin Eisa Sati
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor 47500, Malaysia
| | - Prakrithi Narayanan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor 47500, Malaysia
| | - Mastura Monif
- Department of Neuroscience, Central Clinical School, Monash University, VIC, Melbourne, Australia; Department of Physiology, The University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia; Department of Neurology, The Alfred, Melbourne, VIC, Australia
| | - Muhamad Noor Alfarizal Kamarudin
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor 47500, Malaysia.
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Obrador E, Moreno-Murciano P, Oriol-Caballo M, López-Blanch R, Pineda B, Gutiérrez-Arroyo JL, Loras A, Gonzalez-Bonet LG, Martinez-Cadenas C, Estrela JM, Marqués-Torrejón MÁ. Glioblastoma Therapy: Past, Present and Future. Int J Mol Sci 2024; 25:2529. [PMID: 38473776 PMCID: PMC10931797 DOI: 10.3390/ijms25052529] [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: 12/23/2023] [Revised: 02/10/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16ink4, TP53/MDM2/P14arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood-brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.
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Affiliation(s)
- Elena Obrador
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Paz Moreno-Murciano
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
| | - María Oriol-Caballo
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Rafael López-Blanch
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Begoña Pineda
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
| | - Julia Lara Gutiérrez-Arroyo
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain; (J.L.G.-A.); (A.L.); (C.M.-C.)
| | - Alba Loras
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain; (J.L.G.-A.); (A.L.); (C.M.-C.)
| | - Luis G. Gonzalez-Bonet
- Department of Neurosurgery, Castellon General University Hospital, 12004 Castellon, Spain;
| | - Conrado Martinez-Cadenas
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon, Spain; (J.L.G.-A.); (A.L.); (C.M.-C.)
| | - José M. Estrela
- Scientia BioTech S.L., 46002 Valencia, Spain; (P.M.-M.); (M.O.-C.); (R.L.-B.); (J.M.E.)
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain;
- Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Burjassot, Spain
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Sarkami SA, Molavipordanjani S, Abediankenari S, Akhtari J, Gill P, Ghalehnoei H, Lemoni SK. Engineering HEK293T cell line by lentivirus to produce miR34a-loaded exosomes. Mol Biol Rep 2023; 50:8827-8837. [PMID: 37658928 DOI: 10.1007/s11033-023-08754-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/10/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND RNA (ribonucleic acid) antisense is developing as a possible treatment option. As an RNA, miR-34a is involved in P53 function and cancer cell apoptosis. Although the therapeutic applications of miRNAs have several limitations, such as structural instability and susceptibility to nucleases. To resolve these issues, this study aims to apply exosomes as a delivery vehicle for miR-34a. AIMS This study aims to create a cell factory to generate miR34a-enriched exosomes. The produced nanoparticles act as a delivery system and improve the structural stability of miR34a. METHODS First exosome specific sequences were inserted into miR34a. The resulting miR34a oligonucleotide was transduced HEK293T cells genome with a lentiviral system. In the structure of miR34a oligonucleotide, six nucleotides were substituted to increase its packaging rate into exosomes. To maintain the secondary structure, stability, and expression of the miRNA gene, changes to the miR34a oligonucleotide were made using PCR (polymerase chain reaction) Extension. The forward-34a (5-TGGGGAGAGGCAGGACAGG-3) and Reverse-34a primers (5-TCCGAAGTCCTGGCGTCTCC-3) were used for amplification of the miR34a gene from DNA. RESULTS The results confirmed that the changes in miR34a oligonucleotide do not affect its secondary structure. The energy level of the manipulated miR34a oligonucleotide was kept the same compared to the original one. Moreover, the loading of miR34a to the exosomes was increased. CONCLUSION Our findings revealed that normal HEK293T did not express miR34a. However, lentiviral transduced miR34a oligonucleotide induced the loading of miR34a into the exosome. Moreover, replacing six nucleic acids in the 3' end of miR34a increased the loading of miR34a to exosome.
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Affiliation(s)
- Sahar Abdi Sarkami
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sajjad Molavipordanjani
- Pharmaceutical Sciences Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Saeed Abediankenari
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, FarahAbad Road, Sari, Iran
| | - Javad Akhtari
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, FarahAbad Road, Sari, Iran
| | - Pooria Gill
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, FarahAbad Road, Sari, Iran
| | - Hossein Ghalehnoei
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, FarahAbad Road, Sari, Iran
| | - Shabanali Khodashenas Lemoni
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, FarahAbad Road, Sari, Iran.
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Tluli O, Al-Maadhadi M, Al-Khulaifi AA, Akomolafe AF, Al-Kuwari SY, Al-Khayarin R, Maccalli C, Pedersen S. Exploring the Role of microRNAs in Glioma Progression, Prognosis, and Therapeutic Strategies. Cancers (Basel) 2023; 15:4213. [PMID: 37686489 PMCID: PMC10486509 DOI: 10.3390/cancers15174213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/05/2023] [Accepted: 08/08/2023] [Indexed: 09/10/2023] Open
Abstract
Gliomas, which arise from glial cells in the brain, remain a significant challenge due to their location and resistance to traditional treatments. Despite research efforts and advancements in healthcare, the incidence of gliomas has risen dramatically over the past two decades. The dysregulation of microRNAs (miRNAs) has prompted the creation of therapeutic agents that specially target them. However, it has been reported that they are involved in complex signaling pathways that contribute to the loss of expression of tumor suppressor genes and the upregulation of the expression of oncogenes. In addition, numerous miRNAs promote the development, progression, and recurrence of gliomas by targeting crucial proteins and enzymes involved in metabolic pathways such as glycolysis and oxidative phosphorylation. However, the complex interplay among these pathways along with other obstacles hinders the ability to apply miRNA targeting in clinical practice. This highlights the importance of identifying specific miRNAs to be targeted for therapy and having a complete understanding of the diverse pathways they are involved in. Therefore, the aim of this review is to provide an overview of the role of miRNAs in the progression and prognosis of gliomas, emphasizing the different pathways involved and identifying potential therapeutic targets.
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Affiliation(s)
- Omar Tluli
- College of Medicine, Qatar University, Doha P.O. Box 2713, Qatar; (O.T.); (M.A.-M.); (A.A.A.-K.); (A.F.A.); (R.A.-K.)
| | - Mazyona Al-Maadhadi
- College of Medicine, Qatar University, Doha P.O. Box 2713, Qatar; (O.T.); (M.A.-M.); (A.A.A.-K.); (A.F.A.); (R.A.-K.)
| | - Aisha Abdulla Al-Khulaifi
- College of Medicine, Qatar University, Doha P.O. Box 2713, Qatar; (O.T.); (M.A.-M.); (A.A.A.-K.); (A.F.A.); (R.A.-K.)
| | - Aishat F. Akomolafe
- College of Medicine, Qatar University, Doha P.O. Box 2713, Qatar; (O.T.); (M.A.-M.); (A.A.A.-K.); (A.F.A.); (R.A.-K.)
| | - Shaikha Y. Al-Kuwari
- College of Medicine, Qatar University, Doha P.O. Box 2713, Qatar; (O.T.); (M.A.-M.); (A.A.A.-K.); (A.F.A.); (R.A.-K.)
| | - Roudha Al-Khayarin
- College of Medicine, Qatar University, Doha P.O. Box 2713, Qatar; (O.T.); (M.A.-M.); (A.A.A.-K.); (A.F.A.); (R.A.-K.)
| | | | - Shona Pedersen
- College of Medicine, Qatar University, Doha P.O. Box 2713, Qatar; (O.T.); (M.A.-M.); (A.A.A.-K.); (A.F.A.); (R.A.-K.)
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Makowska M, Smolarz B, Romanowicz H. microRNAs (miRNAs) in Glioblastoma Multiforme (GBM)-Recent Literature Review. Int J Mol Sci 2023; 24:3521. [PMID: 36834933 PMCID: PMC9965735 DOI: 10.3390/ijms24043521] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/25/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most common, malignant, poorly promising primary brain tumor. GBM is characterized by an infiltrating growth nature, abundant vascularization, and a rapid and aggressive clinical course. For many years, the standard treatment of gliomas has invariably been surgical treatment supported by radio- and chemotherapy. Due to the location and significant resistance of gliomas to conventional therapies, the prognosis of glioblastoma patients is very poor and the cure rate is low. The search for new therapy targets and effective therapeutic tools for cancer treatment is a current challenge for medicine and science. microRNAs (miRNAs) play a key role in many cellular processes, such as growth, differentiation, cell division, apoptosis, and cell signaling. Their discovery was a breakthrough in the diagnosis and prognosis of many diseases. Understanding the structure of miRNAs may contribute to the understanding of the mechanisms of cellular regulation dependent on miRNA and the pathogenesis of diseases underlying these short non-coding RNAs, including glial brain tumors. This paper provides a detailed review of the latest reports on the relationship between changes in the expression of individual microRNAs and the formation and development of gliomas. The use of miRNAs in the treatment of this cancer is also discussed.
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Affiliation(s)
- Marianna Makowska
- Department of Anesthesiology and Operative Intensive Care Medicine, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Beata Smolarz
- Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, Rzgowska 281/289, 93-338 Lodz, Poland
| | - Hanna Romanowicz
- Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, Rzgowska 281/289, 93-338 Lodz, Poland
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Role of MicroRNAs in the Development and Progression of the Four Medulloblastoma Subgroups. Cancers (Basel) 2021; 13:cancers13246323. [PMID: 34944941 PMCID: PMC8699467 DOI: 10.3390/cancers13246323] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 12/21/2022] Open
Abstract
Medulloblastoma is the most frequent malignant brain tumour in children. Medulloblastoma originate during the embryonic stage. They are located in the cerebellum, which is the area of the central nervous system (CNS) responsible for controlling equilibrium and coordination of movements. In 2012, medulloblastoma were divided into four subgroups based on a genome-wide analysis of RNA expression. These subgroups are named Wingless, Sonic Hedgehog, Group 3 and Group 4. Each subgroup has a different cell of origin, prognosis, and response to therapies. Wingless and Sonic Hedgehog medulloblastoma are so named based on the main mutation originating these tumours. Group 3 and Group 4 have generic names because we do not know the key mutation driving these tumours. Gene expression at the post-transcriptional level is regulated by a group of small single-stranded non-coding RNAs. These microRNA (miRNAs or miRs) play a central role in several cellular functions such as cell differentiation and, therefore, any malfunction in this regulatory system leads to a variety of disorders such as cancer. The role of miRNAs in medulloblastoma is still a topic of intense clinical research; previous studies have mostly concentrated on the clinical entity of the single disease rather than in the four molecular subgroups. In this review, we summarize the latest discoveries on miRNAs in the four medulloblastoma subgroups.
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Chen S, Deng X, Sheng H, Rong Y, Zheng Y, Zhang Y, Lin J. Noncoding RNAs in pediatric brain tumors: Molecular functions and pathological implications. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:417-431. [PMID: 34552822 PMCID: PMC8426460 DOI: 10.1016/j.omtn.2021.07.024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Brain tumors are common solid pediatric malignancies and the main reason for cancer-related death in the pediatric setting. Recently, evidence has revealed that noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), play a critical role in brain tumor development and progression. Therefore, in this review article, we describe the functions and molecular mechanisms of ncRNAs in multiple types of cancer, including medulloblastoma, pilocytic astrocytoma, ependymoma, atypical teratoid/rhabdoid tumor, glioblastoma, diffuse intrinsic pontine glioma, and craniopharyngioma. We also mention the limitations of using ncRNAs as therapeutic targets because of the nonspecificity of ncRNA targets and the delivery methods of ncRNAs. Due to the critical role of ncRNAs in brain oncogenesis, targeting aberrantly expressed ncRNAs might be an effective strategy to improve the outcomes of pediatric patients with brain tumors.
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Affiliation(s)
- Shaohuai Chen
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiangyang Deng
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hansong Sheng
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yuxi Rong
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yanhao Zheng
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yusong Zhang
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jian Lin
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
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Wang CZ, Luo Y, Huang WH, Zeng J, Zhang CF, Lager M, Du W, Xu M, Yuan CS. Falcarindiol and dichloromethane fraction are bioactive components in Oplopanax elatus: Colorectal cancer chemoprevention via induction of apoptosis and G2/M cell cycle arrest mediated by cyclin A upregulation. J Appl Biomed 2021; 19:113-124. [PMID: 34754259 DOI: 10.32725/jab.2021.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Oplopanax elatus (Nakai) Nakai has a long history of use as an ethnomedicine by the people living in eastern Asia. However, its bioactive constituents and cancer chemopreventive mechanisms are largely unknown. The aim of this study was to prepare O. elatus extracts, fractions, and single compounds and to investigate the herb's antiproliferative effects on colon cancer cells and the involved mechanisms of action. Two polyyne compounds were isolated from O. elatus, falcarindiol and oplopandiol. Based on our HPLC analysis, falcarindiol and oplopandiol are major constituents in the dichloromethane (CH2Cl2) fraction. For the HCT-116 cell line, the dichloromethane fraction showed significant effects. Furthermore, the IC50 for falcarindiol and oplopandiol was 1.7 μM and 15.5 μM, respectively. In the mechanistic study, after treatment with 5 μg/ml for 48 h, dichloromethane fraction induced cancer cell apoptosis by 36.5% (p < 0.01% vs. control of 3.9%). Under the same treatment condition, dichloromethane fraction caused cell cycle arrest at the G2/M phase by 32.6% (p < 0.01% vs. control of 23.4%), supported by upregulation of key cell cycle regulator cyclin A to 21.6% (p < 0.01% vs. control of 8.6%). Similar trends were observed by using cell line HT-29. Data from this study filled the gap between phytochemical components and the cancer chemoprevention of O. elatus. The dichloromethane fraction is a bioactive fraction, and falcarindiol is identified as an active constituent. The mechanisms involved in cancer chemoprevention by O. elatus were apoptosis induction and G2/M cell cycle arrest mediated by a key cell cycle regulator cyclin A.
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Affiliation(s)
- Chong-Zhi Wang
- Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Nanchang, P.R. China.,University of Chicago, Tang Center for Herbal Medicine Research, and Department of Anesthesia and Critical Care, Chicago, Illinois, USA
| | - Yun Luo
- Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Nanchang, P.R. China.,University of Chicago, Tang Center for Herbal Medicine Research, and Department of Anesthesia and Critical Care, Chicago, Illinois, USA
| | - Wei-Hua Huang
- University of Chicago, Tang Center for Herbal Medicine Research, and Department of Anesthesia and Critical Care, Chicago, Illinois, USA
| | - Jinxiang Zeng
- University of Chicago, Tang Center for Herbal Medicine Research, and Department of Anesthesia and Critical Care, Chicago, Illinois, USA
| | - Chun-Feng Zhang
- University of Chicago, Tang Center for Herbal Medicine Research, and Department of Anesthesia and Critical Care, Chicago, Illinois, USA
| | - Mallory Lager
- University of Chicago, Tang Center for Herbal Medicine Research, and Department of Anesthesia and Critical Care, Chicago, Illinois, USA
| | - Wei Du
- University of Chicago, Ben May Department for Cancer Research, Chicago, Illinois, USA
| | - Ming Xu
- University of Chicago, Committee on Clinical Pharmacology and Pharmacogenomics, Chicago, Illinois, USA
| | - Chun-Su Yuan
- University of Chicago, Tang Center for Herbal Medicine Research, and Department of Anesthesia and Critical Care, Chicago, Illinois, USA.,University of Chicago, Committee on Clinical Pharmacology and Pharmacogenomics, Chicago, Illinois, USA
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11
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Lambrou GI, Poulou M, Giannikou K, Themistocleous M, Zaravinos A, Braoudaki M. Differential and Common Signatures of miRNA Expression and Methylation in Childhood Central Nervous System Malignancies: An Experimental and Computational Approach. Cancers (Basel) 2021; 13:5491. [PMID: 34771655 PMCID: PMC8583574 DOI: 10.3390/cancers13215491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 10/24/2021] [Accepted: 10/26/2021] [Indexed: 11/16/2022] Open
Abstract
Epigenetic modifications are considered of utmost significance for tumor ontogenesis and progression. Especially, it has been found that miRNA expression, as well as DNA methylation plays a significant role in central nervous system tumors during childhood. A total of 49 resected brain tumors from children were used for further analysis. DNA methylation was identified with methylation-specific MLPA and, in particular, for the tumor suppressor genes CASP8, RASSF1, MGMT, MSH6, GATA5, ATM1, TP53, and CADM1. miRNAs were identified with microarray screening, as well as selected samples, were tested for their mRNA expression levels. CASP8, RASSF1 were the most frequently methylated genes in all tumor samples. Simultaneous methylation of genes manifested significant results with respect to tumor staging, tumor type, and the differentiation of tumor and control samples. There was no significant dependence observed with the methylation of one gene promoter, rather with the simultaneous presence of all detected methylated genes' promoters. miRNA expression was found to be correlated to gene methylation. Epigenetic regulation appears to be of major importance in tumor progression and pathophysiology, making it an imperative field of study.
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Affiliation(s)
- George I. Lambrou
- Choremeio Research Laboratory, First Department of Pediatrics, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Myrto Poulou
- Department of Medical Genetics, Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Krinio Giannikou
- Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA;
| | - Marios Themistocleous
- Department of Neurosurgery, “Aghia Sofia” Children’s Hospital, 11527 Athens, Greece;
| | - Apostolos Zaravinos
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia 2404, Cyprus
- Basic and Translational Cancer Research Center (BTCRC), Cancer Genetics, Genomics and Systems Biology Group, European University Cyprus, Nicosia 1516, Cyprus
| | - Maria Braoudaki
- Department of Life and Environmental Sciences, School of Life and Health Sciences, University of Hertfordshire, Hertfordshire AL10 9AB, UK
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12
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Chen M, Medarova Z, Moore A. Role of microRNAs in glioblastoma. Oncotarget 2021; 12:1707-1723. [PMID: 34434499 PMCID: PMC8378762 DOI: 10.18632/oncotarget.28039] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/27/2021] [Indexed: 11/25/2022] Open
Abstract
Glioblastoma is the most common and aggressive primary human brain cancer. MicroRNAs (miRNAs) are a set of small endogenous non-coding RNA molecules which play critical roles in different biological processes including cancer. The realization of miRNA regulatory functions in GBM has demonstrated that these molecules play a critical role in its initiation, progression and response to therapy. In this review we discuss the studies related to miRNA discovery and function in glioblastoma. We first summarize the typical miRNAs and their roles in GBM. Then we debate the potential for miRNA-based therapy for glioblastoma, including various delivery strategies. We surmise that future directions identified by these studies will point towards the necessity for therapeutic development and optimization to improve the outcomes for patients with glioblastoma.
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Affiliation(s)
- Ming Chen
- Precision Health Program, Michigan State University, East Lansing, MI 48824, USA.,Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Zdravka Medarova
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Anna Moore
- Precision Health Program, Michigan State University, East Lansing, MI 48824, USA.,Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
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13
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Ishikawa M, Iwasaki M, Sakamoto A, Ma D. Anesthetics may modulate cancer surgical outcome: a possible role of miRNAs regulation. BMC Anesthesiol 2021; 21:71. [PMID: 33750303 PMCID: PMC7941705 DOI: 10.1186/s12871-021-01294-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 03/01/2021] [Indexed: 02/06/2023] Open
Abstract
Background microRNAs (miRNAs) are single-stranded and noncoding RNA molecules that control post-transcriptional gene regulation. miRNAs can be tumor suppressors or oncogenes through various mechanism including cancer cell biology, cell-to-cell communication, and anti-cancer immunity. Main Body Anesthetics can affect cell biology through miRNA-mediated regulation of messenger RNA (mRNA). Indeed, sevoflurane was reported to upregulate miR-203 and suppresses breast cancer cell proliferation. Propofol reduces matrix metalloproteinase expression through its impact on miRNAs, leading to anti-cancer microenvironmental changes. Propofol also modifies miRNA expression profile in circulating extracellular vesicles with their subsequent anti-cancer effects via modulating cell-to-cell communication. Conclusion Inhalational and intravenous anesthetics can alter cancer cell biology through various cellular signaling pathways induced by miRNAs’ modification. However, this area of research is insufficient and further study is needed to figure out optimal anesthesia regimens for cancer patients.
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Affiliation(s)
- Masashi Ishikawa
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo, Tokyo, 113-8603, Japan. .,Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 369 Fulham Rd, London, SW10 9NH, UK.
| | - Masae Iwasaki
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo, Tokyo, 113-8603, Japan.,Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 369 Fulham Rd, London, SW10 9NH, UK
| | - Atsuhiro Sakamoto
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo, Tokyo, 113-8603, Japan
| | - Daqing Ma
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 369 Fulham Rd, London, SW10 9NH, UK
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14
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Ye Z, Xie T, Yan F, Wang L, Fang J, Wang Z, Hu F, Wang F, Fu Z. MiR-34a reverses radiation resistance on ECA-109 cells by inhibiting PI3K/AKT/mTOR signal pathway through downregulating the expression of SIRT1. Int J Radiat Biol 2021; 97:452-463. [PMID: 33507132 DOI: 10.1080/09553002.2021.1866225] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 12/10/2020] [Accepted: 12/14/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Radiotherapy is an effective treatment for esophageal squamous cell carcinoma (ESCC). However, many ESCC patients relapsed after receiving radiotherapy due to the inherent resistance. The function of miR-34a and SIRT1, as well as the correlation between miR-34a and SIRT1 has been widely claimed in multiple types of malignant tumors. This study aimed to investigate the effects of miR-34a on radiation resistance against ESCC and the underlying mechanism. METHODS In this study, CCK8, flow cytometry, wounding healing assays, and cell clone formation assay were used to determine the in vitro anti-tumor effects of radiation on radiation-resistant ESCC cell line (rECA-109). The luciferase activity and Western Blot assays were used to investigate the relationship among miR-34a, SIRT1, and the anti-radiation resistant effects. The xenograft experiments were used to verify the important function of miR-34a and SIRT1 in radiation resistance against ESCC. The apoptosis state of tumor tissues was evaluated by TUNEL assay. RESULTS The introduction of miR-34a significantly induced the cell death and apoptosis of rECA-109 and inhibit the migration of rECA-109 treated by radiation. The anti-tumor effect was accompanied by the downregulation of SIRT1 and the inhibition of PI3K/AKT/mTOR signal pathway. The radiation resistance on rECA-109 cells was reversed by silencing SIRT1, accompanied by the PI3K/AKT/mTOR signal pathway inhibited. In vivo experiments revealed that the radiation resistance on ESCC was reversed by the introduction of miR-34a, the effect of which was promoted by the activation of SIRT1. CONCLUSION Our results showed that miR-34a could reverse the radiation resistance on rECA-109 cells by downregulating the expression of SIRT1through inhibiting the PI3K-AKT-mTOR signal pathway.
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Affiliation(s)
- Zhimin Ye
- Department of Radiation Oncology, Hangzhou City, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Pronvince, Hangzhou City, China
| | - Tieming Xie
- Department of Radiation Oncology, Hangzhou City, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Pronvince, Hangzhou City, China
| | - Fengqin Yan
- Department of Radiation Oncology, Hangzhou City, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Pronvince, Hangzhou City, China
| | - Lei Wang
- Department of Radiation Oncology, Hangzhou City, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Pronvince, Hangzhou City, China
| | - Jun Fang
- Department of Radiation Oncology, Hangzhou City, China
| | - Zhun Wang
- Department of Radiation Oncology, Hangzhou City, China
| | - Fujun Hu
- Department of Radiation Oncology, Hangzhou City, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Pronvince, Hangzhou City, China
| | - Fangzheng Wang
- Department of Radiation Oncology, Hangzhou City, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Pronvince, Hangzhou City, China
| | - Zhenfu Fu
- Department of Radiation Oncology, Hangzhou City, China
- Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Pronvince, Hangzhou City, China
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15
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Naghizadeh S, Mohammadi A, Duijf PHG, Baradaran B, Safarzadeh E, Cho WCS, Mansoori B. The role of miR-34 in cancer drug resistance. J Cell Physiol 2020; 235:6424-6440. [PMID: 32064620 DOI: 10.1002/jcp.29640] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/31/2020] [Indexed: 12/25/2022]
Abstract
Resistance to conventional chemotherapy remains a major cause of cancer relapse and cancer-related deaths. Therefore, there is an urgent need to overcome resistance barriers. To improve cancer treatment approaches, it is critical to elucidate the basic mechanisms underlying drug resistance. Increasingly, the mechanisms involving micro-RNAs (miRNAs) are studied because miRNAs are also considered practical therapeutic options due to high degrees of specificity, efficacy, and accuracy, as well as their ability to target multiple genes at the same time. Years of research have firmly established miR-34 as a key tumor suppressor miRNA whose target genes are involved in drug resistance mechanisms. Indeed, numerous articles show that low levels of circulating miR-34 or tumor-specific miR-34 expression are associated with poor response to chemotherapy. In addition, elevation of inherently low miR-34 levels in resistant cancer cells effectively restores sensitivity to chemotherapeutic agents. Here, we review this literature, also highlighting some contradictory observations. In addition, we discuss the potential utility of miR-34 expression as a predictive biomarker for chemotherapeutic drug response. Although caution needs to be exercised, miR-34 is emerging as a biomarker that could improve cancer precision medicine.
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Affiliation(s)
- Sanaz Naghizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mohammadi
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Pascal H G Duijf
- University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Australia
- Institute of Health and Biomedical Innovation, Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Safarzadeh
- Department of Microbiology and Immunology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | | | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
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16
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Laneve P, Caffarelli E. The Non-coding Side of Medulloblastoma. Front Cell Dev Biol 2020; 8:275. [PMID: 32528946 PMCID: PMC7266940 DOI: 10.3389/fcell.2020.00275] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 03/31/2020] [Indexed: 12/18/2022] Open
Abstract
Medulloblastoma (MB) is the most common pediatric brain tumor and a primary cause of cancer-related death in children. Until a few years ago, only clinical and histological features were exploited for MB pathological classification and outcome prognosis. In the past decade, the advancement of high-throughput molecular analyses that integrate genetic, epigenetic, and expression data, together with the availability of increasing wealth of patient samples, revealed the existence of four molecularly distinct MB subgroups. Their further classification into 12 subtypes not only reduced the well-characterized intertumoral heterogeneity, but also provided new opportunities for the design of targets for precision oncology. Moreover, the identification of tumorigenic and self-renewing subpopulations of cancer stem cells in MB has increased our knowledge of its biology. Despite these advancements, the origin of MB is still debated, and its molecular bases are poorly characterized. A major goal in the field is to identify the key genes that drive tumor growth and the mechanisms through which they are able to promote tumorigenesis. So far, only protein-coding genes acting as oncogenic drivers have been characterized in each MB subgroup. The contribution of the non-coding side of the genome, which produces a plethora of transcripts that control fundamental biological processes, as the cell choice between proliferation and differentiation, is still unappreciated. This review wants to fill this major gap by summarizing the recent findings on the impact of non-coding RNAs in MB initiation and progression. Furthermore, their potential role as specific MB biomarkers and novel therapeutic targets is also highlighted.
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Affiliation(s)
- Pietro Laneve
- Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
| | - Elisa Caffarelli
- Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
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17
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Kim JW, Yang JH, Kim EJ. SIRT1 and AROS suppress doxorubicin-induced apoptosis via inhibition of GSK3β activity in neuroblastoma cells. Anim Cells Syst (Seoul) 2020; 24:53-59. [PMID: 32158616 PMCID: PMC7048222 DOI: 10.1080/19768354.2020.1726461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/14/2020] [Accepted: 02/03/2020] [Indexed: 01/27/2023] Open
Abstract
SIRT1, the best-characterized member of the sirtuin family of deacetylases, is involved in cancer, apoptosis, inflammation, and metabolism. Active regulator of SIRT1 (AROS) was the first identified direct regulator of SIRT1. An increasing number of reports have indicated that SIRT1 plays an important role in controlling brain tumors. Here, we demonstrated that depletion of SIRT1 and AROS increases doxorubicin-mediated apoptosis in human neuroblastoma SH-SY5Y cells. Glycogen synthase kinase 3β (GSK3β) promoted doxorubicin-mediated apoptosis, but this effect was abolished by overexpression of SIRT1 and AROS. Interestingly, SIRT1 and AROS interacted with GSK3β and increased inhibitory phosphorylation of GSK3β on Ser9. Finally, we determined that AROS cooperates with SIRT1 to suppress GSK3β acetylation. Taken together, our results suggest that SIRT1 and AROS inhibit GSK3β activity and provide additional insight into drug resistance in the treatment of neuroblastoma.
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Affiliation(s)
- Jeong Woo Kim
- Department of Molecular Biology, Dankook University, Cheonan-si, Korea
| | - Ji Hye Yang
- Department of Molecular Biology, Dankook University, Cheonan-si, Korea
| | - Eun-Joo Kim
- Department of Molecular Biology, Dankook University, Cheonan-si, Korea
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18
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Braoudaki M, Koutsouris DD, Kouris I, Paidi A, Koutsouri G, George Lambrou I. Bioinformatics and Regression Analyses Manifest Tumor-Specific miRNA Expression Dynamics in Pediatric Embryonal Malignancies. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2019; 2018:5834-5837. [PMID: 30441662 DOI: 10.1109/embc.2018.8513587] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Pediatric Central Nervous System (CNS) neoplasms are the second most prevalent tumors of childhood. Further on, prognosis of this type of neoplasms still remain poor and the comprehension of the etiology and pathogenesis of the disease still remains scarce. Several reports have identified microRNAs as significant molecules in the development of central nervous system tumors and propose that they might compose key molecules underlying oncogenesis. In a previous study we have identified several miRNAs, common to different subtypes of pediatric embryonal CNS malignancies as well as, we have identified miRNAs that manifest significant dynamics with respect to their expression and the neoplasmatic subtype. Overall, 19 tumor cases from children diagnosed with embryonal brain tumors were investigated. As controls, children who suffered a sudden death underwent autopsy and were not present with any brain malignancy were used (13 samples of varying localization). Our experimental approach included microarrays covering 1211 miRNAs, which appeared to manifest tumor-specific dynamics. In conclusion, it appeared that certain miRNAs are neoplasm specific and in particular, their expression manifests linear dynamics. Thus, the investigation of miRNA expression in pediatric embryonal brain tumors might contribute towards the discovery of tumor-specific miRNA signatures, which could potentially afford the identification of gene-specific biomarkers related to diagnosis, prognosis and patient targeted therapy, as well as help us understand oncogenetic dynamics.
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19
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Janaki Ramaiah M, Divyapriya K, Kartik Kumar S, Rajesh YBRD. Drug-induced modifications and modulations of microRNAs and long non-coding RNAs for future therapy against Glioblastoma Multiforme. Gene 2019; 723:144126. [PMID: 31589963 DOI: 10.1016/j.gene.2019.144126] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 09/11/2019] [Accepted: 09/12/2019] [Indexed: 02/07/2023]
Abstract
Non-coding RNAs are known to participate in cancer initiation, progression, and metastasis by regulating the status of chromatin epigenetics and gene expression. Although these non-coding RNAs do not possess defined protein-coding potential, they are involved in the expression and stability of messenger RNA (mRNA). The length of microRNAs (miRs) ranges between 20 and 22 nt, whereas, long non-coding RNAs (lncRNAs) length ranges between 200 nt to 1 Kb. In the case of circular RNAs (circRNAs), the size varies depending upon the length of the exon from where they were derived. Epigenetic regulations of miR and lncRNA genes will influence the gene expression by modulating histone acetylation and methylation patterns. Especially, lncRNAs will act as a scaffold for various epigenetic proteins, such as EZH2 and LSD1, and influence the chromatin epigenetic state at various genomic loci involved at silencing. Thus investigations on the expression of lncRNAs and designing drugs to modulate the expression of these genes will have a profound impact on future therapeutics against cancers such as Glioblastoma Multiforme (GBM) and also against various other diseases. With the recent advancements in genome-wide transcriptomic studies, scientists are focused on the non-coding RNAs and their regulations on various cellular processes involved in GBM and on other types of cancer as well as trying to understand possible epigenetic modulations that help in generating promising therapeutics for the future generations. In this review, the involvement of epigenetic proteins, enzymes that change chromatin architecture and epigenetic landscape and new roles of lncRNAs that are involved in GBM progression are elaborately discussed.
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Affiliation(s)
- M Janaki Ramaiah
- Laboratory of Functional Genomics and Disease Biology, School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur 613401, Tamil Nadu, India.
| | - Karthikeyan Divyapriya
- Laboratory of Functional Genomics and Disease Biology, School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur 613401, Tamil Nadu, India
| | - Sarwareddy Kartik Kumar
- Laboratory of Functional Genomics and Disease Biology, School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur 613401, Tamil Nadu, India
| | - Y B R D Rajesh
- Organic Synthesis and Catalysis Laboratory, School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur 613401, Tamil Nadu, India
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20
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Zheng SZ, Sun P, Wang JP, Liu Y, Gong W, Liu J. MiR-34a overexpression enhances the inhibitory effect of doxorubicin on HepG2 cells. World J Gastroenterol 2019; 25:2752-2762. [PMID: 31235998 PMCID: PMC6580351 DOI: 10.3748/wjg.v25.i22.2752] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/13/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the third leading cause of death from malignant tumors worldwide. More than 50% of HCC cases occur in China. The prognosis remains poor and overall efficacy is still unsatisfactory. Chemotherapy resistance is the most important reason for the poor outcome. Much progress has been made in the study of chemotherapy resistance of HCC; however, the specific mechanisms of progression of HCC have still only been partially established. Therefore, the mechanism of chemotherapy resistance in HCC requires more research.
AIM To investigate the effect of miR-34a expression on the growth inhibition of HepG2 cells by doxorubicin.
METHODS A recombinant lentiviral vector containing miR-34a was constructed and transfected into HepG2 cells. The expression of miR-34a was detected by reverse transcription-polymerase chain reaction (commonly known as RT-PCR) before and after transfection. Cells were exposed to 2 μM doxorubicin or phosphate-buffered saline before and after transfection. Cell viability in each group was detected by MTT assay, and cell cycle and apoptosis were detected by flow cytometry. Changes in expression levels of phospho (p)-p53, sirtuin (SIRT) 1, cyclin D1, cyclin-dependent kinase (CDK) 4, CDK6, BCL-2, multidrug resistance protein (MDR) 1/P glycoprotein (P-gp), and AXL were detected by Western blotting.
RESULTS Recombinant lentiviral vector LV-hsa-mir-34a was successfully constructed by restriction endonuclease digestion and sequencing. RT-PCR showed that expression of miR-34a in HepG2 cells was significantly upregulated after transfection (P < 0.01). MTT assay showed that growth of HepG2 cells was inhibited after upregulation of miR-34a, and viability was significantly decreased after combined treatment with doxorubicin (P < 0.01). Flow cytometry showed that the number of HepG2 cells in G1 phase increased, and G1 phase arrest was more obvious after intervention with doxorubicin (P < 0.01). The apoptosis rate of HepG2 cells was increased after upregulation of miR-34a, and became more obvious after intervention with doxorubicin (P < 0.01). Western blotting showed that upregulation of miR-34a combined with treatment with doxorubicin caused significant changes in the expression levels of p-p53, SIRT1, cyclin D1, CDK4, CDK6, BCL-2, MDR1/P-gp and AXL proteins (P < 0.01).
CONCLUSION MiR-34a may enhance the inhibitory effect of doxorubicin by downregulating MDR1/P-gp and AXL, which may be related to p53 expression.
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Affiliation(s)
- Shun-Zhen Zheng
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China
| | - Ping Sun
- Department of Clinical Laboratory, Blood Station of Jinan, Jinan 250021, Shandong Province, China
| | - Jian-Ping Wang
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China
| | - Yong Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China
| | - Wei Gong
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China
| | - Jun Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China
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21
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Cowman S, Fan YN, Pizer B, Sée V. Decrease of Nibrin expression in chronic hypoxia is associated with hypoxia-induced chemoresistance in some brain tumour cells. BMC Cancer 2019; 19:300. [PMID: 30943920 PMCID: PMC6446413 DOI: 10.1186/s12885-019-5476-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 03/14/2019] [Indexed: 12/03/2022] Open
Abstract
Background Solid tumours are less oxygenated than normal tissues. This is called tumour hypoxia and leads to resistance to radiotherapy and chemotherapy. The molecular mechanisms underlying such resistance have been investigated in a range of tumour types, including the adult brain tumours glioblastoma, yet little is known for paediatric brain tumours. Medulloblastoma (MB) is the most common malignant brain tumour in children. We aimed to elucidate the impact of hypoxia on the sensitivity of MB cells to chemo- and radiotherapy. Methods We used two MB cell line (D283-MED and MEB-Med8A) and a widely used glioblastoma cell line (U87MG) for comparison. We applied a range of molecular and cellular techniques to measure cell survival, cell cycle progression, protein expression and DNA damage combined with a transcriptomic micro-array approach in D283-MED cells, for global gene expression analysis in acute and chronic hypoxic conditions. Results In D283-MED and U87MG, chronic hypoxia (5 days), but not acute hypoxia (24 h) induced resistance to chemotherapy and X-ray irradiation. This acquired resistance upon chronic hypoxia was present but less pronounced in MEB-Med8A cells. Using transcriptomic analysis in D283-MED cells, we found a large transcriptional remodelling upon long term hypoxia, in particular the expression of a number of genes involved in detection and repair of double strand breaks (DSB) was altered. The levels of Nibrin (NBN) and MRE11, members of the MRN complex (MRE11/Rad50/NBN) responsible for DSB recognition, were significantly down-regulated. This was associated with a reduction of Ataxia Telangiectasia Mutated (ATM) activation by etoposide, indicating a profound dampening of the DNA damage signalling in hypoxic conditions. As a consequence, p53 activation by etoposide was reduced, and cell survival enhanced. Whilst U87MG shared the same dampened p53 activity, upon chemotherapeutic drug treatment in chronic hypoxic conditions, these cells used a different mechanism, independent of the DNA damage pathway. Conclusion Together our results demonstrate a new mechanism explaining hypoxia-induced resistance involving the alteration of the response to DSB in D283-MED cells, but also highlight the cell type to cell type diversity and the necessity to take into account the differing tumour genetic make-up when considering re-sensitisation therapeutic protocols. Electronic supplementary material The online version of this article (10.1186/s12885-019-5476-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sophie Cowman
- University of Liverpool, Institute of Integrated Biology, Department of Biochemistry, Centre for Cell Imaging, L69 7ZB, Liverpool, UK
| | - Yuen Ngan Fan
- University of Liverpool, Institute of Integrated Biology, Department of Biochemistry, Centre for Cell Imaging, L69 7ZB, Liverpool, UK.,University of Manchester, Faculty of Biology, Medicine and Health, M13 9PT, Manchester, UK
| | - Barry Pizer
- University of Liverpool and Alder Hey Children's NHS Foundation Trust, member of Liverpool Health Partners., Liverpool, UK
| | - Violaine Sée
- University of Liverpool, Institute of Integrated Biology, Department of Biochemistry, Centre for Cell Imaging, L69 7ZB, Liverpool, UK.
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Jesionek-Kupnicka D, Braun M, Trąbska-Kluch B, Czech J, Szybka M, Szymańska B, Kulczycka-Wojdala D, Bieńkowski M, Kordek R, Zawlik I. MiR-21, miR-34a, miR-125b, miR-181d and miR-648 levels inversely correlate with MGMT and TP53 expression in primary glioblastoma patients. Arch Med Sci 2019; 15:504-512. [PMID: 30899304 PMCID: PMC6425218 DOI: 10.5114/aoms.2017.69374] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 03/25/2017] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION TP53 and MGMT alterations play a crucial role in glioblastoma (GB) pathogenesis. TP53 and MGMT function is affected by several pathologic mechanisms, such as point mutations or promoter methylation, which are well characterized. Expression of both genes can be regulated by other mechanisms as well, e.g., microRNAs (miRNAs). Moreover, cross-talk among various pathologic processes may occur, further affecting MGMT and TP53 functionality. MATERIAL AND METHODS In 49 GB patients, we analyzed the possible associations between TP53 and its miRNA regulators miR-125b, miR-21, and miR-34a, as well as MGMT and its miRNA regulators miR-181d and miR-648. We evaluated the possible influence of mutational and methylation status on the pre-identified associations. RESULTS In patients with immunohistochemistry-detected TP53 overexpression, expression levels of miR-34a and TP53 were negatively correlated (r = -0.56, p = 0.0195), and in patients with TP53 mutations, expression levels of TP53 and miR-21 were negatively correlated (r = -0.67, p = 0.0330). In patients with MGMT methylation, expression levels of MGMT were negatively correlated with miR-648 and miR-125b expression levels (r = -0.61, p = 0.0269 and r = -0.34, p = 0.0727, respectively). CONCLUSIONS Our findings demonstrate that selected miRNAs are significantly correlated with MGMT and TP53 levels, but the extent of this correlation differs regarding the TP53 and MGMT mutational and promoter methylation status.
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Affiliation(s)
| | - Marcin Braun
- Department of Pathology, Chair of Oncology, Medical University of Lodz, Lodz, Poland
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Joanna Czech
- Department of Genetics, Chair of Molecular Medicine, Faculty of Medicine, University of Rzeszow, Rzeszow, Poland
- Laboratory of Molecular Biology, Centre for Innovative Research in Medical and Natural Sciences, University of Rzeszow, Rzeszow, Poland
| | - Małgorzata Szybka
- Department of Microbiology and Laboratory Medical Immunology, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Bożena Szymańska
- Central Scientific Laboratory, Medical University of Lodz, Lodz, Poland
| | | | - Michał Bieńkowski
- Department of Pathomorphology, Medical University of Gdansk, Gdansk, Poland
| | - Radzisław Kordek
- Department of Pathology, Chair of Oncology, Medical University of Lodz, Lodz, Poland
| | - Izabela Zawlik
- Department of Genetics, Chair of Molecular Medicine, Faculty of Medicine, University of Rzeszow, Rzeszow, Poland
- Laboratory of Molecular Biology, Centre for Innovative Research in Medical and Natural Sciences, University of Rzeszow, Rzeszow, Poland
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23
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Wang X, Holgado BL, Ramaswamy V, Mack S, Zayne K, Remke M, Wu X, Garzia L, Daniels C, Kenney AM, Taylor MD. miR miR on the wall, who's the most malignant medulloblastoma miR of them all? Neuro Oncol 2019; 20:313-323. [PMID: 28575493 DOI: 10.1093/neuonc/nox106] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
microRNAs (miRNAs) have wide-ranging effects on large-scale gene regulation. As such, they play a vital role in dictating normal development, and their aberrant expression has been implicated in cancer. There has been a large body of research on the role of miRNAs in medulloblastoma, the most common malignant brain tumor of childhood. The identification of the 4 molecular subgroups with distinct biological, genetic, and transcriptional features has revolutionized the field of medulloblastoma research over the past 5 years. Despite this, the growing body of research on miRNAs in medulloblastoma has largely focused on the clinical entity of a single disease rather than the molecular subgroups. This review begins by highlighting the role of miRNAs in development and progresses to explore their myriad of implications in cancer. Medulloblastoma is characterized by increased proliferation, inhibition of apoptosis, and maintenance of stemness programs-features that are inadvertently regulated by altered expression patterns in miRNAs. This review aims to contextualize the large body of work on miRNAs within the framework of medulloblastoma subgroups. The goal of this review is to stimulate new areas of research, including potential therapeutics, within a rapidly growing field.
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Affiliation(s)
- Xin Wang
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Borja L Holgado
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Vijay Ramaswamy
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.,Department of Haematology & Oncology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Stephen Mack
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Kory Zayne
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Marc Remke
- German Cancer Consortium, University of Düsseldorf, Düsseldorf, Germany
| | - Xiaochong Wu
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Livia Garzia
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Craig Daniels
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Anna M Kenney
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.,Department of Pediatric Oncology, Emory University, Atlanta, Georgia, USA.,Winship Cancer Institute, Atlanta, Georgia, USA
| | - Michael D Taylor
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.,Division of Neurosurgery, Hospital for Sick Children, Toronto, Ontario, Canada
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24
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Molecular pathways involved in microRNA-mediated regulation of multidrug resistance. Mol Biol Rep 2018; 45:2913-2923. [DOI: 10.1007/s11033-018-4358-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Accepted: 09/03/2018] [Indexed: 12/23/2022]
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25
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Grohmann T, Penke M, Petzold-Quinque S, Schuster S, Richter S, Kiess W, Garten A. Inhibition of NAMPT sensitizes MOLT4 leukemia cells for etoposide treatment through the SIRT2-p53 pathway. Leuk Res 2018; 69:39-46. [PMID: 29653431 DOI: 10.1016/j.leukres.2018.04.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 03/31/2018] [Accepted: 04/04/2018] [Indexed: 10/17/2022]
Abstract
NAMPT (Nicotinamide phosphoribosyltransferase) catalyses the rate-limiting step in the NAD biosynthesis from nicotinamide and thereby regulates the activity of NAD-dependent enzymes. Cancer cells are highly dependent on NAD for energy and DNA repair processes and are assumed to be more susceptible to an inhibition of NAD synthesis than non-transformed cells. We aimed to investigate whether or not inhibition of NAMPT with its specific inhibitor FK866 can sensitize leukemia cells for chemotherapeutic agents. NAMPT protein abundance, enzymatic activity and NAD concentrations were significantly higher in Jurkat and Molt-4 leukemia cell lines compared to normal peripheral blood mononuclear cells. Combination of etoposide and FK866 caused increased cell death in leukemia cell lines compared to etoposide alone. Etoposide decreased protein abundance of NAD-dependent deacetylases SIRTUIN1. After combining etoposide and FK866 treatment SIRTUIN2 was further decreased and accumulation and acetylation of the downstream target p53 was further enhanced in MOLT4 cells. Concomitantly, protein abundance of p21 and cleaved BAX was increased. Targeting NAMPT could be a novel therapeutic strategy to enhance the efficacy of chemotherapeutic agents such as etoposide against leukemia.
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Affiliation(s)
- Theresa Grohmann
- Hospital for Children & Adolescents, Center for Pediatric Research Leipzig, University of Leipzig, Germany
| | - Melanie Penke
- Hospital for Children & Adolescents, Center for Pediatric Research Leipzig, University of Leipzig, Germany
| | - Stefanie Petzold-Quinque
- Hospital for Children & Adolescents, Center for Pediatric Research Leipzig, University of Leipzig, Germany
| | - Susanne Schuster
- Hospital for Children & Adolescents, Center for Pediatric Research Leipzig, University of Leipzig, Germany
| | - Sandy Richter
- Hospital for Children & Adolescents, Center for Pediatric Research Leipzig, University of Leipzig, Germany
| | - Wieland Kiess
- Hospital for Children & Adolescents, Center for Pediatric Research Leipzig, University of Leipzig, Germany
| | - Antje Garten
- Hospital for Children & Adolescents, Center for Pediatric Research Leipzig, University of Leipzig, Germany; University of Birmingham, Institute of Metabolism and Systems Research (IMSR), Birmingham, UK.
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26
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Yue Z, Zhou Y, Zhao P, Chen Y, Yuan Y, Jing Y, Wang X. p53 Deletion promotes myeloma cells invasion by upregulating miR19a/CXCR5. Leuk Res 2017; 60:115-122. [PMID: 28783539 DOI: 10.1016/j.leukres.2017.07.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 06/08/2017] [Accepted: 07/23/2017] [Indexed: 01/07/2023]
Abstract
P53 deletion has been identified as one of the few factors that defined high risk and poor prognosis in MM. It has been reported p53 deletion is associated with resistance to chemotherapy and organ infiltrations of MM. However, p53 deletion in the migration and dissemination of MM cells has not been totally elucidated. In this research, first, we investigated whether p53 is associated with migration of MM cells. We found that p53 regulates the migration of NCI-H929 cells with wild-type p53 but not U266 cells with mutated-type p53. Next, we investigated the related mechanism by which p53 regulates the migration. We found that down-regulation of p53 reduced adhesion of NCI-H929 cells to the BM stroma via decreased expression of E-cadherin and increased EMT-regulating proteins. Further study have identified the miR-19a/CXCR5 pathway as a candidate p53-induced migration mechanism. In conclusion, we have demonstrated for the first time the critical value of p53 deletion in MM cell migration and dissemination, as well as the acquisition of an EMT-like phenotype. Our research provides new insights into the function of p53 in migration of MM and suggests p53/miRNA19a/CXCR5 may provide potentially therapeutic targets for the treatment of myeloma with p53 deletion.
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Affiliation(s)
- Zhijie Yue
- Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Cancer Hospital of Tianjin, China
| | - Yongxia Zhou
- Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Cancer Hospital of Tianjin, China
| | - Pan Zhao
- Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Cancer Hospital of Tianjin, China
| | - Yafang Chen
- Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Cancer Hospital of Tianjin, China
| | - Ying Yuan
- Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Cancer Hospital of Tianjin, China
| | - Yaoyao Jing
- Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Cancer Hospital of Tianjin, China
| | - Xiaofang Wang
- Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Cancer Hospital of Tianjin, China.
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27
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An X, Sarmiento C, Tan T, Zhu H. Regulation of multidrug resistance by microRNAs in anti-cancer therapy. Acta Pharm Sin B 2017; 7:38-51. [PMID: 28119807 PMCID: PMC5237711 DOI: 10.1016/j.apsb.2016.09.002] [Citation(s) in RCA: 153] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 05/30/2016] [Accepted: 07/06/2016] [Indexed: 12/31/2022] Open
Abstract
Multidrug resistance (MDR) remains a major clinical obstacle to successful cancer treatment. Although diverse mechanisms of MDR have been well elucidated, such as dysregulation of drugs transporters, defects of apoptosis and autophagy machinery, alterations of drug metabolism and drug targets, disrupti on of redox homeostasis, the exact mechanisms of MDR in a specific cancer patient and the cross-talk among these different mechanisms and how they are regulated are poorly understood. MicroRNAs (miRNAs) are a new class of small noncoding RNAs that could control the global activity of the cell by post-transcriptionally regulating a large variety of target genes and proteins expression. Accumulating evidence shows that miRNAs play a key regulatory role in MDR through modulating various drug resistant mechanisms mentioned above, thereby holding much promise for developing novel and more effective individualized therapies for cancer treatment. This review summarizes the various MDR mechanisms and mainly focuses on the role of miRNAs in regulating MDR in cancer treatment.
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Affiliation(s)
- Xin An
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Cesar Sarmiento
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Tao Tan
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Corresponding authors..
| | - Hua Zhu
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Corresponding authors..
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28
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The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells. Aging (Albany NY) 2016; 7:854-68. [PMID: 26540407 PMCID: PMC4637210 DOI: 10.18632/aging.100831] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Medulloblastoma (MB), a primitive neuroectodermal tumor, is the most common malignant childhood brain tumor and remains incurable in about a third of patients. Currently, survivors carry a significant burden of late treatment effects. The p53 tumor suppressor protein plays a crucial role in influencing cell survival in response to cellular stress and while the p53 pathway is considered a key determinant of anti-tumor responses in many tumors, its role in cell survival in MB is much less well defined. Herein, we report that the experimental drug VMY-1-103 acts through induction of a partial DNA damage-like response as well induction of non-survival autophagy. Surprisingly, the genetic or chemical silencing of p53 significantly enhanced the cytotoxic effects of both VMY and the DNA damaging drug, doxorubicin. The inhibition of p53 in the presence of VMY revealed increased late stage apoptosis, increased DNA fragmentation and increased expression of genes involved in apoptosis, including CAPN12 and TRPM8, p63, p73, BIK, EndoG, CIDEB, P27Kip1 and P21cip1. These data provide the groundwork for additional studies on VMY as a therapeutic drug and support further investigations into the intriguing possibility that targeting p53 function may be an effective means of enhancing clinical outcomes in MB.
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29
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Shea A, Harish V, Afzal Z, Chijioke J, Kedir H, Dusmatova S, Roy A, Ramalinga M, Harris B, Blancato J, Verma M, Kumar D. MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics. Cancer Med 2016; 5:1917-46. [PMID: 27282910 PMCID: PMC4971921 DOI: 10.1002/cam4.775] [Citation(s) in RCA: 151] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 04/05/2016] [Accepted: 04/14/2016] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and lethal cancer of the adult brain, remaining incurable with a median survival time of only 15 months. In an effort to identify new targets for GBM diagnostics and therapeutics, recent studies have focused on molecular phenotyping of GBM subtypes. This has resulted in mounting interest in microRNAs (miRNAs) due to their regulatory capacities in both normal development and in pathological conditions such as cancer. miRNAs have a wide range of targets, allowing them to modulate many pathways critical to cancer progression, including proliferation, cell death, metastasis, angiogenesis, and drug resistance. This review explores our current understanding of miRNAs that are differentially modulated and pathologically involved in GBM as well as the current state of miRNA-based therapeutics. As the role of miRNAs in GBM becomes more well understood and novel delivery methods are developed and optimized, miRNA-based therapies could provide a critical step forward in cancer treatment.
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Affiliation(s)
- Amanda Shea
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | | | - Zainab Afzal
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | - Juliet Chijioke
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | - Habib Kedir
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | - Shahnoza Dusmatova
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | - Arpita Roy
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | - Malathi Ramalinga
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | - Brent Harris
- Department of Neurology and PathologyGeorgetown UniversityWashingtonDistrict of Columbia20057
| | - Jan Blancato
- Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonDistrict of Columbia20057
| | - Mukesh Verma
- Division of Cancer Control and Population SciencesNational Cancer Institute (NCI)National Institutes of Health (NIH)RockvilleMaryland20850
| | - Deepak Kumar
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
- Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonDistrict of Columbia20057
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30
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Ye Z, Fang J, Dai S, Wang Y, Fu Z, Feng W, Wei Q, Huang P. MicroRNA-34a induces a senescence-like change via the down-regulation of SIRT1 and up-regulation of p53 protein in human esophageal squamous cancer cells with a wild-type p53 gene background. Cancer Lett 2015; 370:216-21. [PMID: 26523671 DOI: 10.1016/j.canlet.2015.10.023] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 10/21/2015] [Accepted: 10/22/2015] [Indexed: 12/16/2022]
Abstract
MiR-34a has been reported as a non-coding RNA universally expressed in normal old cells and a probable suppressor of diverse cancer cells; however, this miRNA's expression and anti-tumor mechanism in esophageal squamous cancer cells (ESCC) remains unclear. We explored these questions in three human ESCC lines, KYSE-450, KYSE-410, and ECa-109, with wild-type p53 and mutant p53 backgrounds. Through a specific stem-loop RT primer for miR-34a, we examined the relevant expression level of miR-34a in these three cell lines using real-time reverse transcription PCR (qRT-PCR). We found that the expression level of miR-34a induced by the DNA damage agent adrmycin (ADR) was both p53- and time-dependent. Following incubation with miR-34a, cellular growth inhibition was exhibited differently in the three cell lines harbored with different p53 backgrounds. Furthermore, the MTT assay demonstrated an miR-34a-related cytotoxic effect in cell growth. Senescence-associated β-galactosidase (SA-β-Gal) staining was used to examine senescence-like phenotypes induced by miR-34a. Mechanistic investigation suggested that the down-regulation of Sirtuin1 (SIRT1) and up-regulation of p53/p21 contributed to the anti-tumor mechanism of miR-34a in wild-type p53 ECa-109 cells, while neither of the apoptosis-related proteins PARP and caspase-3 caused significant changes. In summary, our findings indicated that the intrinsic expression of miR-34a was relatively low and was expressed differently among different p53 backgrounds and ADR treatment times. The anti-tumor effect of miR-34a was primarily dependent on the regulation of SIRT1 and p53/p21 protein, not apoptosis-associated proteins.
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Affiliation(s)
- Zhimin Ye
- Department of Radiation Oncology, Zhejiang Province Cancer Hospital, NO. 38 of Guang ji Road, Hangzhou 310022, China
| | - Jun Fang
- Department of Radiation Oncology, Zhejiang Province Cancer Hospital, NO. 38 of Guang ji Road, Hangzhou 310022, China
| | - Shujun Dai
- Department of Intense Care Unit, the Second Affiliated Hospital, Zhejiang University School of Medicine, NO. 88 of Jie fang Road, Hangzhou 310009, China
| | - Yuezhen Wang
- Department of Radiation Oncology, Zhejiang Province Cancer Hospital, NO. 38 of Guang ji Road, Hangzhou 310022, China
| | - Zhenfu Fu
- Department of Radiation Oncology, Zhejiang Province Cancer Hospital, NO. 38 of Guang ji Road, Hangzhou 310022, China
| | - Wei Feng
- Department of Radiation Oncology, Zhejiang Province Cancer Hospital, NO. 38 of Guang ji Road, Hangzhou 310022, China
| | - Qichun Wei
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, NO. 88 of Jie fang Road, Hangzhou 310009, China
| | - Pintong Huang
- Department of Ultrasonography, the Second Affiliated Hospital, Zhejiang University School of Medicine, NO. 88 of Jie fang Road, Hangzhou 310009, China.
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Braoudaki M, Lambrou GI, Giannikou K, Milionis V, Stefanaki K, Birks DK, Prodromou N, Kolialexi A, Kattamis A, Spiliopoulou CA, Tzortzatou-Stathopoulou F, Kanavakis E. Microrna expression signatures predict patient progression and disease outcome in pediatric embryonal central nervous system neoplasms. J Hematol Oncol 2014; 7:96. [PMID: 25551588 PMCID: PMC4342799 DOI: 10.1186/s13045-014-0096-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 12/12/2014] [Indexed: 02/07/2023] Open
Abstract
Background Although, substantial experimental evidence related to diagnosis and treatment of pediatric central nervous system (CNS) neoplasms have been demonstrated, the understanding of the etiology and pathogenesis of the disease remains scarce. Recent microRNA (miRNA)-based research reveals the involvement of miRNAs in various aspects of CNS development and proposes that they might compose key molecules underlying oncogenesis. The current study evaluated miRNA differential expression detected between pediatric embryonal brain tumors and normal controls to characterize candidate biomarkers related to diagnosis, prognosis and therapy. Methods Overall, 19 embryonal brain tumors; 15 Medulloblastomas (MBs) and 4 Atypical Teratoid/Rabdoid Tumors (AT/RTs) were studied. As controls, 13 samples were used; The First-Choice Human Brain Reference RNA and 12 samples from deceased children who underwent autopsy and were not present with any brain malignancy. RNA extraction was carried out using the Trizol method, whilst miRNA extraction was performed with the mirVANA miRNA isolation kit. The experimental approach included miRNA microarrays covering 1211 miRNAs. Quantitative Real-Time Polymerase Chain Reaction was performed to validate the expression profiles of miR-34a and miR-601 in all 32 samples initially screened with miRNA microarrays and in an additional independent cohort of 30 patients (21MBs and 9 AT/RTs). Moreover, meta-analyses was performed in total 27 embryonal tumor samples; 19 MBs, 8 ATRTs and 121 control samples. Twelve germinomas were also used as an independent validation cohort. All deregulated miRNAs were correlated to patients’ clinical characteristics and pathological measures. Results In several cases, there was a positive correlation between individual miRNA expression levels and laboratory or clinical characteristics. Based on that, miR-601 could serve as a putative tumor suppressor gene, whilst miR-34a as an oncogene. In general, miR-34a demonstrated oncogenic roles in all pediatric embryonal CNS neoplasms studied. Conclusions Deeper understanding of the aberrant miRNA expression in pediatric embryonal brain tumors might aid in the development of tumor-specific miRNA signatures, which could potentially afford promising biomarkers related to diagnosis, prognosis and patient targeted therapy. Electronic supplementary material The online version of this article (doi:10.1186/s13045-014-0096-y) contains supplementary material, which is available to authorized users.
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