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1
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Cihan M, Schmauck G, Sprang M, Andrade-Navarro MA. Unveiling cell-type-specific microRNA networks through alternative polyadenylation in glioblastoma. BMC Biol 2025; 23:15. [PMID: 39838429 PMCID: PMC11752630 DOI: 10.1186/s12915-024-02104-8] [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: 04/10/2024] [Accepted: 12/20/2024] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is characterized by its cellular complexity, with a microenvironment consisting of diverse cell types, including oligodendrocyte precursor cells (OPCs) and neoplastic CD133 + radial glia-like cells. This study focuses on exploring the distinct cellular transitions in GBM, emphasizing the role of alternative polyadenylation (APA) in modulating microRNA-binding and post-transcriptional regulation. RESULTS Our research identified unique APA profiles that signify the transitional phases between neoplastic cells and OPCs, underscoring the importance of APA in cellular identity and transformation in GBM. A significant finding was the disconnection between differential APA events and gene expression alterations, indicating that APA operates as an independent regulatory mechanism. We also highlighted the specific genes in neoplastic cells and OPCs that lose microRNA-binding sites due to APA, which are crucial for maintaining stem cell characteristics and DNA repair, respectively. The constructed networks of microRNA-transcription factor-target genes provide insights into the cellular mechanisms influencing cancer cell survival and therapeutic resistance. CONCLUSIONS This study elucidates the APA-driven regulatory framework within GBM, spotlighting its influence on cell state transitions and microRNA network dynamics. Our comprehensive analysis using single-cell RNA sequencing data to investigate the microRNA-binding sites altered by APA profiles offers a robust foundation for future research, presenting a novel approach to understanding and potentially targeting the complex molecular interplay in GBM.
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Affiliation(s)
- Mert Cihan
- Faculty of Biology, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Greta Schmauck
- Faculty of Biology, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Maximilian Sprang
- Faculty of Biology, Johannes Gutenberg University Mainz, Mainz, Germany
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2
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Motamed-Sanaye A, Mortezaei A, Afshari AR, Saadatian Z, Faraji AH, Sheehan JP, Mokhtari AM. Angiogenesis inhibitors effects on overall survival and progression-free survival in newly diagnosed primary glioblastoma multiforme: a meta-analysis of twelve randomized clinical trials. J Neurooncol 2025; 171:313-328. [PMID: 39636552 DOI: 10.1007/s11060-024-04865-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 10/23/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Typically treated with initial surgical resection, and chemoradiotherapy, despite current treatments, patients typically survive only 12-14 months, necessitating new therapeutic approaches. Our meta-analysis evaluates combining antiangiogenic medications with chemoradiotherapy versus using chemoradiotherapy alone in treating newly diagnosed GBM. METHODS A comprehensive literature search was conducted using PubMed/MEDLINE, Scopus, Cochrane and the Web of Science databases. The search aimed to identify studies reporting overall survival (OS), progression-free survival (PFS), and hazard ratio (HR) with corresponding confidence intervals (CIs) in patients with newly diagnosed GBM. We employed random-effect meta-analysis. RESULTS Twelve randomized clinical trials (RCTs) involved 3,309 patients included in the study. The findings showed that angiogenesis inhibitors significantly prolonged PFS [HR 0.85, 95% CI (0.73, 0.99), p-value = 0.04], while there was no significant difference on OS [HR 1.014, 95%CI (0.89, 1.15), p-value = 0.84]. Bevacizumab (BEV) exhibited the highest [HR 0.67, 95% CI (0.56, 0.79), p-value < 0.0001] and thalidomide exhibited the lowest [HR 1.46, 95% CI (1.004, 2.1), p-value = 0.048] improvements of PFS. Meta-regression revealed that age, white race, study sample size, infection, vascular disease complications, KPS > 60, biopsy, gross and subtotal resection can significantly influenced the PFS, while only the year of publication affected OS. CONCLUSIONS The current study showed that improve the PFS with no significant effect on OS. Our findings may provide some evidence for decision-making regarding the utilization of angiogenesis inhibitors for the treatment of adult patients with newly diagnosed GBM.
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Affiliation(s)
- Ali Motamed-Sanaye
- Student Research Committee, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Ali Mortezaei
- Student Research Committee, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Amir R Afshari
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Zahra Saadatian
- Department of Physiology, Faculty of Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran.
| | - Amir H Faraji
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
| | - Jason P Sheehan
- Department of Neurological Surgery, University of Virginia, Charlottesville, VA, USA
| | - Ali Mohammad Mokhtari
- Department of Epidemiology and Biostatistics, School of Health, Reproductive Health and Population Research Center, Gonabad University of Medical Sciences, Gonabad, Iran.
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3
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Sandhanam K, Tamilanban T. Unraveling the noncoding RNA landscape in glioblastoma: from pathogenesis to precision therapeutics. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:9475-9502. [PMID: 39007929 DOI: 10.1007/s00210-024-03265-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024]
Abstract
Glioblastoma (GBM) is an aggressive type IV brain tumor that originates from astrocytes and has a poor prognosis. Despite intensive research, survival rates have not significantly improved. Noncoding RNAs (ncRNAs) are emerging as critical regulators of carcinogenesis, progression, and increased treatment resistance in GBM cells. They influence angiogenesis, migration, epithelial-to-mesenchymal transition, and invasion in GBM cells. ncRNAs, such as long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are commonly dysregulated in GBM. miRNAs, such as miR-21, miR-133a, and miR-27a-3p, are oncogenes that increase cell proliferation, metastasis, and migration by targeting TGFBR1 and BTG2. In contrast, lncRNAs, such as HOXD-AS2 and LINC00511, are oncogenes that increase the migration, invasion, and proliferation of cells. CircRNAs, such as circ0001730, circENTPD7, and circFOXO3, are oncogenes responsible for cell growth, angiogenesis, and viability. Developing novel therapeutic strategies targeting ncRNAs, cell migration, and angiogenesis is a promising approach for GBM. By targeting these dysregulated ncRNAs, we can potentially restore a healthy balance in gene expression and influence disease progression. ncRNAs abound within GBM, demonstrating significant roles in governing the growth and behavior of these tumors. They may also be useful as biomarkers or targets for therapy. The use of morpholino oligonucleotides (MOs) suppressing the oncogene expression of HOTAIR, BCYRN1, and cyrano, antisense oligonucleotides (ASOs) suppressing the expression of ncRNAs such as MALAT1 and miR-10b, locked nucleic acids (LNAs) suppressing miR-21, and peptide nucleic acids (PNAs) suppressing the expression of miR-155 inhibited the PI3K pathway, tumor growth, angiogenesis, proliferation, migration, and invasion. Targeting oncogenic ncRNAs with RNA-interfering strategies such as MOs, ASOs, LNAs, CRISPR-Cas9 gene editing, and PNA approaches may represent a promising therapeutic strategy for GBM. This review emphasizes the critical role of ncRNAs in GBM pathogenesis, as well as the potential for new therapeutic strategies targeting these pathways to improve the prognosis and quality of life for GBM patients.
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Affiliation(s)
- K Sandhanam
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, 603203, Tamil Nadu, India
| | - T Tamilanban
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, 603203, Tamil Nadu, India.
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4
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Dakal TC, Kakde GS, Maurya PK. Genomic, epigenomic and transcriptomic landscape of glioblastoma. Metab Brain Dis 2024; 39:1591-1611. [PMID: 39180605 DOI: 10.1007/s11011-024-01414-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/13/2024] [Indexed: 08/26/2024]
Abstract
The mostly aggressive and extremely malignant type of central nervous system is Glioblastoma (GBM), which is characterized by an extremely short average survival time of lesser than 16 months. The primary cause of this phenomenon can be attributed to the extensively altered genome of GBM, which is characterized by the dysregulation of numerous critical signaling pathways and epigenetics regulations associated with proliferation, cellular growth, survival, and apoptosis. In light of this, different genetic alterations in critical signaling pathways and various epigenetics regulation mechanisms are associated with GBM and identified as distinguishing markers. Such GBM prognostic alterations are identified in PI3K/AKT, p53, RTK, RAS, RB, STAT3 and ZIP4 signaling pathways, metabolic pathway (IDH1/2), as well as alterations in epigenetic regulation genes (MGMT, CDKN2A-p16INK4aCDKN2B-p15INK4b). The exploration of innovative diagnostic and therapeutic approaches that specifically target these pathways is utmost importance to enhance the future medication for GBM. This study provides a comprehensive overview of dysregulated epigenetic mechanisms and signaling pathways due to mutations, methylation, and copy number alterations of in critical genes in GBM with prevalence and emphasizing their significance.
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Affiliation(s)
- Tikam Chand Dakal
- Genome and Computational Biology Lab, Mohanlal Sukhadia, University, Udaipur, Rajasthan, 313001, India.
| | - Ganesh S Kakde
- Department of Biochemistry, Central University of Haryana, Mahendergarh, 123031, Haryana, India
| | - Pawan Kumar Maurya
- Department of Biochemistry, Central University of Haryana, Mahendergarh, 123031, Haryana, India.
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5
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Silvia Lima RQD, Vasconcelos CFM, Gomes JPA, Bezerra de Menezes EDS, de Oliveira Silva B, Montenegro C, Paiva Júnior SDSL, Pereira MC. miRNA-21, an oncomiR that regulates cell proliferation, migration, invasion and therapy response in lung cancer. Pathol Res Pract 2024; 263:155601. [PMID: 39413459 DOI: 10.1016/j.prp.2024.155601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 09/10/2024] [Accepted: 09/24/2024] [Indexed: 10/18/2024]
Abstract
Lung cancer is the leading cause of cancer-related death globally, with poor survival rates due mostly to a lack of early detection. The usual diagnostic technique includes a biopsy, which is frequently performed later in the disease's progression. In order to uncover processes that improve illness detection and prognosis, miRNA-21 emerges as a major miRNA identified in a variety of cancer types, including lung cancer. This review compiles insights into the involvement of miRNA-21 within the distinct cellular processes underlying lung cancer. To achieve this, we conducted an extensive literature review, drawing from published in vitro, in vivo and clinical trials studies. Searches were performed in the PubMed, Scielo, CAPES Journal Portal, BVS, INCA, and Clinical Trials.Gov. Only English written articles were selected. As screening criteria, we selected articles that explored the modulation pathways of miRNA-21, along with the proteins and genes implicated in tumorigenesis, metastasis, therapy resistance to established treatments, and their significance in the diagnosis and prognosis of lung cancer. A total of 3294 articles were identified, and 37 papers were selected to compose the review, after analysing selection criteria. Of these, 57 % studies presented in vitro evaluation, 22 % studies showed in vivo analysis, and 12 clinical trials were found. This study elucidates the principal signaling pathways influenced by miRNA-21, which play a pivotal role in lung cancer development. This comprehensive review sheds light on the potential significance of miRNA-21 as a critical mechanism for improving the prognosis of lung cancer patients, facilitating the transition of experimental data into the clinical phase. Therefore, we summarized published articles of miRNA-21 modulated signal pathways in lung cancer.
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Affiliation(s)
| | | | - João Pedro Alves Gomes
- Research Center for Therapeutic Innovation Suely Galdino, Federal University of Pernambuco, Recife, Brazil
| | | | - Barbara de Oliveira Silva
- Research Center for Therapeutic Innovation Suely Galdino, Federal University of Pernambuco, Recife, Brazil
| | - Claudio Montenegro
- Research Center for Therapeutic Innovation Suely Galdino, Federal University of Pernambuco, Recife, Brazil
| | | | - Michelly Cristiny Pereira
- Research Center for Therapeutic Innovation Suely Galdino, Federal University of Pernambuco, Recife, Brazil.
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Sandhanam K, Tamilanban T, Manasa K, Bhattacharjee B. Unlocking novel therapeutic avenues in glioblastoma: Harnessing 4-amino cyanine and miRNA synergy for next-gen treatment convergence. Neuroscience 2024; 553:1-18. [PMID: 38944146 DOI: 10.1016/j.neuroscience.2024.06.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/01/2024]
Abstract
Glioblastoma (GBM) poses a formidable challenge in oncology due to its aggressive nature and dismal prognosis, with average survival rates around 15 months despite conventional treatments. This review proposes a novel therapeutic strategy for GBM by integrating microRNA (miRNA) therapy with 4-amino cyanine molecules possessing near-infrared (NIR) properties. miRNA holds promise in regulating gene expression, particularly in GBM, making it an attractive therapeutic target. 4-amino cyanine molecules, especially those with NIR properties, have shown efficacy in targeted tumor cell degradation. The combined approach addresses gene expression regulation and precise tumor cell degradation, offering a breakthrough in GBM treatment. Additionally, the review explores noncoding RNAs classification and characteristics, highlighting their role in GBM pathogenesis. Advanced technologies such as antisense oligonucleotides (ASOs), locked nucleic acids (LNAs), and peptide nucleic acids (PNAs) show potential in targeting noncoding RNAs therapeutically, paving the way for precision medicine in GBM. This synergistic combination presents an innovative approach with the potential to advance cancer therapy in the challenging landscape of GBM.
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Affiliation(s)
- K Sandhanam
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Chengalpattu 603203, Tamil Nadu, India
| | - T Tamilanban
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Chengalpattu 603203, Tamil Nadu, India.
| | - K Manasa
- Department of Pharmacology, MNR College of Pharmacy, Sangareddy 502294, Telangana, India
| | - Bedanta Bhattacharjee
- Department of Pharmacology, Girijananda Chowdhury University-Tezpur Campus, 784501 Assam, India
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Fiorentino F, Fabbrizi E, Raucci A, Noce B, Fioravanti R, Valente S, Paolini C, De Maria R, Steinkühler C, Gallinari P, Rotili D, Mai A. Uracil- and Pyridine-Containing HDAC Inhibitors Displayed Cytotoxicity in Colorectal and Glioblastoma Cancer Stem Cells. ChemMedChem 2024; 19:e202300655. [PMID: 38529661 DOI: 10.1002/cmdc.202300655] [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: 11/23/2023] [Revised: 03/01/2024] [Accepted: 03/25/2024] [Indexed: 03/27/2024]
Abstract
Cancer stem cells (CSCs) are a niche of highly tumorigenic cells featuring self-renewal, activation of pluripotency genes, multidrug resistance, and ability to cause cancer relapse. Seven HDACi (1-7), showing either hydroxamate or 2'-aminoanilide function, were tested in colorectal cancer (CRC) and glioblastoma multiforme (GBM) CSCs to determine their effects on cell proliferation, H3 acetylation levels and in-cell HDAC activity. Two uracil-based hydroxamates, 5 and 6, which differ in substitution at C5 and C6 positions of the pyrimidine ring, exhibited the greatest cytotoxicity in GBM (5) and CRC (6) CSCs, followed by the pyridine-hydroxamate 2, with 2- to 6-fold higher potency than the positive control SAHA. Finally, increased H3 acetylation as well as HDAC inhibition directly in cells by selected 2'-aminoanilide 4 and hydroxamate 5 confirmed target engagement. Further investigation will be conducted into the broad-spectrum anticancer properties of the most potent derivatives and their effects in combination with approved, conventional anticancer drugs.
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Affiliation(s)
- Francesco Fiorentino
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Emanuele Fabbrizi
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Alessia Raucci
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Beatrice Noce
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Rossella Fioravanti
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Chantal Paolini
- IRBM S.p.A., Via Pontina km 30.600, 00071, Pomezia, Rome, Italy
| | - Ruggero De Maria
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168, Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy
| | - Christian Steinkühler
- Research and Development, Italfarmaco Group, Via dei Lavoratori 54, 20092, Cinisello Balsamo, Italy
| | - Paola Gallinari
- Exiris S.r.l., Tecnopolo Castel, Romano, Via Castel Romano 100, 00128, Rome, Italy
| | - Dante Rotili
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy
- Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P. de Aldo Moro n. 5, 00185, Rome, Italy
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8
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Bondarev AA, Evpak AS, Novoselov AL, Kudriaeva AA, Jr. Belogurov AA. The Correlation Patterns of miRNA Expression with Targeted mRNA Transcripts in Glioma Patients with Wild-Type and Mutated Isocitrate Dehydrogenase (IDH) Genotypes. Acta Naturae 2024; 16:38-45. [PMID: 39539523 PMCID: PMC11557213 DOI: 10.32607/actanaturae.27363] [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: 12/28/2023] [Accepted: 07/01/2024] [Indexed: 11/16/2024] Open
Abstract
Low-grade gliomas are divided into two main genetic phenotypes based on the presence or absence of mutations in the isocitrate dehydrogenase (IDH) genes. The mutated IDH phenotype (IDHmut), in contrast to the wild-type phenotype (IDHwt), is characterized by a more positive response to pharmacological intervention and a significantly longer survival time. In this study, we analyzed the differential co-expression of 225,000 microRNA-mRNA pairs at the level of correlations between microRNA levels and their potential mRNA targets. Analysis of the associative relationships of individual representatives of the selected pairs revealed that the level of mRNAs encoded by the ELN, ARL4C, C9orf64, PLAT, and FKBP9 genes associated with aggressive progression of glioma was increased in the IDHwt group. Meanwhile, the levels of miRNA-182, miRNA-455, and miRNA-891a associated with the negative prognosis in glioma were generally increased in the IDHmut group. Most (16/21) of the detected 21 microRNA-mRNA pairs with significant difference in regulation between IDHwt and IDHmut glioma samples had a weak or moderate positive correlation in IDHmut samples and a negative correlation in IDHwt samples. Therefore, our findings indicate that glioma samples from the IDHmut group with a positive prognosis potentially have a significantly less pronounced ability to microRNA-mediated regulation. We further suggest that such physiological disorders can lead to reduced tumor viability, resulting in an increased ability of the host to resist the spread of a malignant transformation of this genetic phenotype.
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Affiliation(s)
- A. A. Bondarev
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997 Russian Federation
| | - A. S. Evpak
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997 Russian Federation
| | - A. L. Novoselov
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997 Russian Federation
| | - A. A. Kudriaeva
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997 Russian Federation
| | - A. A. Jr. Belogurov
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997 Russian Federation
- Russian University of Medicine, Department of Biological Chemistry, Ministry of Health of the Russian Federation, Moscow, 127473 Russian Federation
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9
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Rezaie M, Nasehi M, Shimia M, Ebrahimnezhad M, Yousefi B, Majidinia M. Polyphenols Modulate the miRNAs Expression that Involved in Glioblastoma. Mini Rev Med Chem 2024; 24:1953-1969. [PMID: 38639278 DOI: 10.2174/0113895575304605240408105201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 03/11/2024] [Accepted: 03/16/2024] [Indexed: 04/20/2024]
Abstract
Glioblastoma multiforme (GBM), a solid tumor that develops from astrocytes, is one of the most aggressive types of brain cancer. While there have been improvements in the efficacy of treating GBM, many problems remain, especially with traditional therapy methods. Therefore, recent studies have extensively focused on developing novel therapeutic agents for combating glioblastoma. Natural polyphenols have been studied for their potential as chemopreventive and chemotherapeutic agents due to their wide range of positive qualities, including antioxidant, antiinflammatory, cytotoxic, antineoplastic, and immunomodulatory activities. These natural compounds have been suggested to act via modulated various macromolecules within cells, including microRNAs (miRNAs), which play a crucial role in the molecular milieu. In this article, we focus on how polyphenols may inhibit tumor growth by influencing the expression of key miRNAs that regulate oncogenes and tumor suppressor genes.
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Affiliation(s)
- Maede Rezaie
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammad Nasehi
- Cognitive and Neuroscience Research Center, Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Shimia
- Department of Neurosurgery, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohamad Ebrahimnezhad
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Bahman Yousefi
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
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10
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Shahcheraghi SH, Asl ER, Lotfi M, Ayatollahi J, Khaleghinejad SH, Aljabali AAA, Bakshi HA, El-Tanani M, Charbe NB, Serrano-Aroca Á, Mishra V, Mishra Y, Goyal R, Hromić-Jahjefendić A, Uversky VN, Lotfi M, Tambuwala MM. Non-coding RNAs as Key Regulators of the Notch Signaling Pathway in Glioblastoma: Diagnostic, Prognostic, and Therapeutic Targets. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:1203-1216. [PMID: 38279763 DOI: 10.2174/0118715273277458231213063147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 10/20/2023] [Accepted: 10/31/2023] [Indexed: 01/28/2024]
Abstract
Glioblastoma multiforme (GBM) is a highly invasive brain malignancy originating from astrocytes, accounting for approximately 30% of central nervous system malignancies. Despite advancements in therapeutic strategies including surgery, chemotherapy, and radiopharmaceutical drugs, the prognosis for GBM patients remains dismal. The aggressive nature of GBM necessitates the identification of molecular targets and the exploration of effective treatments to inhibit its proliferation. The Notch signaling pathway, which plays a critical role in cellular homeostasis, becomes deregulated in GBM, leading to increased expression of pathway target genes such as MYC, Hes1, and Hey1, thereby promoting cellular proliferation and differentiation. Recent research has highlighted the regulatory role of non-coding RNAs (ncRNAs) in modulating Notch signaling by targeting critical mRNA expression at the post-transcriptional or transcriptional levels. Specifically, various types of ncRNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been shown to control multiple target genes and significantly contribute to the carcinogenesis of GBM. Furthermore, these ncRNAs hold promise as prognostic and predictive markers for GBM. This review aims to summarize the latest studies investigating the regulatory effects of ncRNAs on the Notch signaling pathway in GBM.
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Affiliation(s)
- Seyed Hossein Shahcheraghi
- Department of Medical Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Infectious Diseases Research Center, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Elmira Roshani Asl
- Social Determinants of Health Research Center, Saveh University of Medical Sciences, Saveh, Iran
| | - Malihe Lotfi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Jamshid Ayatollahi
- Infectious Diseases Research Center, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Hematology and Oncology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Alaa A A Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid, Jordan
| | - Hamid A Bakshi
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
| | - Mohamed El-Tanani
- Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Nitin B Charbe
- Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics (Lake Nona), University of Florida, Orlando, FL, USA
| | - Ángel Serrano-Aroca
- Biomaterials & Bioengineering Lab, Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia, San Vicente Mártir, Valencia, 46001, Spain
| | - Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India
| | - Yachana Mishra
- Department of Zoology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, 144411, India
| | - Rohit Goyal
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology & Management Sciences, Solan, India
| | - Altijana Hromić-Jahjefendić
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnicka cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
| | - Vladimir N Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Marzieh Lotfi
- Abortion Research Center, Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Murtaza M Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS, UK
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11
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Zhang Q, Jiang Q, Sa K, Liang J, Sun D, Li H, Chen L. Research progress of plant-derived natural alkaloids in central nervous system diseases. Phytother Res 2023; 37:4885-4907. [PMID: 37455555 DOI: 10.1002/ptr.7955] [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: 10/24/2022] [Revised: 05/14/2023] [Accepted: 06/30/2023] [Indexed: 07/18/2023]
Abstract
Central nervous system (CNS) disease is one of the most important causes of human death. Because of their complex pathogenesis, more and more attention has been paid to them. At present, drug treatment of the CNS is the main means; however, most drugs only relieve symptoms, and some have certain toxicity and side effects. Natural compounds derived from plants can provide safer and more effective alternatives. Alkaloids are common nitrogenous basic organic compounds found in nature, which exist widely in many kinds of plants and have unique application value in modern medicine. For example, Galantamine and Huperzine A from medicinal plants are widely used drugs on the market to treat Alzheimer's disease. Therefore, the main purpose of this review is to provide the available information on natural alkaloids with the activity of treating central nervous system diseases in order to explore the trends and perspectives for the further study of central nervous system drugs. In this paper, 120 alkaloids with the potential effect of treating central nervous system diseases are summarized from the aspects of sources, structure types, mechanism of action and structure-activity relationship.
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Affiliation(s)
- Qingqing Zhang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Qinghua Jiang
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China
| | - Kuiru Sa
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Junming Liang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Dejuan Sun
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Hua Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Lixia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
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12
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Cecchi N, Romanelli R, Ricevuti F, Amitrano M, Carbone MG, Dinardo M, Burgio E. Current knowledges in pharmaconutrition: " Ketogenics" in pediatric gliomas. Front Nutr 2023; 10:1222908. [PMID: 37614745 PMCID: PMC10442509 DOI: 10.3389/fnut.2023.1222908] [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: 05/17/2023] [Accepted: 07/20/2023] [Indexed: 08/25/2023] Open
Abstract
Brain tumors account for 20-25% of pediatric cancers. The most frequent type of brain tumor is Glioma from grade I to grade IV according to the rate of malignancy. Current treatments for gliomas use chemotherapy, radiotherapy, tyrosine kinase inhibitors, monoclonal antibodies and surgery, but each of the treatment strategies has several serious side effects. Therefore, to improve treatment efficacy, it is necessary to tailor therapies to patient and tumor characteristics, using appropriate molecular targets. An increasingly popular strategy is pharmaconutrition, which combines a tailored pharmacological treatment with a diet designed to synergize the effects of drugs. In this review we deal in the molecular mechanisms, the epigenetic effects and modulation of the oxidative stress pathway of ketogenic diets, that underlie its possible role, in the treatment of infantile gliomas, as a complementary approach to conventional cancer therapy.
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Affiliation(s)
- Nicola Cecchi
- Clinical Nutrition Unit – A.O.R.N. Santobono-Pausilipon Children’s Hospital, Naples, Italy
| | - Roberta Romanelli
- Clinical Nutrition Unit – A.O.R.N. Santobono-Pausilipon Children’s Hospital, Naples, Italy
| | - Flavia Ricevuti
- Clinical Nutrition Unit – A.O.R.N. Santobono-Pausilipon Children’s Hospital, Naples, Italy
| | - Marianna Amitrano
- Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy
| | - Maria Grazia Carbone
- Clinical Nutrition Unit – A.O.R.N. Santobono-Pausilipon Children’s Hospital, Naples, Italy
| | - Michele Dinardo
- Clinical Nutrition Unit – A.O.R.N. Santobono-Pausilipon Children’s Hospital, Naples, Italy
| | - Ernesto Burgio
- ECERI-European Cancer and Environment Research Institute, Brussels, Belgium
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13
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Kumari S, Gupta R, Ambasta RK, Kumar P. Multiple therapeutic approaches of glioblastoma multiforme: From terminal to therapy. Biochim Biophys Acta Rev Cancer 2023; 1878:188913. [PMID: 37182666 DOI: 10.1016/j.bbcan.2023.188913] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/24/2023] [Accepted: 05/10/2023] [Indexed: 05/16/2023]
Abstract
Glioblastoma multiforme (GBM) is an aggressive brain cancer showing poor prognosis. Currently, treatment methods of GBM are limited with adverse outcomes and low survival rate. Thus, advancements in the treatment of GBM are of utmost importance, which can be achieved in recent decades. However, despite aggressive initial treatment, most patients develop recurrent diseases, and the overall survival rate of patients is impossible to achieve. Currently, researchers across the globe target signaling events along with tumor microenvironment (TME) through different drug molecules to inhibit the progression of GBM, but clinically they failed to demonstrate much success. Herein, we discuss the therapeutic targets and signaling cascades along with the role of the organoids model in GBM research. Moreover, we systematically review the traditional and emerging therapeutic strategies in GBM. In addition, we discuss the implications of nanotechnologies, AI, and combinatorial approach to enhance GBM therapeutics.
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Affiliation(s)
- Smita Kumari
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, India
| | - Rohan Gupta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, India
| | - Rashmi K Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, India.
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14
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Singh S, Saini H, Sharma A, Gupta S, Huddar VG, Tripathi R. Breast cancer: miRNAs monitoring chemoresistance and systemic therapy. Front Oncol 2023; 13:1155254. [PMID: 37397377 PMCID: PMC10312137 DOI: 10.3389/fonc.2023.1155254] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 06/05/2023] [Indexed: 07/04/2023] Open
Abstract
With a high mortality rate that accounts for millions of cancer-related deaths each year, breast cancer is the second most common malignancy in women. Chemotherapy has significant potential in the prevention and spreading of breast cancer; however, drug resistance often hinders therapy in breast cancer patients. The identification and the use of novel molecular biomarkers, which can predict response to chemotherapy, might lead to tailoring breast cancer treatment. In this context, accumulating research has reported microRNAs (miRNAs) as potential biomarkers for early cancer detection, and are conducive to designing a more specific treatment plan by helping analyze drug resistance and sensitivity in breast cancer treatment. In this review, miRNAs are discussed in two alternative ways-as tumor suppressors to be used in miRNA replacement therapy to reduce oncogenesis and as oncomirs to lessen the translation of the target miRNA. Different miRNAs like miR-638, miR-17, miR-20b, miR-342, miR-484, miR-21, miR-24, miR-27, miR-23 and miR-200 are involved in the regulation of chemoresistance through diverse genetic targets. For instance, tumor-suppressing miRNAs like miR-342, miR-16, miR-214, and miR-128 and tumor-promoting miRNAs like miR101 and miR-106-25 cluster regulate the cell cycle, apoptosis, epithelial to mesenchymal transition and other pathways to impart breast cancer drug resistance. Hence, in this review, we have discussed the significance of miRNA biomarkers that could assist in providing novel therapeutic targets to overcome potential chemotherapy resistance to systemic therapy and further facilitate the design of tailored therapy for enhanced efficacy against breast cancer.
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Affiliation(s)
- Shivam Singh
- Department of Radiation Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Heena Saini
- Integrated translational Molecular Biology laboratory, Department of Rog Nidan and Vikriti vigyan (Pathology), All India Institute of Ayurveda (AIIA), New Delhi, India
| | - Ashok Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Subhash Gupta
- Department of Radiation Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - V. G. Huddar
- Department of Kaya Chikitsa (Internal Medicine), All India Institute of Ayurveda (AIIA), New Delhi, India
| | - Richa Tripathi
- Integrated translational Molecular Biology laboratory, Department of Rog Nidan and Vikriti vigyan (Pathology), All India Institute of Ayurveda (AIIA), New Delhi, India
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15
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Al-Hawary SIS, Asghar W, Amin A, Mustafa YF, Hjazi A, Almulla AF, Ali SAJ, Ali SS, Romero-Parra RM, Abdulhussien Alazbjee AA, Mahmoudi R, Fard SRH. Circ_0067934 as a novel therapeutic target in cancer: From mechanistic to clinical perspectives. Pathol Res Pract 2023; 245:154469. [PMID: 37100022 DOI: 10.1016/j.prp.2023.154469] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/12/2023] [Accepted: 04/18/2023] [Indexed: 04/28/2023]
Abstract
Circular RNAs, as a type of non-coding RNAs, are identified in a various cell. Circular RNAs have stable structures, conserved sequence, and tissue and cell-specific level. High throughput technologies have proposed that circular RNAs act via various mechanisms like sponging microRNAs and proteins, regulating transcription factors, and scaffolding mediators. Cancer is one of the major threat for human health. Emerging data have proposed that circular RNAs are dysregulated in cancers as well as are associated with aggressive behaviors of cancer -related behaviors like cell cycle, proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT). Among them, circ_0067934 was shown to act as an oncogene in cancers to enhance migration, invasion, proliferation, cell cycle, EMT, and inhibit cell apoptosis. In addition, these studies have proposed that it could be a promising diagnostic and prognostic biomarker in cancer. This study aimed to review the expression and molecular mechanism of circ_0067934 in modulating the malignant behaviors of cancers as well as to explore its potential as a target in cancer chemotherapy, diagnosis, prognosis and treatment.
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Affiliation(s)
| | | | - Aaima Amin
- Quaid e Azam Medical College, Bahawal Victorial Hospital, Bahawalpur, Pakistan
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Abbas F Almulla
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Sally Saad Ali
- College of Dentistry, Al-Bayan University, Baghdad, Iraq
| | | | | | - Reza Mahmoudi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
| | - Seyed Reza Hosseini Fard
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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16
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Burko P, D’Amico G, Miltykh I, Scalia F, Conway de Macario E, Macario AJL, Giglia G, Cappello F, Caruso Bavisotto C. Molecular Pathways Implicated in Radioresistance of Glioblastoma Multiforme: What Is the Role of Extracellular Vesicles? Int J Mol Sci 2023; 24:ijms24054883. [PMID: 36902314 PMCID: PMC10003080 DOI: 10.3390/ijms24054883] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/16/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Glioblastoma multiforme (GBM) is a primary brain tumor that is very aggressive, resistant to treatment, and characterized by a high degree of anaplasia and proliferation. Routine treatment includes ablative surgery, chemotherapy, and radiotherapy. However, GMB rapidly relapses and develops radioresistance. Here, we briefly review the mechanisms underpinning radioresistance and discuss research to stop it and install anti-tumor defenses. Factors that participate in radioresistance are varied and include stem cells, tumor heterogeneity, tumor microenvironment, hypoxia, metabolic reprogramming, the chaperone system, non-coding RNAs, DNA repair, and extracellular vesicles (EVs). We direct our attention toward EVs because they are emerging as promising candidates as diagnostic and prognostication tools and as the basis for developing nanodevices for delivering anti-cancer agents directly into the tumor mass. EVs are relatively easy to obtain and manipulate to endow them with the desired anti-cancer properties and to administer them using minimally invasive procedures. Thus, isolating EVs from a GBM patient, supplying them with the necessary anti-cancer agent and the capability of recognizing a specified tissue-cell target, and reinjecting them into the original donor appears, at this time, as a reachable objective of personalized medicine.
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Affiliation(s)
- Pavel Burko
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy
| | - Giuseppa D’Amico
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy
| | - Ilia Miltykh
- Department of Human Anatomy, Institute of Medicine, Penza State University, 440026 Penza, Russia
| | - Federica Scalia
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy
- Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA
| | - Everly Conway de Macario
- Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
| | - Alberto J. L. Macario
- Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
| | - Giuseppe Giglia
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
- Section of Human Physiology, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy
| | - Francesco Cappello
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
| | - Celeste Caruso Bavisotto
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
- Correspondence: ; Tel.: +39-0916553501
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17
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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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18
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Lu ZG, Shen J, Yang J, Wang JW, Zhao RC, Zhang TL, Guo J, Zhang X. Nucleic acid drug vectors for diagnosis and treatment of brain diseases. Signal Transduct Target Ther 2023; 8:39. [PMID: 36650130 PMCID: PMC9844208 DOI: 10.1038/s41392-022-01298-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/08/2022] [Accepted: 12/21/2022] [Indexed: 01/18/2023] Open
Abstract
Nucleic acid drugs have the advantages of rich target selection, simple in design, good and enduring effect. They have been demonstrated to have irreplaceable superiority in brain disease treatment, while vectors are a decisive factor in therapeutic efficacy. Strict physiological barriers, such as degradation and clearance in circulation, blood-brain barrier, cellular uptake, endosome/lysosome barriers, release, obstruct the delivery of nucleic acid drugs to the brain by the vectors. Nucleic acid drugs against a single target are inefficient in treating brain diseases of complex pathogenesis. Differences between individual patients lead to severe uncertainties in brain disease treatment with nucleic acid drugs. In this Review, we briefly summarize the classification of nucleic acid drugs. Next, we discuss physiological barriers during drug delivery and universal coping strategies and introduce the application methods of these universal strategies to nucleic acid drug vectors. Subsequently, we explore nucleic acid drug-based multidrug regimens for the combination treatment of brain diseases and the construction of the corresponding vectors. In the following, we address the feasibility of patient stratification and personalized therapy through diagnostic information from medical imaging and the manner of introducing contrast agents into vectors. Finally, we take a perspective on the future feasibility and remaining challenges of vector-based integrated diagnosis and gene therapy for brain diseases.
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Affiliation(s)
- Zhi-Guo Lu
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China.
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
| | - Jie Shen
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Jun Yang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Jing-Wen Wang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
| | - Rui-Chen Zhao
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Tian-Lu Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
| | - Jing Guo
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
| | - Xin Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China.
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
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19
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Saha S, Sachdev M, Mitra SK. Recent advances in label-free optical, electrochemical, and electronic biosensors for glioma biomarkers. BIOMICROFLUIDICS 2023; 17:011502. [PMID: 36844882 PMCID: PMC9949901 DOI: 10.1063/5.0135525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 02/06/2023] [Indexed: 06/18/2023]
Abstract
Gliomas are the most commonly occurring primary brain tumor with poor prognosis and high mortality rate. Currently, the diagnostic and monitoring options for glioma mainly revolve around imaging techniques, which often provide limited information and require supervisory expertise. Liquid biopsy is a great alternative or complementary monitoring protocol that can be implemented along with other standard diagnosis protocols. However, standard detection schemes for sampling and monitoring biomarkers in different biological fluids lack the necessary sensitivity and ability for real-time analysis. Lately, biosensor-based diagnostic and monitoring technology has attracted significant attention due to several advantageous features, including high sensitivity and specificity, high-throughput analysis, minimally invasive, and multiplexing ability. In this review article, we have focused our attention on glioma and presented a literature survey summarizing the diagnostic, prognostic, and predictive biomarkers associated with glioma. Further, we discussed different biosensory approaches reported to date for the detection of specific glioma biomarkers. Current biosensors demonstrate high sensitivity and specificity, which can be used for point-of-care devices or liquid biopsies. However, for real clinical applications, these biosensors lack high-throughput and multiplexed analysis, which can be achieved via integration with microfluidic systems. We shared our perspective on the current state-of-the-art different biosensor-based diagnostic and monitoring technologies reported and the future research scopes. To the best of our knowledge, this is the first review focusing on biosensors for glioma detection, and it is anticipated that the review will offer a new pathway for the development of such biosensors and related diagnostic platforms.
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Affiliation(s)
| | - Manoj Sachdev
- Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada
| | - Sushanta K. Mitra
- Micro and Nanoscale Transport Laboratory, Department of Mechanical and Mechatronics Engineering, Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada
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20
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Visintin R, Ray SK. Intersections of Ubiquitin-Proteosome System and Autophagy in Promoting Growth of Glioblastoma Multiforme: Challenges and Opportunities. Cells 2022; 11:cells11244063. [PMID: 36552827 PMCID: PMC9776575 DOI: 10.3390/cells11244063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/09/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022] Open
Abstract
Glioblastoma multiforme (GBM) is a brain tumor notorious for its propensity to recur after the standard treatments of surgical resection, ionizing radiation (IR), and temozolomide (TMZ). Combined with the acquired resistance to standard treatments and recurrence, GBM is an especially deadly malignancy with hardly any worthwhile treatment options. The treatment resistance of GBM is influenced, in large part, by the contributions from two main degradative pathways in eukaryotic cells: ubiquitin-proteasome system (UPS) and autophagy. These two systems influence GBM cell survival by removing and recycling cellular components that have been damaged by treatments, as well as by modulating metabolism and selective degradation of components of cell survival or cell death pathways. There has recently been a large amount of interest in potential cancer therapies involving modulation of UPS or autophagy pathways. There is significant crosstalk between the two systems that pose therapeutic challenges, including utilization of ubiquitin signaling, the degradation of components of one system by the other, and compensatory activation of autophagy in the case of proteasome inhibition for GBM cell survival and proliferation. There are several important regulatory nodes which have functions affecting both systems. There are various molecular components at the intersections of UPS and autophagy pathways that pose challenges but also show some new therapeutic opportunities for GBM. This review article aims to provide an overview of the recent advancements in research regarding the intersections of UPS and autophagy with relevance to finding novel GBM treatment opportunities, especially for combating GBM treatment resistance.
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Affiliation(s)
- Rhett Visintin
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA
| | - Swapan K. Ray
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
- Correspondence: ; Tel.: +1-803-216-3420; Fax: +1-803-216-3428
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21
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Microglia and Brain Macrophages as Drivers of Glioma Progression. Int J Mol Sci 2022; 23:ijms232415612. [PMID: 36555253 PMCID: PMC9779147 DOI: 10.3390/ijms232415612] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/05/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Evidence is accumulating that the tumour microenvironment (TME) has a key role in the progression of gliomas. Non-neoplastic cells in addition to the tumour cells are therefore finding increasing attention. Microglia and other glioma-associated macrophages are at the centre of this interest especially in the context of therapeutic considerations. New ideas have emerged regarding the role of microglia and, more recently, blood-derived brain macrophages in glioblastoma (GBM) progression. We are now beginning to understand the mechanisms that allow malignant glioma cells to weaken microglia and brain macrophage defence mechanisms. Surface molecules and cytokines have a prominent role in microglia/macrophage-glioma cell interactions, and we discuss them in detail. The involvement of exosomes and microRNAs forms another focus of this review. In addition, certain microglia and glioma cell pathways deserve special attention. These "synergistic" (we suggest calling them "Janus") pathways are active in both glioma cells and microglia/macrophages where they act in concert supporting malignant glioma progression. Examples include CCN4 (WISP1)/Integrin α6β1/Akt and CHI3L1/PI3K/Akt/mTOR. They represent attractive therapeutic targets.
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22
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Ketogenic Diet in the Treatment of Gliomas and Glioblastomas. Nutrients 2022; 14:nu14183851. [PMID: 36145228 PMCID: PMC9504425 DOI: 10.3390/nu14183851] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 11/29/2022] Open
Abstract
In recent years, scientific interest in the use of the ketogenic diet (KD) as a complementary approach to the standard cancer therapy has grown, in particular against those of the central nervous system (CNS). In metabolic terms, there are the following differences between healthy and neoplastic cells: neoplastic cells divert their metabolism to anaerobic glycolysis (Warburg effect), they alter the normal mitochondrial functioning, and they use mainly certain amino acids for their own metabolic needs, to gain an advantage over healthy cells and to lead to a pro-oncogenetic effect. Several works in literature speculate which are the molecular targets of KD used against cancer. The following different mechanisms of action will be explored in this review: metabolic, inflammatory, oncogenic and oncosuppressive, ROS, and epigenetic modulation. Preclinical and clinical studies on the use of KD in CNS tumors have also increased in recent years. An interesting hypothesis emerged from the studies about the possible use of a ketogenic diet as a combination therapy along with chemotherapy (CT) and radiotherapy (RT) for the treatment of cancer. Currently, however, clinical data are still very limited but encouraging, so we need further studies to definitively validate or disprove the role of KD in fighting against cancer.
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23
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Mafi A, Rahmati A, Babaei Aghdam Z, Salami R, Salami M, Vakili O, Aghadavod E. Recent insights into the microRNA-dependent modulation of gliomas from pathogenesis to diagnosis and treatment. Cell Mol Biol Lett 2022; 27:65. [PMID: 35922753 PMCID: PMC9347108 DOI: 10.1186/s11658-022-00354-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 06/22/2022] [Indexed: 11/11/2022] Open
Abstract
Gliomas are the most lethal primary brain tumors in adults. These highly invasive tumors have poor 5-year survival for patients. Gliomas are principally characterized by rapid diffusion as well as high levels of cellular heterogeneity. However, to date, the exact pathogenic mechanisms, contributing to gliomas remain ambiguous. MicroRNAs (miRNAs), as small noncoding RNAs of about 20 nucleotides in length, are known as chief modulators of different biological processes at both transcriptional and posttranscriptional levels. More recently, it has been revealed that these noncoding RNA molecules have essential roles in tumorigenesis and progression of multiple cancers, including gliomas. Interestingly, miRNAs are able to modulate diverse cancer-related processes such as cell proliferation and apoptosis, invasion and migration, differentiation and stemness, angiogenesis, and drug resistance; thus, impaired miRNAs may result in deterioration of gliomas. Additionally, miRNAs can be secreted into cerebrospinal fluid (CSF), as well as the bloodstream, and transported between normal and tumor cells freely or by exosomes, converting them into potential diagnostic and/or prognostic biomarkers for gliomas. They would also be great therapeutic agents, especially if they could cross the blood–brain barrier (BBB). Accordingly, in the current review, the contribution of miRNAs to glioma pathogenesis is first discussed, then their glioma-related diagnostic/prognostic and therapeutic potential is highlighted briefly.
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Affiliation(s)
- Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Atefe Rahmati
- Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Basic Science, Neyshabur University of Medical Science, Neyshabur, Iran
| | - Zahra Babaei Aghdam
- Imaging Sciences Research Group, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Raziyeh Salami
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Marziyeh Salami
- Department of Clinical Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Esmat Aghadavod
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran. .,Department of Clinical Biochemistry, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
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24
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Gundamaraju R, Wu J, William JNG, Lu W, Jha NK, Ramasamy S, Rao PV. Ascendancy of unfolded protein response over glioblastoma: estimating progression, prognosis and survival. Biotechnol Genet Eng Rev 2022; 39:143-165. [PMID: 35904341 DOI: 10.1080/02648725.2022.2106002] [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: 11/02/2022]
Abstract
Glioblastoma (GBM) is presented with a poor prognosis. The endoplasmic reticulum stress (ERS) has been implicated as a major contributor to disease progression and chemoresistance in GBM. Triggering ERS by chemical agents or genetic modulations is identified as some of the reasons for regulating gene expression and the pathogenesis of GBM. ERS initiates unfolded protein response (UPR), an integrated system useful in restoring homeostasis or inducing apoptosis. Modulation of UPR might have positive outcomes in GBM treatment as UPR inducers have been shown to alter cell survival and migration. In the current review, we have utilized GSE7806, a publicly available dataset from Gene Expression Omnibus (GEO), to evaluate the genes expressed during 6.5 hr and 18 hr, which can be comparable to the early and late-onset of the disease. Subsequently, we have elucidated the prognosis and survival information whilst the expression of these genes in the GBM was noted in previous studies. This is the first of its kind review summarizing the most recent gene information correlating UPR and GBM.
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Affiliation(s)
- Rohit Gundamaraju
- ER stress and Mucosal Immunology Laboratory, School of Health Sciences, University of Tasmania, Launceston, Tasmania, Australia
| | - Jian Wu
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Jonahunnatha Nesson George William
- Department of Medical, Oral and Biotechnological Sciences (DSMOB), Ageing Research Center and Translational medicine-CeSI-MeT, "G. d'Annunzio" University Chieti-Pescara, Chieti, Italy
| | - Wenying Lu
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Launceston, Tasmania, Australia
| | - Niraj Kumar Jha
- Department of Biotechnology, School of engineering and Technology, Sharda University, Greater Noida, UP, Indonesia
| | | | - Pasupuleti Visweswara Rao
- f Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, India.,g Department of Biotechnology, School of applied and Life Sciences, Uttaranchal University, Dehradun, 248007, India.,h Cardiac Hypertrophy Laboratory, Department of Molecular Biology, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, India.,i Department of Biomedical Sciences and Therapeutics, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia.,j Department of Biochemistry, Faculty of Medicine and Health Sciences, Abdurrab University, Pekanbaru, Riau, Indonesia
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25
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Senhaji N, Squalli Houssaini A, Lamrabet S, Louati S, Bennis S. Molecular and Circulating Biomarkers in Patients with Glioblastoma. Int J Mol Sci 2022; 23:7474. [PMID: 35806478 PMCID: PMC9267689 DOI: 10.3390/ijms23137474] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/28/2022] [Accepted: 05/16/2022] [Indexed: 02/04/2023] Open
Abstract
Glioblastoma is the most aggressive malignant tumor of the central nervous system with a low survival rate. The difficulty of obtaining this tumor material represents a major limitation, making the real-time monitoring of tumor progression difficult, especially in the events of recurrence or resistance to treatment. The identification of characteristic biomarkers is indispensable for an accurate diagnosis, the rigorous follow-up of patients, and the development of new personalized treatments. Liquid biopsy, as a minimally invasive procedure, holds promise in this regard. The purpose of this paper is to summarize the current literature regarding the identification of molecular and circulating glioblastoma biomarkers and the importance of their integration as a valuable tool to improve patient care.
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Affiliation(s)
- Nadia Senhaji
- Department of Biology, Faculty of Sciences, Moulay Ismail University, Meknes 50000, Morocco
- Laboratory of Biomedical and Translational Research, Faculty of Medicine, Pharmacy and Dental Medicine of Fez, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco; (A.S.H.); (S.L.); (S.B.)
| | - Asmae Squalli Houssaini
- Laboratory of Biomedical and Translational Research, Faculty of Medicine, Pharmacy and Dental Medicine of Fez, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco; (A.S.H.); (S.L.); (S.B.)
| | - Salma Lamrabet
- Laboratory of Biomedical and Translational Research, Faculty of Medicine, Pharmacy and Dental Medicine of Fez, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco; (A.S.H.); (S.L.); (S.B.)
| | - Sara Louati
- Medical Biotechnology Laboratory, Faculty of Medicine and Pharmacy of Rabat, Mohammed Vth University, Rabat 10000, Morocco;
| | - Sanae Bennis
- Laboratory of Biomedical and Translational Research, Faculty of Medicine, Pharmacy and Dental Medicine of Fez, Sidi Mohamed Ben Abdellah University, Fez 30070, Morocco; (A.S.H.); (S.L.); (S.B.)
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26
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Abraham M, Mundorf A, Brodmann K, Freund N. Unraveling the mystery of white matter in depression: A translational perspective on recent advances. Brain Behav 2022; 12:e2629. [PMID: 35652161 PMCID: PMC9304855 DOI: 10.1002/brb3.2629] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 04/15/2022] [Accepted: 04/23/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Numerous cortical and subcortical structures have been studied extensively concerning alterations of their integrity as well as their neurotransmitters in depression. However, connections between these structures have received considerably less attention. OBJECTIVE This systematic review presents results from recent neuroimaging as well as neuropathologic studies conducted on humans and other mammals. It aims to provide evidence for impaired white matter integrity in individuals expressing a depressive phenotype. METHODS A systematic database search in accordance with the PRISMA guidelines was conducted to identify imaging and postmortem studies conducted on humans with a diagnosis of major depressive disorder, as well as on rodents and primates subjected to an animal model of depression. RESULTS Alterations are especially apparent in frontal gyri, as well as in structures establishing interhemispheric connectivity between frontal regions. Translational neuropathological findings point to alterations in oligodendrocyte density and morphology, as well as to alterations in the expression of genes related to myelin synthesis. An important role of early life adversities in the development of depressive symptoms and white matter alterations across species is thereby revealed. Data indicating that stress can interfere with physiological myelination patterns is presented. Altered myelination is most notably present in regions that are subject to maturation during the developmental stage of exposure to adversities. CONCLUSION Translational studies point to replicable alterations in white matter integrity in subjects suffering from depression across multiple species. Impaired white matter integrity is apparent in imaging as well as neuropathological studies. Future studies should focus on determining to what extent influencing white matter integrity is able to improve symptoms of depression in animals as well as humans.
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Affiliation(s)
- Mate Abraham
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Annakarina Mundorf
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Bochum, Germany.,Institute for Systems Medicine and Department of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany
| | - Katja Brodmann
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Nadja Freund
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr-University Bochum, Bochum, Germany
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27
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Nieland L, van Solinge TS, Cheah PS, Morsett LM, El Khoury J, Rissman JI, Kleinstiver BP, Broekman ML, Breakefield XO, Abels ER. CRISPR-Cas knockout of miR21 reduces glioma growth. Mol Ther Oncolytics 2022; 25:121-136. [PMID: 35572197 PMCID: PMC9052041 DOI: 10.1016/j.omto.2022.04.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 04/04/2022] [Indexed: 12/21/2022] Open
Abstract
Non-coding RNAs, including microRNAs (miRNAs), support the progression of glioma. miR-21 is a small, non-coding transcript involved in regulating gene expression in multiple cellular pathways, including the regulation of proliferation. High expression of miR-21 has been shown to be a major driver of glioma growth. Manipulating the expression of miRNAs is a novel strategy in the development of therapeutics in cancer. In this study we aimed to target miR-21. Using CRISPR genome-editing technology, we disrupted the miR-21 coding sequences in glioma cells. Depletion of this miRNA resulted in the upregulation of many downstream miR-21 target mRNAs involved in proliferation. Phenotypically, CRISPR-edited glioma cells showed reduced migration, invasion, and proliferation in vitro. In immunocompetent mouse models, miR-21 knockout tumors showed reduced growth resulting in an increased overall survival. In summary, we show that by knocking out a key miRNA in glioma, these cells have decreased proliferation capacity both in vitro and in vivo. Overall, we identified miR-21 as a potential target for CRISPR-based therapeutics in glioma.
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Affiliation(s)
- Lisa Nieland
- Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA
- Department of Neurosurgery, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Thomas S. van Solinge
- Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA
| | - Pike See Cheah
- Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang 43400, Malaysia
| | - Liza M. Morsett
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Joseph El Khoury
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
| | - Joseph I. Rissman
- Center for Genomic Medicine and Department of Pathology, Massachusetts General Hospital, Boston, MA 02115, USA
| | - Benjamin P. Kleinstiver
- Center for Genomic Medicine and Department of Pathology, Massachusetts General Hospital, Boston, MA 02115, USA
- Department of Pathology, Harvard Medical School, Boston, MA 02114, USA
| | - Marike L.D. Broekman
- Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA
- Department of Neurosurgery, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
- Department of Neurosurgery, Haaglanden Medical Center, 2512 VA The Hague, the Netherlands
| | - Xandra O. Breakefield
- Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA
| | - Erik R. Abels
- Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
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28
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Wang G, Lin X, Han H, Zhang H, Li X, Feng M, Jiang C. lncRNA H19 promotes glioblastoma multiforme development by activating autophagy by sponging miR-491-5p. Bioengineered 2022; 13:11440-11455. [PMID: 35506168 PMCID: PMC9275997 DOI: 10.1080/21655979.2022.2065947] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 04/01/2022] [Accepted: 04/06/2022] [Indexed: 12/20/2022] Open
Abstract
Glioblastoma multiforme (GBM) is a malignant cancer with severely poor survival, and the cells continue to thrive during hypoxia and toxic stress through autophagy. To validate the oncogenic role of long noncoding RNA H19 in GBM progression and examine whether autophagy and/or miR-491-5p participate in the process. The expression of H19 and autophagy-related genes in GBM and healthy control tissues was assessed via quantitative polymerase chain reaction. In addition, cell viability, proliferation, apoptosis and autophagy were respectively determined via cell counting kit-8 assay, clone formation assay, flow cytometry, western blotting and green fluorescent protein-microtubule-associated protein 1 light chain 3 alpha fluorescence analysis in vitro. Furthermore, a rescue assay was performed using rapamycin or miR-491-5p antagomir to examine the role of autophagy or miR-491-5p in H19-mediated regulation of proliferation and apoptosis. RNA pull-down and dual-luciferase reporter assays were employed to analyze the interaction between H19 and miR-491-5p. Additionally, tumor growth in a xenograft-bearing mouse model and autophagy in tumor mass were analyzed in vivo. The expression H19 was increased in GBM and was positively correlated with LC3 or Beclin-1. Silencing H19 inhibited growth and promoted apoptosis in GBM cells both in vitro and in vivo, and miR-491-5p was identified as one of the important mediators. H19 regulated the autophagy signaling pathway at least partly via miR-491-5p. Increased H19 expression in GBM exerts oncogenic effects by sponging miR-491-5p and enhancing autophagy. Therefore, H19 may be explored as a target for GBM therapy.
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Affiliation(s)
- Guo Wang
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Xiaoyan Lin
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Han Han
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Hongxu Zhang
- Department of Ophthalmology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Ophthalmology, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Xiaoli Li
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Mei Feng
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
| | - Chunming Jiang
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
- Department of Pediatrics, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People’s Hospital, Hangzhou Zhejiang, P.R. China
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29
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Schäfer A, Evers L, Meier L, Schlomann U, Bopp MHA, Dreizner GL, Lassmann O, Ben Bacha A, Benescu AC, Pojskic M, Preußer C, von Strandmann EP, Carl B, Nimsky C, Bartsch JW. The Metalloprotease-Disintegrin ADAM8 Alters the Tumor Suppressor miR-181a-5p Expression Profile in Glioblastoma Thereby Contributing to Its Aggressiveness. Front Oncol 2022; 12:826273. [PMID: 35371977 PMCID: PMC8964949 DOI: 10.3389/fonc.2022.826273] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/16/2022] [Indexed: 01/08/2023] Open
Abstract
Glioblastoma (GBM) as the most common and aggressive brain tumor is characterized by genetic heterogeneity, invasiveness, radio-/chemoresistance, and occurrence of GBM stem-like cells. The metalloprotease-disintegrin ADAM8 is highly expressed in GBM tumor and immune cells and correlates with poor survival. In GBM, ADAM8 affects intracellular kinase signaling and increases expression levels of osteopontin/SPP1 and matrix metalloproteinase 9 (MMP9) by an unknown mechanism. Here we explored whether microRNA (miRNA) expression levels could be regulators of MMP9 expression in GBM cells expressing ADAM8. Initially, we identified several miRNAs as dysregulated in ADAM8-deficient U87 GBM cells. Among these, the tumor suppressor miR-181a-5p was significantly upregulated in ADAM8 knockout clones. By inhibiting kinase signaling, we found that ADAM8 downregulates expression of miR-181a-5p via activation of signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling suggesting an ADAM8-dependent silencing of miR-181a-5p. In turn, mimic miR-181a-5p transfection caused decreased cell proliferation and lower MMP9 expression in GBM cells. Furthermore, miR-181a-5p was detected in GBM cell-derived extracellular vesicles (EVs) as well as patient serum-derived EVs. We identified miR-181a-5p downregulating MMP9 expression via targeting the MAPK pathway. Analysis of patient tissue samples (n=22) revealed that in GBM, miR-181a-5p is strongly downregulated compared to ADAM8 and MMP9 mRNA expression, even in localized tumor areas. Taken together, we provide evidence for a functional axis involving ADAM8/miR-181a-5p/MAPK/MMP9 in GBM tumor cells.
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Affiliation(s)
- Agnes Schäfer
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Lara Evers
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Lara Meier
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Uwe Schlomann
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Miriam H A Bopp
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany.,Marburg Center for Mind, Brain and Behavior (MCMBB), Marburg, Germany
| | - Gian-Luca Dreizner
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Olivia Lassmann
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Aaron Ben Bacha
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | | | - Mirza Pojskic
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Christian Preußer
- Core Facility Extracellular Vesicles, Philipps University of Marburg - Medical Faculty, Marburg, Germany
| | - Elke Pogge von Strandmann
- Core Facility Extracellular Vesicles, Philipps University of Marburg - Medical Faculty, Marburg, Germany
| | - Barbara Carl
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany
| | - Christopher Nimsky
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany.,Marburg Center for Mind, Brain and Behavior (MCMBB), Marburg, Germany
| | - Jörg W Bartsch
- Department of Neurosurgery, Philipps University Marburg, Marburg, Germany.,Marburg Center for Mind, Brain and Behavior (MCMBB), Marburg, Germany
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30
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Mulcahy EQX, Zhang Y, Colόn RR, Cain SR, Gibert MK, Dube CJ, Hafner M, Abounader R. MicroRNA 3928 Suppresses Glioblastoma through Downregulation of Several Oncogenes and Upregulation of p53. Int J Mol Sci 2022; 23:3930. [PMID: 35409289 PMCID: PMC8998958 DOI: 10.3390/ijms23073930] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/24/2022] [Accepted: 03/29/2022] [Indexed: 12/16/2022] Open
Abstract
Glioblastoma (GBM) is the most frequent and lethal primary malignant brain tumor. Despite decades of research, therapeutic advances that significantly prolong life are non-existent. In recent years, microRNAs (miRNAs) have been a focus of study in the pathobiology of cancer because of their ability to simultaneously regulate multiple genes. The aim of this study was to determine the functional and mechanistic effects of miR-3928 in GBM both in vitro and in vivo. To the best of our knowledge, this is the first article investigating the role of miR-3928 in GBM. We measured endogenous miR-3928 expression levels in a panel of patient-derived GBM tissue samples and cell lines. We found that GBM tissue samples and cell lines express lower levels of miR-3928 than normal brain cortex and astrocytes, respectively. Therefore, we hypothesized that miR-3928 is a tumor suppressive microRNA. We verified this hypothesis by showing that exogenous expression of miR-3928 has a strong inhibitory effect on both cell growth and invasiveness of GBM cells. Stable ex vivo overexpression of miR-3928 in GBM cells led to a reduction in tumor size in nude mice xenografts. We identified many targets (MDM2, CD44, DDX3X, HMGA2, CCND1, BRAF, ATOH8, and BMI1) of miR-3928. Interestingly, inhibition of the oncogene MDM2 also led to an upregulation of wild-type p53 expression and phosphorylation. In conclusion, we find that miR-3928, through the downregulation of several oncogenes and upregulation and activation of wild-type p53, is a strong tumor suppressor in GBM. Furthermore, the fact that miR-3928 can target many important dysregulated proteins in GBM suggests it might be a "master" regulatory microRNA that could be therapeutically exploited.
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Affiliation(s)
- Elizabeth Q. X. Mulcahy
- Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA; (E.Q.X.M.); (Y.Z.); (R.R.C.); (S.R.C.); (M.K.G.J.); (C.J.D.)
| | - Ying Zhang
- Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA; (E.Q.X.M.); (Y.Z.); (R.R.C.); (S.R.C.); (M.K.G.J.); (C.J.D.)
| | - Rossymar R. Colόn
- Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA; (E.Q.X.M.); (Y.Z.); (R.R.C.); (S.R.C.); (M.K.G.J.); (C.J.D.)
| | - Shelby R. Cain
- Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA; (E.Q.X.M.); (Y.Z.); (R.R.C.); (S.R.C.); (M.K.G.J.); (C.J.D.)
| | - Myron K. Gibert
- Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA; (E.Q.X.M.); (Y.Z.); (R.R.C.); (S.R.C.); (M.K.G.J.); (C.J.D.)
| | - Collin J. Dube
- Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA; (E.Q.X.M.); (Y.Z.); (R.R.C.); (S.R.C.); (M.K.G.J.); (C.J.D.)
| | - Markus Hafner
- National Institutes of Health (NIH), Bethesda, MD 20894, USA;
| | - Roger Abounader
- Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA; (E.Q.X.M.); (Y.Z.); (R.R.C.); (S.R.C.); (M.K.G.J.); (C.J.D.)
- Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA
- University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22908, USA
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31
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Liu G, Rong X, Lin X, Wang H, He L, Peng Y. Construction of a novel microRNA-based signature for predicting the prognosis of glioma. Int J Neurosci 2022:1-11. [PMID: 35353669 DOI: 10.1080/00207454.2021.1993848] [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: 10/18/2022]
Abstract
Background and purpose: Glioma is a frequent primary brain tumor. MicroRNAs (miRNA) have been shown to potentially play a crucial part in tumor development. Based on miRNAs and clinical factors, a model was constructed to predict the glioma prognosis. Methods: The miRNA expression profiles of glioma come from The Cancer Genome Atlas (TCGA, training group) and Chinese Glioma Genome Atlas (CGGA, validation group). Regression analyses of Cox and Lasso were applied to identity miRNAs associated with glioma prognosis in the TCGA database. The miRNAs were combined with clinical factors to construct individualized prognostic prediction models, whose performance was validated in the CGGA database. The role of miRNA in glioma development was investigated by in vitro experiments.Results: We identified five key miRNAs associated with glioma prognosis and constructed a prediction model. The area under ROC curve for predicting 3-year survival of glioma patients in the TCGA and CGGA groups was 0.844 and 0.770, respectively. The nomogram constructed using the miRNA risk scores and clinical factors showed high accuracy of prediction in the TCGA group (C-index of 0.820) and the CGGA group (C-index of 0.722). The miR-196b-5p altered the migration, proliferation, invasion, and apoptosis of glioma cells by regulating target genes, according to in vitro experiments.Conclusions: A miRNA-based individualized prognostic prediction model was constructed for glioma and miR-196b-5p was identified as a potential biomarker of glioma development.
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Affiliation(s)
- Gaoxin Liu
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaoming Rong
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xinrou Lin
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hongxuan Wang
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Lei He
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ying Peng
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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Celastrol with a Knockdown of miR-9-2, miR-17 and miR-19 Causes Cell Cycle Changes and Induces Apoptosis and Autophagy in Glioblastoma Multiforme Cells. Processes (Basel) 2022. [DOI: 10.3390/pr10030441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Glioblastoma multiforme (GBM) is a cancer with extremely high aggressiveness, malignancy and mortality. Because of all of the poor prognosis features of GBM, new methods should be sought that will effectively cure it. We examined the efficacy of a combination of celastrol and a knockdown of the miR-9-2, miR-17 and miR-19 genes in the human glioblastoma U251MG cell line. U251MG cells were transfected with specific siRNA and exposed to celastrol. The effect of the knockdown of the miRs genes in combination with exposure to celastrol on the cell cycle (flow cytometry) and the expression of selected genes related to its regulation (RT-qPCR) and the regulation of apoptosis and autophagy was investigated. We found a significant reduction in cell viability and proliferation, an accumulation of the subG1-phase cells and a decreased population of cells in the S and G2/M phases, as well as the induction of apoptosis and autophagy. The observed changes were not identical in the case of the silencing of each of the tested miRNAs, which indicates a different mechanism of action of miR9-2, miR-17, miR-19 silencing on GBM cells in combination with celastrol. The multidirectional effects of the silencing of the genes encoding miR-9-2, miR-17 and miR-19 in combination with exposure to celastrol is possible. The studied strategy of silencing the miR overexpressed in GBM could be important in developing more effective treatments for glioblastoma. Additional studies are necessary in order to obtain a more detailed interpretation of the obtained results. The siRNA-induced miR-9-2, miR-17 and miR-19 mRNA knockdowns in combination with celastrol could offer a novel therapeutic strategy to more effectively control the growth of human GBM cells.
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Salami R, Salami M, Mafi A, Vakili O, Asemi Z. Circular RNAs and glioblastoma multiforme: focus on molecular mechanisms. Cell Commun Signal 2022; 20:13. [PMID: 35090496 PMCID: PMC8796413 DOI: 10.1186/s12964-021-00809-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma multiforme (GBM), as a deadly and almost incurable brain cancer, is the most invasive form of CNS tumors that affects both children and adult population. It accounts for approximately half of all primary brain tumors. Despite the remarkable advances in neurosurgery, radiotherapy, and chemotherapeutic approaches, cell heterogeneity and numerous genetic alterations in cell cycle control, cell growth, apoptosis, and cell invasion, result in an undesirable resistance to therapeutic strategies; thereby, the median survival duration for GBM patients is unfortunately still less than two years. Identifying new therapeutics and employing the combination therapies may be considered as wonderful strategies against the GBM. In this regard, circular RNAs (circRNAs), as tumor inhibiting and/or stimulating RNA molecules, can regulate the cancer-developing processes, including cell proliferation, cell apoptosis, invasion, and chemoresistance. Hereupon, these molecules have been introduced as potentially effective therapeutic targets to defeat GBM. The current study aims to investigate the fundamental molecular and cellular mechanisms in association with circRNAs involved in GBM pathogenesis. Among multiple mechanisms, the PI3K/Akt/mTOR, Wnt/β-catenin, and MAPK signaling, angiogenic processes, and metastatic pathways will be thoroughly discussed to provide a comprehensive understanding of the role of circRNAs in pathophysiology of GBM. Video Abstract.
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Affiliation(s)
- Raziyeh Salami
- Department of Clinical Biochemistry, School of Medicine, Hamedan University of Medical Sciences, Hamedan, Iran
| | - Marziyeh Salami
- Department of Clinical Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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“Silicon-On-Insulator”-Based Nanosensor for the Revelation of MicroRNA Markers of Autism. Genes (Basel) 2022; 13:genes13020199. [PMID: 35205244 PMCID: PMC8872218 DOI: 10.3390/genes13020199] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 01/10/2022] [Accepted: 01/19/2022] [Indexed: 02/04/2023] Open
Abstract
MicroRNAs (miRNAs), which represent short (20 to 22 nt) non-coding RNAs, were found to play a direct role in the development of autism in children. Herein, a highly sensitive “silicon-on-insulator”-based nanosensor (SOI-NS) has been developed for the revelation of autism-associated miRNAs. This SOI-NS comprises an array of nanowire sensor structures fabricated by complementary metal–oxide–semiconductor (CMOS)-compatible technology, gas-phase etching, and nanolithography. In our experiments described herein, we demonstrate the revelation of ASD-associated miRNAs in human plasma with the SOI-NS, whose sensor elements were sensitized with oligonucleotide probes. In order to determine the concentration sensitivity of the SOI-NS, experiments on the detection of synthetic DNA analogues of autism-associated miRNAs in purified buffer were performed. The lower limit of miRNA detection attained in our experiments amounted to 10−17 M.
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Garnier D, Ratcliffe E, Briand J, Cartron PF, Oliver L, Vallette FM. The Activation of Mesenchymal Stem Cells by Glioblastoma Microvesicles Alters Their Exosomal Secretion of miR-100-5p, miR-9-5p and let-7d-5p. Biomedicines 2022; 10:biomedicines10010112. [PMID: 35052791 PMCID: PMC8773192 DOI: 10.3390/biomedicines10010112] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/28/2021] [Accepted: 12/31/2021] [Indexed: 02/01/2023] Open
Abstract
Glioblastoma (GBM) is the most aggressive brain tumor, and despite initial response to chemo- and radio-therapy, the persistence of glioblastoma stem cells (GSCs) unfortunately always results in tumor recurrence. It is now largely admitted that tumor cells recruit normal cells, including mesenchymal stem cells (MSCs), and components of their environment, to participate in tumor progression, building up what is called the tumor microenvironment (TME). While growth factors and cytokines constitute essential messengers to pass on signals between tumor and TME, recent uncovering of extracellular vesicles (EVs), composed of microvesicles (MVs) and exosomes, opened new perspectives to define the modalities of this communication. In the GBM context particularly, we investigated what could be the nature of the EV exchange between GSCs and MSCs. We show that GSCs MVs can activate MSCs into cancer-associated fibroblasts (CAFs)-like cells, that subsequently increase their secretion of exosomes. Moreover, a significant decrease in anti-tumoral miR-100-5p, miR-9-5p and let-7d-5p was observed in these exosomes. This clearly suggests a miRNA-mediated GBM tumor promotion by MSCs exosomes, after their activation by GBM MVs.
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Affiliation(s)
- Delphine Garnier
- CRCINA INSERM U1232, CHU de Nantes, Université de Nantes, 44000 Nantes, France; (E.R.); (J.B.); (P.-F.C.); (L.O.); (F.M.V.)
- LaBCT, Institut de Cancérologie de L’Ouest, 44800 Saint Herblain, France
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, 75006 Paris, France
- Correspondence:
| | - Edward Ratcliffe
- CRCINA INSERM U1232, CHU de Nantes, Université de Nantes, 44000 Nantes, France; (E.R.); (J.B.); (P.-F.C.); (L.O.); (F.M.V.)
- LaBCT, Institut de Cancérologie de L’Ouest, 44800 Saint Herblain, France
| | - Joséphine Briand
- CRCINA INSERM U1232, CHU de Nantes, Université de Nantes, 44000 Nantes, France; (E.R.); (J.B.); (P.-F.C.); (L.O.); (F.M.V.)
- LaBCT, Institut de Cancérologie de L’Ouest, 44800 Saint Herblain, France
| | - Pierre-François Cartron
- CRCINA INSERM U1232, CHU de Nantes, Université de Nantes, 44000 Nantes, France; (E.R.); (J.B.); (P.-F.C.); (L.O.); (F.M.V.)
- LaBCT, Institut de Cancérologie de L’Ouest, 44800 Saint Herblain, France
| | - Lisa Oliver
- CRCINA INSERM U1232, CHU de Nantes, Université de Nantes, 44000 Nantes, France; (E.R.); (J.B.); (P.-F.C.); (L.O.); (F.M.V.)
- LaBCT, Institut de Cancérologie de L’Ouest, 44800 Saint Herblain, France
| | - François M. Vallette
- CRCINA INSERM U1232, CHU de Nantes, Université de Nantes, 44000 Nantes, France; (E.R.); (J.B.); (P.-F.C.); (L.O.); (F.M.V.)
- LaBCT, Institut de Cancérologie de L’Ouest, 44800 Saint Herblain, France
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Pavlova GV, Golbin DA, Kubyshkina VE, Galkin MV, Pronin IN, Karandashov IV. [Cell cultures of human CNS tumors as in vitro model for individualized therapeutic approach]. ZHURNAL VOPROSY NEIROKHIRURGII IMENI N. N. BURDENKO 2022; 86:84-90. [PMID: 36534628 DOI: 10.17116/neiro20228606184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Tumor cell lines and cultures are widely used in biomedical research. They are excellent model systems for analysis of oncological mechanisms and understanding the biology of tumor cells. Cell cultures are used to develop and test new anticancer drugs, radiosensitizers and radiotherapy methods. Clinical application of tumor cell cultures is directly related to development of personalized medicine. Using tumor cell culture in a particular patient, physicians can select treatment considering molecular genetic characteristics of patient and tumor. In addition, it is possible to choose the optimal drug or radiotherapy regimen with obvious effectiveness in certain cell culture. This review describes the advantages of such an approach.
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Affiliation(s)
- G V Pavlova
- Sechenov First Moscow State Medical University, Moscow, Russia
- Institute of Higher Nervous Activity and Neurophysiology, Moscow, Russia
- Burdenko Neurosurgical Center, Moscow, Russia
| | - D A Golbin
- Burdenko Neurosurgical Center, Moscow, Russia
| | - V E Kubyshkina
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - M V Galkin
- Burdenko Neurosurgical Center, Moscow, Russia
| | - I N Pronin
- Burdenko Neurosurgical Center, Moscow, Russia
| | - I V Karandashov
- Sechenov First Moscow State Medical University, Moscow, Russia
- Institute of Higher Nervous Activity and Neurophysiology, Moscow, Russia
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Belyashova AS, Galkin MV, Antipina NA, Pavlova GV, Golanov AV. Cell cultures in assessing radioresistance of glioblastomas. ZHURNAL VOPROSY NEIROKHIRURGII IMENI N. N. BURDENKO 2022; 86:126-132. [PMID: 36252203 DOI: 10.17116/neiro202286051126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
To date, no modern methods of treatment allow overcoming malignant potential of glial neoplasms and significant increase of survival. Analysis of glioblastoma radioresistance using cancer cell cultures is one of the perspective directions, as radiotherapy is standard and available treatment method for these neoplasms. This review summarizes current studies identifying many factors of radioresistance of glial tumors, such as hypoxia, microenvironment and metabolic features of tumor, stem cells, internal heterogeneity of tumor, microRNA, features of cell cycle, DNA damage and reparation. We obtained data on involvement of various molecular pathways in development of radioresistance such as MEK/ERK, c-MYC, PI3K/Akt, PTEN, Wnt, JAK/STAT, Notch, etc. Changes in activity of RAD51 APC, FZD1, LEF1, TCF4, WISP1, p53 and many others are determined in radioresistant cells. Further study of radioresistance pathways will allow development of specific target aptamers and inhibitors.
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Affiliation(s)
| | - M V Galkin
- Burdenko Neurosurgical Center, Moscow, Russia
| | | | - G V Pavlova
- Burdenko Neurosurgical Center, Moscow, Russia
| | - A V Golanov
- Burdenko Neurosurgical Center, Moscow, Russia
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38
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SENCAR L, YILMAZ DM, GÖKTÜRK D, ÖZANDAÇ POLAT S, COŞKUN G, ŞAKER D, SAPMAZ T, KARA S, ÇELENK A, POLAT S. Glioblastoma hücre hattında (U87) siklopamin ve temozolomid kombine tedavisinin miR-20a ekspresyonu üzerine etkileri. CUKUROVA MEDICAL JOURNAL 2021. [DOI: 10.17826/cumj.996520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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Huang Y, Qi L, Kogiso M, Du Y, Braun FK, Zhang H, Huang LF, Xiao S, Teo W, Lindsay H, Zhao S, Baxter P, Su JMF, Adesina A, Yang J, Brabetz S, Kool M, Pfister SM, Chintagumpala M, Perlaky L, Wang Z, Zhou Y, Man T, Li X. Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2101923. [PMID: 34719887 PMCID: PMC8655179 DOI: 10.1002/advs.202101923] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 09/15/2021] [Indexed: 06/13/2023]
Abstract
Diffuse invasion is the primary cause of treatment failure of glioblastoma (GBM). Previous studies on GBM invasion have long been forced to use the resected tumor mass cells. Here, a strategy to reliably isolate matching pairs of invasive (GBMINV ) and tumor core (GBMTC ) cells from the brains of 6 highly invasive patient-derived orthotopic models is described. Direct comparison of these GBMINV and GBMTC cells reveals a significantly elevated invasion capacity in GBMINV cells, detects 23/768 miRNAs over-expressed in the GBMINV cells (miRNAINV ) and 22/768 in the GBMTC cells (miRNATC ), respectively. Silencing the top 3 miRNAsINV (miR-126, miR-369-5p, miR-487b) successfully blocks invasion of GBMINV cells in vitro and in mouse brains. Integrated analysis with mRNA expression identifies miRNAINV target genes and discovers KCNA1 as the sole common computational target gene of which 3 inhibitors significantly suppress invasion in vitro. Furthermore, in vivo treatment with 4-aminopyridine (4-AP) effectively eliminates GBM invasion and significantly prolongs animal survival times (P = 0.035). The results highlight the power of spatial dissection of functionally accurate GBMINV and GBMTC cells in identifying novel drivers of GBM invasion and provide strong rationale to support the use of biologically accurate starting materials in understanding cancer invasion and metastasis.
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Affiliation(s)
- Yulun Huang
- Department of NeurosurgeryDushu Lake HospitalSoochow UniversitySuzhou205124China
- Department of Neurosurgery and Brain and Nerve Research Laboratorythe First Affiliated HospitalSoochow UniversitySuzhou215007China
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - Lin Qi
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
- Program of Precision Medicine PDOX Modeling of Pediatric TumorsAnn & Robert H. Lurie Children's Hospital of ChicagoDepartment of PediatricsNorthwestern University Feinberg School of MedicineChicagoIL60611USA
- Department of PharmacologySchool of MedicineSun Yat‐Sen UniversityShenzhen518107China
| | - Mari Kogiso
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - Yuchen Du
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
- Program of Precision Medicine PDOX Modeling of Pediatric TumorsAnn & Robert H. Lurie Children's Hospital of ChicagoDepartment of PediatricsNorthwestern University Feinberg School of MedicineChicagoIL60611USA
| | - Frank K. Braun
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - Huiyuan Zhang
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - L. Frank Huang
- Department of Systems Medicine and BioegineeringHouston Methodist Hospital Research Institute and Cancer CenterWeill Cornell MedicineHoustonTX77030USA
- Division of Experimental Hematology and Cancer BiologyBrain Tumor CenterCincinnati Children’s Hospital Medical CenterDepartment of PediatricsUniversity of Cincinnati College of MedicineCincinnatiUnited States45229United States
| | - Sophie Xiao
- Program of Precision Medicine PDOX Modeling of Pediatric TumorsAnn & Robert H. Lurie Children's Hospital of ChicagoDepartment of PediatricsNorthwestern University Feinberg School of MedicineChicagoIL60611USA
| | - Wan‐Yee Teo
- Humphrey Oei Institute of Cancer ResearchNational Cancer Center SingaporeSingapore169610Singapore
| | - Holly Lindsay
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - Sibo Zhao
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - Patricia Baxter
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - Jack M. F. Su
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - Adekunle Adesina
- Department of PathologyTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - Jianhua Yang
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - Sebastian Brabetz
- Hopp Children's Cancer Center (KiTZ)Heidelberg69120Germany
- Division of Pediatric Neuro‐oncologyGerman Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Heidelberg69120Germany
| | - Marcel Kool
- Hopp Children's Cancer Center (KiTZ)Heidelberg69120Germany
- Division of Pediatric Neuro‐oncologyGerman Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Heidelberg69120Germany
| | - Stefan M. Pfister
- Hopp Children's Cancer Center (KiTZ)Heidelberg69120Germany
- Division of Pediatric Neuro‐oncologyGerman Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)Heidelberg69120Germany
- Department of Pediatric Hematology and OncologyHeidelberg University HospitalHeidelberg69120Germany
| | - Murali Chintagumpala
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - Laszlo Perlaky
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - Zhong Wang
- Department of Neurosurgery and Brain and Nerve Research Laboratorythe First Affiliated HospitalSoochow UniversitySuzhou215007China
| | - Youxin Zhou
- Department of Neurosurgery and Brain and Nerve Research Laboratorythe First Affiliated HospitalSoochow UniversitySuzhou215007China
| | - Tsz‐Kwong Man
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
| | - Xiao‐Nan Li
- Texas Children's Cancer CenterTexas Children's HospitalBaylor College of MedicineHoustonTX77030USA
- Program of Precision Medicine PDOX Modeling of Pediatric TumorsAnn & Robert H. Lurie Children's Hospital of ChicagoDepartment of PediatricsNorthwestern University Feinberg School of MedicineChicagoIL60611USA
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Kukreja L, Li CJ, Ezhilan S, Iyer VR, Kuo JS. Emerging Epigenetic Therapies for Brain Tumors. Neuromolecular Med 2021; 24:41-49. [PMID: 34677796 DOI: 10.1007/s12017-021-08691-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 09/14/2021] [Indexed: 01/30/2023]
Abstract
Malignant brain tumors are among the most intractable cancers, including malignancies such as glioblastoma, diffuse midline glioma, medulloblastoma, and ependymoma. Unfortunately, treatment options for these brain tumors have been inadequate and complex, leading to poor prognoses and creating a need for new treatment modalities. Aberrant epigenetics define these types of tumors, with underlying changes in DNA methylation, histone modifications, chromatin structure and noncoding RNAs. Epigenetic-targeted therapies are an alternative that have the potential to reverse the epigenetic deregulation underpinning brain malignancies. Various drugs targeting epigenetic regulators have shown promise in preclinical and clinical testing. In this review, we highlight some of the recent emerging epigenetic targeted therapies for brain tumors being evaluated in the discovery phase and in clinical trials.
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Affiliation(s)
- Lokesh Kukreja
- Department of Neurosurgery, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
| | - Catherine J Li
- Department of Neurosurgery, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
| | - Sathyapriya Ezhilan
- Department of Neurosurgery, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
| | - Vishwanath R Iyer
- Department of Molecular Biosciences, LIVESTRONG Cancer Institutes and Department of Oncology, Dell Medical School, The University of Texas, Austin, TX, USA
| | - John S Kuo
- Department of Neurosurgery, Mulva Clinic for the Neurosciences and LIVESTRONG Cancer Institutes and Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA. .,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
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Śledzińska P, Bebyn MG, Furtak J, Kowalewski J, Lewandowska MA. Prognostic and Predictive Biomarkers in Gliomas. Int J Mol Sci 2021; 22:ijms221910373. [PMID: 34638714 PMCID: PMC8508830 DOI: 10.3390/ijms221910373] [Citation(s) in RCA: 183] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/14/2021] [Accepted: 09/22/2021] [Indexed: 12/17/2022] Open
Abstract
Gliomas are the most common central nervous system tumors. New technologies, including genetic research and advanced statistical methods, revolutionize the therapeutic approach to the patient and reveal new points of treatment options. Moreover, the 2021 World Health Organization Classification of Tumors of the Central Nervous System has fundamentally changed the classification of gliomas and incorporated many molecular biomarkers. Given the rapid progress in neuro-oncology, here we compile the latest research on prognostic and predictive biomarkers in gliomas. In adult patients, IDH mutations are positive prognostic markers and have the greatest prognostic significance. However, CDKN2A deletion, in IDH-mutant astrocytomas, is a marker of the highest malignancy grade. Moreover, the presence of TERT promoter mutations, EGFR alterations, or a combination of chromosome 7 gain and 10 loss upgrade IDH-wildtype astrocytoma to glioblastoma. In pediatric patients, H3F3A alterations are the most important markers which predict the worse outcome. MGMT promoter methylation has the greatest clinical significance in predicting responses to temozolomide (TMZ). Conversely, mismatch repair defects cause hypermutation phenotype predicting poor response to TMZ. Finally, we discussed liquid biopsies, which are promising diagnostic, prognostic, and predictive techniques, but further work is needed to implement these novel technologies in clinical practice.
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Affiliation(s)
- Paulina Śledzińska
- Department of Thoracic Surgery and Tumors, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 85-067 Torun, Poland
- The F. Lukaszczyk Oncology Center, Molecular Oncology and Genetics Department, Innovative Medical Forum, 85-796 Bydgoszcz, Poland
| | - Marek G Bebyn
- The F. Lukaszczyk Oncology Center, Molecular Oncology and Genetics Department, Innovative Medical Forum, 85-796 Bydgoszcz, Poland
- Faculty of Medicine, Medical University of Gdańsk, 80-210 Gdańsk, Poland
| | - Jacek Furtak
- Department of Neurosurgery, 10th Military Research Hospital and Polyclinic, 85-681 Bydgoszcz, Poland
- Franciszek Lukaszczyk Oncology Center, Department of Neurooncology and Radiosurgery, 85-796 Bydgoszcz, Poland
| | - Janusz Kowalewski
- Department of Thoracic Surgery and Tumors, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 85-067 Torun, Poland
| | - Marzena A Lewandowska
- Department of Thoracic Surgery and Tumors, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 85-067 Torun, Poland
- The F. Lukaszczyk Oncology Center, Molecular Oncology and Genetics Department, Innovative Medical Forum, 85-796 Bydgoszcz, Poland
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Wei J, Gilboa E, Calin GA, Heimberger AB. Immune Modulatory Short Noncoding RNAs Targeting the Glioblastoma Microenvironment. Front Oncol 2021; 11:682129. [PMID: 34532286 PMCID: PMC8438301 DOI: 10.3389/fonc.2021.682129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 08/11/2021] [Indexed: 12/22/2022] Open
Abstract
Glioblastomas are heterogeneous and have a poor prognosis. Glioblastoma cells interact with their neighbors to form a tumor-permissive and immunosuppressive microenvironment. Short noncoding RNAs are relevant mediators of the dynamic crosstalk among cancer, stromal, and immune cells in establishing the glioblastoma microenvironment. In addition to the ease of combinatorial strategies that are capable of multimodal modulation for both reversing immune suppression and enhancing antitumor immunity, their small size provides an opportunity to overcome the limitations of blood-brain-barrier (BBB) permeability. To enhance glioblastoma delivery, these RNAs have been conjugated with various molecules or packed within delivery vehicles for enhanced tissue-specific delivery and increased payload. Here, we focus on the role of RNA therapeutics by appraising which types of nucleotides are most effective in immune modulation, lead therapeutic candidates, and clarify how to optimize delivery of the therapeutic RNAs and their conjugates specifically to the glioblastoma microenvironment.
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Affiliation(s)
- Jun Wei
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Eli Gilboa
- Department of Microbiology & Immunology, Dodson Interdisciplinary Immunotherapy Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
| | - George A Calin
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Amy B Heimberger
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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Liu Z, Wu K, Gu S, Wang W, Xie S, Lu T, Li L, Dong C, Wang X, Zhou Y. A methyltransferase-like 14/miR-99a-5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2-mediated epigenetic modulation in esophageal squamous cell carcinoma. Clin Transl Med 2021; 11:e545. [PMID: 34586732 PMCID: PMC8441142 DOI: 10.1002/ctm2.545] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/04/2021] [Accepted: 08/09/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a highly aggressive and treatment-resistant tumor. The biological implications and molecular mechanism of cancer stem-like cells (CSCs) in ESCC, which contribute to therapeutic resistance such as radioresistance, remain elusive. METHODS Quantitative real-time polymerase chain reaction, western blotting, immunohistochemistry, and in situ hybridization assays were used to detect methyltransferase-like 14 miR-99a-5p tribble 2 (METTL14/miR-99a-5p/TRIB2) expression in ESCC. The biological functions of METTL14/miR-99a-5p/TRIB2 were demonstrated in vitro and in vivo. Mass spectrum analysis was used to identify the downstream proteins regulated by TRIB2. Chromatin immunoprecipitation (IP), IP, N6 -methyladenosine (m6 A)-RNA IP, luciferase reporter, and ubiquitination assays were employed to explore the molecular mechanisms underlying this feedback circuit and its downstream pathways. RESULTS We found that miR-99a-5p was significantly decreased in ESCC. miR-99a-5p inhibited CSCs persistence and the radioresistance of ESCC cells, and miR-99a-5p downregulation predicted an unfavorable prognosis of ESCC patients. Mechanically, we unveiled a METTL14-miR-99a-5p-TRIB2 positive feedback loop that enhances CSC properties and radioresistance of ESCC cells. METTL14, an m6 A RNA methyltransferase downregulated in ESCC, suppresses TRIB2 expression via miR-99a-5p-mediated degradation of TRIB2 mRNA by targeting its 3' untranslated region, whereas TRIB2 induces ubiquitin-mediated proteasomal degradation of METTL14 in a COP1-dependent manner. METTL14 upregulates miR-99a-5p by modulating m6 A-mediated, DiGeorge critical region 8-dependent pri-mir-99a processing. Hyperactivation of TRIB2 resulting from this positive circuit was closely correlated with radioresistance and CSC characteristics. Furthermore, TRIB2 activates HDAC2 and subsequently induces p21 epigenetic repression through Akt/mTOR/S6K1 signaling pathway activation. Pharmacologic inhibition of HDAC2 effectively attenuates the TRIB2-mediated effect both in vitro and in patient-derived xenograft models. CONCLUSION Our data highlight the presence of the METTL14/miR-99a-5p/TRIB2 axis and show that it is positively associated with CSC characteristics and radioresistance of ESCC, suggesting potential therapeutic targets for ESCC treatment.
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Affiliation(s)
- Zhenchuan Liu
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of MedicineTongji UniversityShanghaiP.R. China
| | - Kaiqing Wu
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of MedicineTongji UniversityShanghaiP.R. China
| | - Shaorui Gu
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of MedicineTongji UniversityShanghaiP.R. China
| | - Wenli Wang
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of MedicineTongji UniversityShanghaiP.R. China
| | - Shiliang Xie
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of MedicineTongji UniversityShanghaiP.R. China
| | - Tiancheng Lu
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of MedicineTongji UniversityShanghaiP.R. China
| | - Lei Li
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of MedicineTongji UniversityShanghaiP.R. China
| | - Chenglai Dong
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of MedicineTongji UniversityShanghaiP.R. China
| | - Xishi Wang
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of MedicineTongji UniversityShanghaiP.R. China
| | - Yongxin Zhou
- Department of Thoracic Surgery, Shanghai Tongji Hospital, School of MedicineTongji UniversityShanghaiP.R. China
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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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45
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The role of melatonin in angio-miR-associated inhibition of tumorigenesis and invasion in human glioblastoma tumour spheroids. Tissue Cell 2021; 73:101617. [PMID: 34418770 DOI: 10.1016/j.tice.2021.101617] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 07/19/2021] [Accepted: 08/01/2021] [Indexed: 12/13/2022]
Abstract
Micro-RNA (miRNA)-based regulation of hypoxia, angiogenesis and tumour growth provides promising targets for effective therapy in malignant glioblastoma multiforme (GBM). Accumulating evidence suggests a potential role of melatonin in miRNA expression in cancer cells. Despite these findings, the melatonin-miRNA interaction in GBM and the effect of this interaction on GBM tumour development and invasion are not clearly understood. The aim of the present study was to evaluate the effects of melatonin on human GBM tumour spheroid tumorigenesis and invasion in vitro, and to analyse the interaction between 36 angio-miRNAs and the HIF1/VEGF/MMP9 axis, which is known to be associated with the antitumour effect of melatonin. We found that melatonin is able to selectively induce cell death in single-layer U87-MG cells (a GBM cell line) in a dose- and time-dependent manner, as characterized by MTT assay. The use of tumour spheroids and a Matrigel invasion assay revealed that melatonin impairs tumorigenesis, and it significantly reduced both the tumour spheroid area and invasion rate, especially at the 0.5 mM and 1 mM concentrations. This inhibition was accompanied by strong reductions in hypoxia-inducible factor 1-α (HIF1-α) and vascular endothelial growth factor (VEGF) gene expression and protein levels in GBM tumour spheroids. In addition, melatonin significantly reduced the relative gene expression and protein levels of matrix metalloproteinase-9 (MMP-9). This study revealed that six differentially expressed angio-miRs (miR-15b, miR-18a-5p, miR-23a-3p, miR-92a-3p, miR-130a-5p, miR-200b-3p) may play important roles in GBM tumorigenesis and invasion, and all respond to melatonin therapy. Our results suggest that melatonin inhibits tumorigenesis and invasion of human GBM tumour spheroids, possibly by suppressing HIF1-α/VEGF/MMP9 signalling via regulation of angio-miRNAs.
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46
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Phosphatidylinositol 3,4,5-Trisphosphate-Dependent Rac Exchanger 2 Protein Facilitates Glioma Progression via Akt and Stat3 Signaling. J Mol Neurosci 2021; 71:1674-1682. [PMID: 34322848 DOI: 10.1007/s12031-021-01883-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 06/29/2021] [Indexed: 10/20/2022]
Abstract
Glioblastoma multiforme (GBM) is the recognized as the most aggressive brain tumor with poor prognosis and low 1-year and 5-year survival rate. The treatment methods for GBM are limited and inefficient, and novel strategies for GBM treatment are urgently warranted. MiR-338-3p is described as a tumor suppressor in a variety of malignancies, including GBM. However, its role in GBM is not fully understood. The mRNA or protein levels of targets in cells or tissues were determined by quantitative reverse transcription PCR (RT-qPCR) or Western blot, respectively. The GBM cell growth rate in vitro or in vivo was measured by Cell Counting Kit-8 or bioluminescence imaging, respectively. Upregulation of hsa-miR-338-3p and downregulation of phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein (Prex2) were observed in GBM tissues compared to normal brain tissues. We further confirmed that murine Prex2 was a target of mmu-miR-338-3p in GBM. Mmu-miR-338-3p exerted profound inhibition effects on GBM cell growth in vitro or in vivo through targeting Prex2, leading to attenuation of (Protein kinase B) AKT/Signal transducer and activator of transcription 3 (STAT3) signaling activation. Restoration of mmu-miR-338-3p or inhibition of Prex2 may facilitate the development of innovative therapies for GBM treatment.
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47
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Cardoso AM, Morais CM, Sousa M, Rebelo O, Tão H, Barbosa M, Pedroso de Lima MC, Jurado AS. MiR-200c-based metabolic modulation in glioblastoma cells as a strategy to overcome tumor chemoresistance. Hum Mol Genet 2021; 30:2315-2331. [PMID: 34245265 DOI: 10.1093/hmg/ddab193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 11/14/2022] Open
Abstract
Glioblastoma (GB) is the most aggressive and common form of primary brain tumor characterized by fast proliferation, high invasion, and resistance to current standard treatment. The average survival rate post-diagnosis is 14.6 months, despite the aggressive standard post-surgery radiotherapy concomitant with chemotherapy with temozolomide (TMZ). Currently, efforts are being endowed to develop new and more efficient therapeutic approaches capable to overcome chemoresistance, inhibit tumor progression and improve overall patient survival rate. Abnormal microRNA (miRNA) expression has been correlated with chemoresistance, proliferation and resistance to apoptosis, which result from their master regulatory role of gene expression. Altered cell metabolism, favoring glycolysis, was identified as an emerging cancer hallmark and has been described in GB, thus offering a new target for innovative GB therapies. In this work, we hypothesized that a gene therapy-based strategy consisting of the overexpression of a miRNA downregulated in GB and predicted to target crucial metabolic enzymes might promote a shift of GB cell metabolism, decreasing the glycolytic dependence of tumor cells and contributing to their sensitization to chemotherapy with TMZ. The increase of miR-200c levels in DBTRG cells resulted in downregulation of mRNA of enzymes involved in bioenergetics pathways and impaired cell metabolism and mobility. Additionally, miR-200c overexpression prior to DBTRG cell exposure to TMZ resulted in cell cycle arrest. Overall, our results show that miR-200c overexpression could offer a way to overcome chemoresistance developed by GB cells in response to current standard chemotherapy, providing an improvement to current GB standard treatment, with benefit for patient outcome.
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Affiliation(s)
- Ana M Cardoso
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC - Institute for Interdisciplinary Research, Coimbra, Portugal
| | - Catarina M Morais
- Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal.,CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC - Institute for Interdisciplinary Research, Coimbra, Portugal
| | - Madalena Sousa
- Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal.,CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC - Institute for Interdisciplinary Research, Coimbra, Portugal
| | - Olinda Rebelo
- Neuropathology Laboratory, Neurology Service, University Hospital of Coimbra, 3004-561 Coimbra, Portugal
| | - Hermínio Tão
- Neurosurgery Service, University Hospital of Coimbra, 3004-561 Coimbra, Portugal
| | - Marcos Barbosa
- Neurosurgery Service, University Hospital of Coimbra, 3004-561 Coimbra, Portugal.,Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Maria C Pedroso de Lima
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC - Institute for Interdisciplinary Research, Coimbra, Portugal
| | - Amália S Jurado
- Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal.,CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC - Institute for Interdisciplinary Research, Coimbra, Portugal
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48
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Mousavi SR, Khosravian F, Hemmat N, Feizbakhshan S, Salmanizadeh S, Foroutan FS, Ghaedi K, Salehi M. A glance at glioblastoma molecular culprits through in-silico analysis. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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49
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Prieto-Colomina A, Fernández V, Chinnappa K, Borrell V. MiRNAs in early brain development and pediatric cancer: At the intersection between healthy and diseased embryonic development. Bioessays 2021; 43:e2100073. [PMID: 33998002 DOI: 10.1002/bies.202100073] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/12/2021] [Accepted: 04/15/2021] [Indexed: 12/15/2022]
Abstract
The size and organization of the brain are determined by the activity of progenitor cells early in development. Key mechanisms regulating progenitor cell biology involve miRNAs. These small noncoding RNA molecules bind mRNAs with high specificity, controlling their abundance and expression. The role of miRNAs in brain development has been studied extensively, but their involvement at early stages remained unknown until recently. Here, recent findings showing the important role of miRNAs in the earliest phases of brain development are reviewed, and it is discussed how loss of specific miRNAs leads to pathological conditions, particularly adult and pediatric brain tumors. Let-7 miRNA downregulation and the initiation of embryonal tumors with multilayered rosettes (ETMR), a novel link recently discovered by the laboratory, are focused upon. Finally, it is discussed how miRNAs may be used for the diagnosis and therapeutic treatment of pediatric brain tumors, with the hope of improving the prognosis of these devastating diseases.
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Affiliation(s)
- Anna Prieto-Colomina
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d'Alacant, Spain
| | - Virginia Fernández
- Neurobiology of miRNA, Fondazione Istituto Italiano di Tecnologia (IIT), Genoa, Italy
| | - Kaviya Chinnappa
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d'Alacant, Spain
| | - Víctor Borrell
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d'Alacant, Spain
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50
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Grixti JM, Ayers D, Day PJR. An Analysis of Mechanisms for Cellular Uptake of miRNAs to Enhance Drug Delivery and Efficacy in Cancer Chemoresistance. Noncoding RNA 2021; 7:27. [PMID: 33923485 PMCID: PMC8167612 DOI: 10.3390/ncrna7020027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/11/2021] [Accepted: 04/13/2021] [Indexed: 12/15/2022] Open
Abstract
Up until recently, it was believed that pharmaceutical drugs and their metabolites enter into the cell to gain access to their targets via simple diffusion across the hydrophobic lipid cellular membrane, at a rate which is based on their lipophilicity. An increasing amount of evidence indicates that the phospholipid bilayer-mediated drug diffusion is in fact negligible, and that drugs pass through cell membranes via proteinaceous membrane transporters or carriers which are normally used for the transportation of nutrients and intermediate metabolites. Drugs can be targeted to specific cells and tissues which express the relevant transporters, leading to the design of safe and efficacious treatments. Furthermore, transporter expression levels can be manipulated, systematically and in a high-throughput manner, allowing for considerable progress in determining which transporters are used by specific drugs. The ever-expanding field of miRNA therapeutics is not without its challenges, with the most notable one being the safe and effective delivery of the miRNA mimic/antagonist safely to the target cell cytoplasm for attaining the desired clinical outcome, particularly in miRNA-based cancer therapeutics, due to the poor efficiency of neo-vascular systems revolting around the tumour site, brought about by tumour-induced angiogenesis. This acquisition of resistance to several types of anticancer drugs can be as a result of an upregulation of efflux transporters expression, which eject drugs from cells, hence lowering drug efficacy, resulting in multidrug resistance. In this article, the latest available data on human microRNAs has been reviewed, together with the most recently described mechanisms for miRNA uptake in cells, for future therapeutic enhancements against cancer chemoresistance.
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Affiliation(s)
- Justine M. Grixti
- Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Biosciences Building, University of Liverpool, Liverpool L69 7ZB, UK;
| | - Duncan Ayers
- Centre for Molecular Medicine and Biobanking, University of Malta, Msida MSD 2080, Malta
- Faculty of Biology, Medicine and Human Sciences, The University of Manchester, Manchester M1 7DN, UK;
| | - Philip J. R. Day
- Faculty of Biology, Medicine and Human Sciences, The University of Manchester, Manchester M1 7DN, UK;
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