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Aitchison EE, Dimesa AM, Shoari A. Matrix Metalloproteinases in Glioma: Drivers of Invasion and Therapeutic Targets. BIOTECH 2025; 14:28. [PMID: 40265458 PMCID: PMC12015896 DOI: 10.3390/biotech14020028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/08/2025] [Accepted: 04/15/2025] [Indexed: 04/24/2025] Open
Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteolytic enzymes that are crucial for the remodeling of the extracellular matrix, a process that is often co-opted by cancers, including brain tumors, to facilitate growth, invasion, and metastasis. In gliomas, MMPs contribute to a complex interplay involving tumor proliferation, angiogenesis, and immune modulation, thereby influencing tumor progression and patient prognosis. This review provides a comprehensive analysis of the roles of various MMPs in different types of gliomas, from highly malignant gliomas to metastatic lesions. Emphasis is placed on how the dysregulation of MMPs impacts tumor behavior, the association between specific MMPs and the tumor grade, and their potential as biomarkers for diagnosis and prognosis. Additionally, the current therapeutic approaches targeting MMP activity are discussed, exploring both their challenges and future potential. By synthesizing recent findings, this paper aims to clarify the broad significance of MMPs in gliomas and propose avenues for translational research that could enhance treatment strategies and clinical outcomes.
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Affiliation(s)
- Ella E. Aitchison
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; (E.E.A.); (A.M.D.)
- School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PT, UK
| | - Alexandra M. Dimesa
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; (E.E.A.); (A.M.D.)
- Department of Biology, University of North Florida, Jacksonville, FL 32224, USA
| | - Alireza Shoari
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; (E.E.A.); (A.M.D.)
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Kałuzińska-Kołat Ż, Kołat D, Kośla K, Płuciennik E, Bednarek AK. Delineating the glioblastoma stemness by genes involved in cytoskeletal rearrangements and metabolic alterations. World J Stem Cells 2023; 15:302-322. [PMID: 37342224 PMCID: PMC10277965 DOI: 10.4252/wjsc.v15.i5.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 02/03/2023] [Accepted: 03/08/2023] [Indexed: 05/26/2023] Open
Abstract
Literature data on glioblastoma ongoingly underline the link between metabolism and cancer stemness, the latter is one responsible for potentiating the resistance to treatment, inter alia due to increased invasiveness. In recent years, glioblastoma stemness research has bashfully introduced a key aspect of cytoskeletal rearrangements, whereas the impact of the cytoskeleton on invasiveness is well known. Although non-stem glioblastoma cells are less invasive than glioblastoma stem cells (GSCs), these cells also acquire stemness with greater ease if characterized as invasive cells and not tumor core cells. This suggests that glioblastoma stemness should be further investigated for any phenomena related to the cytoskeleton and metabolism, as they may provide new invasion-related insights. Previously, we proved that interplay between metabolism and cytoskeleton existed in glioblastoma. Despite searching for cytoskeleton-related processes in which the investigated genes might have been involved, not only did we stumble across the relation to metabolism but also reported genes that were found to be implicated in stemness. Thus, dedicated research on these genes in GSCs seems justifiable and might reveal novel directions and/or biomarkers that could be utilized in the future. Herein, we review the previously identified cytoskeleton/metabolism-related genes through the prism of glioblastoma stemness.
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Affiliation(s)
- Żaneta Kałuzińska-Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland.
| | - Damian Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Katarzyna Kośla
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Elżbieta Płuciennik
- Department of Functional Genomics, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
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Kałuzińska Ż, Kołat D, Bednarek AK, Płuciennik E. PLEK2, RRM2, GCSH: A Novel WWOX-Dependent Biomarker Triad of Glioblastoma at the Crossroads of Cytoskeleton Reorganization and Metabolism Alterations. Cancers (Basel) 2021; 13:2955. [PMID: 34204789 PMCID: PMC8231639 DOI: 10.3390/cancers13122955] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/30/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma is one of the deadliest human cancers. Its malignancy depends on cytoskeleton reorganization, which is related to, e.g., epithelial-to-mesenchymal transition and metastasis. The malignant phenotype of glioblastoma is also affected by the WWOX gene, which is lost in nearly a quarter of gliomas. Although the role of WWOX in the cytoskeleton rearrangement has been found in neural progenitor cells, its function as a modulator of cytoskeleton in gliomas was not investigated. Therefore, this study aimed to investigate the role of WWOX and its collaborators in cytoskeleton dynamics of glioblastoma. Methodology on RNA-seq data integrated the use of databases, bioinformatics tools, web-based platforms, and machine learning algorithm, and the obtained results were validated through microarray data. PLEK2, RRM2, and GCSH were the most relevant WWOX-dependent genes that could serve as novel biomarkers. Other genes important in the context of cytoskeleton (BMP4, CCL11, CUX2, DUSP7, FAM92B, GRIN2B, HOXA1, HOXA10, KIF20A, NF2, SPOCK1, TTR, UHRF1, and WT1), metabolism (MTHFD2), or correlation with WWOX (COL3A1, KIF20A, RNF141, and RXRG) were also discovered. For the first time, we propose that changes in WWOX expression dictate a myriad of alterations that affect both glioblastoma cytoskeleton and metabolism, rendering new therapeutic possibilities.
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Affiliation(s)
- Żaneta Kałuzińska
- Department of Molecular Carcinogenesis, Medical University of Lodz, 90-752 Lodz, Poland; (D.K.); (A.K.B.); (E.P.)
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Waller V, Pruschy M. Combined Radiochemotherapy: Metalloproteinases Revisited. Front Oncol 2021; 11:676583. [PMID: 34055644 PMCID: PMC8155607 DOI: 10.3389/fonc.2021.676583] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/21/2021] [Indexed: 12/25/2022] Open
Abstract
Besides cytotoxic DNA damage irradiation of tumor cells triggers multiple intra- and intercellular signaling processes, that are part of a multilayered, treatment-induced stress response at the unicellular and tumor pathophysiological level. These processes are intertwined with intrinsic and acquired resistance mechanisms to the toxic effects of ionizing radiation and thereby co-determine the tumor response to radiotherapy. Proteolysis of structural elements and bioactive signaling moieties represents a major class of posttranslational modifications regulating intra- and intercellular communication. Plasma membrane-located and secreted metalloproteinases comprise a family of metal-, usually zinc-, dependent endopeptidases and sheddases with a broad variety of substrates including components of the extracellular matrix, cyto- and chemokines, growth and pro-angiogenic factors. Thereby, metalloproteinases play an important role in matrix remodeling and auto- and paracrine intercellular communication regulating tumor growth, angiogenesis, immune cell infiltration, tumor cell dissemination, and subsequently the response to cancer treatment. While metalloproteinases have long been identified as promising target structures for anti-cancer agents, previous pharmaceutical approaches mostly failed due to unwanted side effects related to the structural similarities among the multiple family members. Nevertheless, targeting of metalloproteinases still represents an interesting rationale alone and in combination with other treatment modalities. Here, we will give an overview on the role of metalloproteinases in the irradiated tumor microenvironment and discuss the therapeutic potential of using more specific metalloproteinase inhibitors in combination with radiotherapy.
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Affiliation(s)
- Verena Waller
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Martin Pruschy
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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Quesnel A, Karagiannis GS, Filippou PS. Extracellular proteolysis in glioblastoma progression and therapeutics. Biochim Biophys Acta Rev Cancer 2020; 1874:188428. [PMID: 32956761 DOI: 10.1016/j.bbcan.2020.188428] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/03/2020] [Accepted: 09/04/2020] [Indexed: 12/20/2022]
Abstract
Gliomas encompass highly invasive primary central nervous system (CNS) tumours of glial cell origin with an often-poor clinical prognosis. Of all gliomas, glioblastoma is the most aggressive form of primary brain cancer. Current treatments in glioblastoma are insufficient due to the invasive nature of brain tumour cells, which typically results in local tumour recurrence following treatment. The latter represents the most important cause of mortality in glioblastoma and underscores the necessity for an in-depth understanding of the underlying mechanisms. Interestingly, increased synthesis and secretion of several proteolytic enzymes within the tumour microenvironment, such as matrix metalloproteinases, lysosomal proteases, cathepsins and kallikreins for extracellular-matrix component degradation may play a major role in the aforementioned glioblastoma invasion mechanisms. These proteolytic networks are key players in establishing and maintaining a tumour microenvironment that promotes tumour cell survival, proliferation, and migration. Indeed, the targeted inhibition of these proteolytic enzymes has been a promisingly useful therapeutic strategy for glioblastoma management in both preclinical and clinical development. We hereby summarize current advances on the biology of the glioblastoma tumour microenvironment, with a particular emphasis on the role of proteolytic enzyme families in glioblastoma invasion and progression, as well as on their subsequent prognostic value as biomarkers and their therapeutic targeting in the era of precision medicine.
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Affiliation(s)
- Agathe Quesnel
- School of Health & Life Sciences, Teesside University, Middlesbrough TS1 3BX, United Kingdom; National Horizons Centre, Teesside University, 38 John Dixon Ln, Darlington, DL1 1HG, United Kingdom
| | - George S Karagiannis
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York, USA; Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, New York, USA; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Panagiota S Filippou
- School of Health & Life Sciences, Teesside University, Middlesbrough TS1 3BX, United Kingdom; National Horizons Centre, Teesside University, 38 John Dixon Ln, Darlington, DL1 1HG, United Kingdom.
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Giamanco KA, Matthews RT. The Role of BEHAB/Brevican in the Tumor Microenvironment: Mediating Glioma Cell Invasion and Motility. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1272:117-132. [PMID: 32845505 DOI: 10.1007/978-3-030-48457-6_7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Malignant gliomas are the most common tumors in the central nervous system (CNS) and, unfortunately, are also the most deadly. The lethal nature of malignant gliomas is due in large part to their unique and distinctive ability to invade the surrounding neural tissue. The invasive and dispersive nature of these tumors makes them particularly challenging to treat, and currently there are no effective therapies for malignant gliomas. The brain tumor microenvironment plays a particularly important role in mediating the invasiveness of gliomas, and, therefore, understanding its function is key to developing novel therapies to treat these deadly tumors. A defining aspect of the tumor microenvironment of gliomas is the unique composition of the extracellular matrix that enables tumors to overcome the typically inhibitory environment found in the CNS. One conspicuous component of the glioma tumor microenvironment is the neural-specific ECM molecule, brain-enriched hyaluronan binding (BEHAB)/brevican (B/b). B/b is highly overexpressed in gliomas, and its expression in these tumors contributes importantly to the tumor invasiveness and aggressiveness. However, B/b is a complicated protein with multiple splice variants, cleavage products, and glycoforms that contribute to its complex functions in these tumors and provide unique targets for tumor therapy. Here we review the role of B/b in glioma tumor microenvironment and explore targeting of this protein for glioma therapy.
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Affiliation(s)
- Kristin A Giamanco
- Department of Biological and Environmental Sciences, Western Connecticut State University, Danbury, CT, USA
| | - Russell T Matthews
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
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Liu C, Ma T, Jiang T, Jia G, Yang C, Peng Y, Qian Y, Wang R, Wang S. Abnormal increase of miR-4262 promotes cell proliferation and migration by targeting large tumor suppressor 1 in gliomas. Pathol Res Pract 2019; 216:152778. [PMID: 31831299 DOI: 10.1016/j.prp.2019.152778] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/20/2019] [Accepted: 12/01/2019] [Indexed: 01/06/2023]
Abstract
BACKGROUND miRNA was recently detected as tumor suppressor or inducer in various cancers including gliomas. Due to the abnormal expression of miR-4262 in glioma cancer, we supposed that miR-4262 made efforts in proliferation and migration in glioma cancer. METHODS CCK-8, Transwell migration Assay and Wound-healing assay were appraisal assays for cell proliferation and migration. qRT-PCR and western blot were performed to test the expression of miR-4262, MMP2, MMP13 and LATS1 in glioma cancers tissues and cancer cells. The targeting detection between miR-4262 and LATS1 was detected by luciferase reporter assay. RESULTS miR-4262 expression was dramatically higher in glioma tumor tissues than in para-tumor control. Inhibition of miR-4262 in glioma cancer cells prominently inhibited cell proliferation and migration. Mechanically, downregulation of miR-4262 inhibited expression of matrix metalloproteinase (MMP) -2, -13. In addition, miR-4262 directly and negatively modulated expression of large tumor suppressor 1 (LATS1). Moreover, we discovered that overexpression of LATS1 could reverse the effects of miR-4262 on cell proliferation and migration, as well as the production of MMP-2, -13. CONCLUSIONS In glioma cancer, miR-4262 regulated cell proliferation and migration mediated by LATS1. This indicated that miR-4262 is a tumor inducer in glioma cancer and may be a feasible target for glioma therapy.
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Affiliation(s)
- Chunbo Liu
- Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou First Peoples' Hospital, Changzhou City, 213003, Jiangsu Province, China
| | - Tao Ma
- Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou First Peoples' Hospital, Changzhou City, 213003, Jiangsu Province, China
| | - Tianwei Jiang
- Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou First Peoples' Hospital, Changzhou City, 213003, Jiangsu Province, China
| | - Geng Jia
- Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou First Peoples' Hospital, Changzhou City, 213003, Jiangsu Province, China
| | - Changchun Yang
- Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou First Peoples' Hospital, Changzhou City, 213003, Jiangsu Province, China
| | - Ya Peng
- Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou First Peoples' Hospital, Changzhou City, 213003, Jiangsu Province, China
| | - Yitao Qian
- Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou First Peoples' Hospital, Changzhou City, 213003, Jiangsu Province, China
| | - Rong Wang
- Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou First Peoples' Hospital, Changzhou City, 213003, Jiangsu Province, China
| | - Suinuan Wang
- Department of Neurosurgery, The Third Affiliated Hospital of Soochow University, Changzhou First Peoples' Hospital, Changzhou City, 213003, Jiangsu Province, China.
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8
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Zeng L, Qian J, Zhu F, Wu F, Zhao H, Zhu H. The prognostic values of matrix metalloproteinases in ovarian cancer. J Int Med Res 2019; 48:300060519825983. [PMID: 31099295 PMCID: PMC7140190 DOI: 10.1177/0300060519825983] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Objective To investigate the prognostic significance of 23 matrix metalloproteinase
(MMP) genes in patients diagnosed with ovarian
carcinoma. Methods The prognostic significance of 23 MMP genes in patients
diagnosed with ovarian carcinoma was investigated using the Kaplan–Meier
plotter (KM plotter), which uses the gene expression data and overall
survival information of patients with ovarian cancer that were downloaded
from the Gene Expression Omnibus, Cancer Biomedical Informatics Grid and The
Cancer Genome Atlas cancer datasets. The correlation between mRNA levels of
individual MMPs (MMP2, MMP9, MMP10, MMP12, MMP13 and MMP25) and
clinicopathological features (histological subtype, pathological grade and
clinical stage) were investigated. The MMP protein level profiles in normal
ovarian tissues and ovarian cancer tissues were examined using the Human
Protein Atlas database. Results The results showed that high mRNA levels of MMP2 and MMP13 were associated
with a worse overall survival in patients with ovarian cancer, whereas high
mRNA levels of MMP9, MMP10, MMP12 and MMP25 were associated with a better
overall survival. The protein levels of MMP2, MMP9, MMP10 and MMP25 in
ovarian cancer tissues were elevated compared with normal ovarian
tissues. Conclusions This study demonstrated that MMPs can be a reliable prognostic biomarker for
ovarian cancer.
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Affiliation(s)
- Linchai Zeng
- Department of Gynaecology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Jie Qian
- Department of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Fangfang Zhu
- Department of Gynaecology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Fang Wu
- Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Hongqin Zhao
- Department of Gynaecology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Haiyan Zhu
- Department of Gynaecology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
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Javadian M, Gharibi T, Shekari N, Abdollahpour‐Alitappeh M, Mohammadi A, Hossieni A, Mohammadi H, Kazemi T. The role of microRNAs regulating the expression of matrix metalloproteinases (MMPs) in breast cancer development, progression, and metastasis. J Cell Physiol 2018; 234:5399-5412. [DOI: 10.1002/jcp.27445] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Mahsa Javadian
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
- Student Research Committee, Tabriz University of Medical Sciences Tabriz Iran
| | - Tohid Gharibi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Najibeh Shekari
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | | | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Arezoo Hossieni
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Hamed Mohammadi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Science Tabriz Iran
- Department of Immunology Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
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10
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Guo JG, Guo CC, He ZQ, Cai XY, Mou YG. High MMP-26 expression in glioma is correlated with poor clinical outcome of patients. Oncol Lett 2018; 16:2237-2242. [PMID: 30008924 PMCID: PMC6036463 DOI: 10.3892/ol.2018.8880] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 05/22/2018] [Indexed: 02/03/2023] Open
Abstract
To date the management of glioma remains a great challenge in cancer therapy worldwide. The identification of novel diagnostic and therapeutic methods is required. Although there is data indicating that matrix metalloproteinase (MMP)-26 serves an important role in many human cancer types, its clinical significance in glioma remains uncertain. The present study aimed to evaluate MMP-26 expression in human astrocytic glioma specimens, and investigate its role and significance in the progression of astrocytic glioma. Immunohistochemistry was performed to assess MMP-26 expression in astrocytic glioma tissues. The levels of MMP-26 expression and its relevance to the clinicopathological features and prognostic factors in patients with astrocytic glioma patients were then investigated. The results demonstrated that MMP-26 expression was significantly assocaited with the World Health Organization grade (P<0.05). Additionally, it was identified that MMP-26 expression was an effective predictor of the overall survival of patients with astrocytic glioma (P<0.05). Analyses of univariate and multivariate Cox regression confirmed that MMP-26 expression was an independent factor for evaluating the prognosis of astrocytic glioma patients (P<0.05). The current results support that MMP-26 may be a novel indicator of diagnosis and an independent factor for evaluating prognosis in patients with glioma.
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Affiliation(s)
- Jian-Gui Guo
- Department of Radiation Oncology, The First People's Hospital of Foshan, Foshan, Guandong 528000, P.R. China
| | - Cheng-Cheng Guo
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, Guandong 510060, P.R. China.,Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University, Guangzhou, Guandong 510060, P.R. China.,Department of Neurosurgery, Cancer Center, Sun Yat-Sen University, Guangzhou, Guandong 510060, P.R. China
| | - Zhen-Qiang He
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, Guandong 510060, P.R. China.,Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University, Guangzhou, Guandong 510060, P.R. China.,Department of Neurosurgery, Cancer Center, Sun Yat-Sen University, Guangzhou, Guandong 510060, P.R. China
| | - Xiu-Yu Cai
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, Guandong 510060, P.R. China.,Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University, Guangzhou, Guandong 510060, P.R. China.,Department of VIP Region, Cancer Center, Sun Yat-Sen University, Guangzhou, Guandong 510060, P.R. China
| | - Yong-Gao Mou
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, Guandong 510060, P.R. China.,Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University, Guangzhou, Guandong 510060, P.R. China.,Department of Neurosurgery, Cancer Center, Sun Yat-Sen University, Guangzhou, Guandong 510060, P.R. China
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11
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Matrix metalloproteinase-13: A special focus on its regulation by signaling cascades and microRNAs in bone. Int J Biol Macromol 2018; 109:338-349. [DOI: 10.1016/j.ijbiomac.2017.12.091] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 12/15/2017] [Accepted: 12/17/2017] [Indexed: 01/03/2023]
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12
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Merchant N, Nagaraju GP, Rajitha B, Lammata S, Jella KK, Buchwald ZS, Lakka SS, Ali AN. Matrix metalloproteinases: their functional role in lung cancer. Carcinogenesis 2017. [DOI: 10.1093/carcin/bgx063] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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13
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Mashimo Y, Sakurai-Yageta M, Watanabe M, Arima T, Morita Y, Inoue Y, Sato K, Nishimuta T, Suzuki S, Watanabe H, Hoshioka A, Tomiita M, Yamaide A, Kohno Y, Okamoto Y, Shimojo N, Hata A, Suzuki Y. Induction of the Matrix Metalloproteinase 13 Gene in Bronchial Epithelial Cells by Interferon and Identification of its Novel Functional Polymorphism. Inflammation 2017; 39:949-62. [PMID: 26635116 DOI: 10.1007/s10753-015-0291-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Matrix metalloproteinases (MMPs) are a class of extra-cellular and membrane-bound proteases involved in a wide array of physiological and pathological processes including tissue remodeling, inflammation, and cytokine secretion and activation. MMP-13 has been shown to be involved in lung diseases such as acute lung injury, viral infections, and chronic obstructive pulmonary disease; however, the molecular pathogenesis of MMP-13 in these conditions is not well understood. In this study, we investigated the mechanisms and roles of MMP-13 secretion in human small airway epithelial cells (SAECs) and functional polymorphisms of the MMP13 gene. Polyinosinic-polycytidylic acid (poly(I:C)) and interferon β (IFN-β) stimulated the secretion of MMP-13 from SAECs by more than several hundred-fold. Stimulation of the secretion by poly(I:C) was abolished by SB304680 (p38 inhibitor), LY294002 (PI3K inhibitor), Janus kinase (JAK) inhibitor I, RNA-activated protein kinase (PKR) inhibitor, and Bay 11-7082 (NF-κB inhibitor), while stimulation by IFN-β was inhibited by all except Bay 11-7082. These data suggested that the secretion of MMP-13 was mediated through IFN receptor pathways independently of nuclear factor kappa B (NF-κB) and that poly(I:C) stimulated IFN secretion in an NF-κB-dependent manner from SAECs, leading to IFN-stimulated MMP-13 secretion. Chemical MMP-13 inhibitors and MMP-13 small interfering RNA (siRNA) inhibited IFN-stimulated secretion of interferon gamma-inducible protein 10 (IP-10) and regulated on activation, normal T-cell expressed and secreted (RANTES), suggesting that MMP-13 is involved in the secretion of these virus-induced proinflammatory chemokines. We identified a novel functional polymorphism in the promoter region of the MMP13 gene. The MMP13 gene may play important roles in defense mechanisms of airway epithelial cells.
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Affiliation(s)
- Yoichi Mashimo
- Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Mika Sakurai-Yageta
- Department of Education and Training, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryomachi, Aobaku, Sendai, 980-8573, Japan
| | - Misa Watanabe
- The Department of Pediatrics, Toho University School of Medicine, Tokyo, Japan
| | - Takayasu Arima
- Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoshinori Morita
- Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yuzaburo Inoue
- Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kazuki Sato
- Department of Pediatrics, National Shimoshizu Hospital, Yotsukaido, Japan
| | | | - Shuichi Suzuki
- Department of Pediatrics, National Shimoshizu Hospital, Yotsukaido, Japan
| | - Hiroko Watanabe
- Department of Pediatrics, National Shimoshizu Hospital, Yotsukaido, Japan
| | - Akira Hoshioka
- Department of Allergy and Rheumatology, Chiba Children's Hospital, Chiba, Japan
| | - Minako Tomiita
- Department of Allergy and Rheumatology, Chiba Children's Hospital, Chiba, Japan
| | - Akiko Yamaide
- Department of Allergy and Rheumatology, Chiba Children's Hospital, Chiba, Japan
| | - Yoichi Kohno
- Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoshitaka Okamoto
- Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoki Shimojo
- Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Akira Hata
- Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoichi Suzuki
- Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan.
- Department of Education and Training, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryomachi, Aobaku, Sendai, 980-8573, Japan.
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14
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Comparative Analysis of Matrix Metalloproteinase Family Members Reveals That MMP9 Predicts Survival and Response to Temozolomide in Patients with Primary Glioblastoma. PLoS One 2016; 11:e0151815. [PMID: 27022952 PMCID: PMC4811585 DOI: 10.1371/journal.pone.0151815] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 03/04/2016] [Indexed: 12/22/2022] Open
Abstract
Background Glioblastoma multiform (GBM) is the most common malignant primary brain tumor in adults. Radiotherapy plus concomitant and adjuvant TMZ chemotherapy is the current standard of care for patients with GBM. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are key modulators of tumor invasion and metastasis due to their ECM degradation capacity. The aim of the present study was to identify the most informative MMP member in terms of prognostic and predictive ability for patients with primary GBM. Method The mRNA expression profiles of all MMP genes were obtained from the Chinese Glioma Genome Atlas (CGGA), the Repository for Molecular Brain Neoplasia Data (REMBRANDT) and the GSE16011 dataset. MGMT methylation status was also examined by pyrosequencing. The correlation of MMP9 expression with tumor progression was explored in glioma specimens of all grades. Kaplan–Meier analysis and Cox proportional hazards regression models were used to investigate the association of MMP9 expression with survival and response to temozolomide. Results MMP9 was the only significant prognostic factor in three datasets for primary glioblastoma patients. Our results indicated that MMP9 expression is correlated with glioma grade (p<0.0001). Additionally, low expression of MMP9 was correlated with better survival outcome (OS: p = 0.0012 and PFS: p = 0.0066), and MMP9 was an independent prognostic factor in primary GBM (OS: p = 0.027 and PFS: p = 0.032). Additionally, the GBM patients with low MMP9 expression benefited from temozolomide (TMZ) chemotherapy regardless of the MGMT methylation status. Conclusions Patients with primary GBMs with low MMP9 expression may have longer survival and may benefit from temozolomide chemotherapy.
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15
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Hirahata M, Osaki M, Kanda Y, Sugimoto Y, Yoshioka Y, Kosaka N, Takeshita F, Fujiwara T, Kawai A, Ito H, Ochiya T, Okada F. PAI-1, a target gene of miR-143, regulates invasion and metastasis by upregulating MMP-13 expression of human osteosarcoma. Cancer Med 2016; 5:892-902. [PMID: 26817521 PMCID: PMC4864819 DOI: 10.1002/cam4.651] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 12/16/2015] [Accepted: 01/03/2016] [Indexed: 11/17/2022] Open
Abstract
Despite recent improvements in the therapy for osteosarcoma, 30–40% of osteosarcoma patients die of this disease, mainly due to its lung metastasis. We have previously reported that intravenous injection of miR‐143 significantly suppresses lung metastasis of human osteosarcoma cells (143B) in a mouse model. In this study, we examined the biological role and mechanism of miR‐143 in the metastasis of human osteosarcoma cells. We identified plasminogen activator inhibitor‐1 (PAI‐1) as a direct target gene of miR‐143. To determine the role of PAI‐1 in human osteosarcoma cells, siRNA was transfected into 143B cells for knockdown of PAI‐1 expression. An in vitro study showed that downregulation of PAI‐1 suppressed cell invasion activity, but not proliferation. Moreover, injection of PAI‐1 siRNA into a primary lesion in the osteosarcoma mouse model inhibited lung metastasis compared to control siRNA‐injected mice, without influencing the proliferative activity of the tumor cells. Subsequent examination using 143B cells revealed that knockdown of PAI‐1 expression resulted in downregulation of the expression and secretion of matrix metalloproteinase‐13 (MMP‐13), which is also a target gene of miR‐143 and a proteolytic enzyme that regulates tumor‐induced osteolysis. Immunohistochemical analysis using clinical samples showed that higher miR‐143 expressing cases showed poor expression of PAI‐1 in the primary tumor cells. All such cases belonged to the lung metastasis‐negative group. Moreover, the frequency of lung metastasis‐positive cases was significantly higher in PAI‐1 and MMP‐13 double‐positive cases than in PAI‐1 or MMP‐13 single‐positive or double‐negative cases (P < 0.05). These results indicated that PAI‐1, a target gene of miR‐143, regulates invasion and lung metastasis via enhancement of MMP‐13 expression and secretion in human osteosarcoma cells, suggesting that these molecules could be potential therapeutic target genes for preventing lung metastasis in osteosarcoma patients.
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Affiliation(s)
- Mio Hirahata
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Mitsuhiko Osaki
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan.,Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Yusuke Kanda
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Yui Sugimoto
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Yusuke Yoshioka
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Nobuyoshi Kosaka
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Fumitaka Takeshita
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tomohiro Fujiwara
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.,Orthopedics Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akira Kawai
- Orthopedics Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hisao Ito
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Futoshi Okada
- Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan.,Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
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16
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Xue J, Chen Z, Gu X, Zhang Y, Zhang W. MicroRNA-148a inhibits migration of breast cancer cells by targeting MMP-13. Tumour Biol 2015; 37:1581-90. [PMID: 26298724 DOI: 10.1007/s13277-015-3926-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 08/12/2015] [Indexed: 01/01/2023] Open
Abstract
Breast cancer is a threat to the health of women, and metastasis of breast cancer cells plays an important role in the deterioration of breast cancer. MicroRNAs play a critical role in the tumorigenesis and development of breast cancer. MicroRNA-148a (miR-148a) is associated with the growth and metastasis of tumor cells. In the present study, we investigated the role of miR-148a in migration of breast cancer cells as well as the underlying mechanism. MiR-148a was found to inhibit the proliferation and migration of breast cancer cells. To further explore the mechanism through which miR-148a plays its antitumor role, matrix metalloproteinase-13 (MMP-13) was identified as a target of miR-148a by western blot and luciferase reporter assay. Moreover, silence of MMP-13 mimicked the effect of miR-148a, whereas overexpression of MMP-13 rescued the impaired migration caused by miR-148a. Our study demonstrates that miR-148a inhibits the migration of breast cancer cells by targeting MMP-13 and also lays theoretical foundation for further exploration for the function of miR-148a.
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Affiliation(s)
- Jinqi Xue
- The Seventh Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, People's Republic of China
| | - Zhiguang Chen
- Department of Spine and Joint Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China
| | - Xi Gu
- The Seventh Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, People's Republic of China
| | - Yang Zhang
- The Seventh Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, People's Republic of China
| | - Wenhai Zhang
- The Seventh Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, People's Republic of China.
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17
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Yu X, Wei F, Yu J, Zhao H, Jia L, Ye Y, Du R, Ren X, Li H. Matrix metalloproteinase 13: a potential intermediate between low expression of microRNA-125b and increasing metastatic potential of non–small cell lung cancer. Cancer Genet 2015; 208:76-84. [DOI: 10.1016/j.cancergen.2015.01.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 01/19/2015] [Accepted: 01/20/2015] [Indexed: 11/24/2022]
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18
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Hsieh WT, Yeh WL, Cheng RY, Lin C, Tsai CF, Huang BR, Wu CYJ, Lin HY, Huang SS, Lu DY. Exogenous endothelin-1 induces cell migration and matrix metalloproteinase expression in U251 human glioblastoma multiforme. J Neurooncol 2014; 118:257-269. [PMID: 24756349 DOI: 10.1007/s11060-014-1442-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 04/09/2014] [Indexed: 10/25/2022]
Abstract
Glioblastoma multiforme (GBM) is the most common and lethal type of primary brain tumor characterized by its rapid infiltration to surrounding tissues during the early stages. The fast spreading of GBM obscures the initiation of the tumor mass making the treatment outcome undesirable. Endothelin-1 is known as a secretory protein presented in various types of brain cells, which has been indicated as a factor for cancer pathology. The aim of the present study was to investigate the molecular mechanism of cell migration in GBM. We found that various malignant glioma cells expressed higher amounts of endothelin-1, ETA, and ETB receptors than nonmalignant human astrocytes. The application of endothelin-1 enhanced the migratory activity in human U251 glioma cells corresponding to increased expression of matrix metalloproteinase (MMP)-9 and MMP-13. The endothelin-1-induced cell migration was attenuated by MMP-9 and MMP-13 inhibitors and inhibitors of mitogen-activated protein (MAP) kinase and PI3 kinase/Akt. Furthermore, the elevated levels of phosphate c-Jun accumulation in the nucleus and activator protein-1 (AP-1)-DNA binding activity were also found in endothelin-1 treated glioma cells. In migration-prone sublines, cells with greater migration ability showed higher endothelin-1, ETB receptor, and MMP expressions. These results indicate that endothelin-1 activates MAP kinase and AP-1 signaling, resulting in enhanced MMP-9 and MMP-13 expressions and cell migration in GBM.
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Affiliation(s)
- Wen-Tsong Hsieh
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Wei-Lan Yeh
- Department of Cell and Tissue Engineering and Department of Medical Research, Changhua Christian Hospital, Changhua, Taiwan
| | - Ruo-Yuo Cheng
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Chingju Lin
- Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Cheng-Fang Tsai
- Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Bor-Ren Huang
- Department of Neurosurgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan
| | - Caren Yu-Ju Wu
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | - Hsiao-Yun Lin
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Shiang-Suo Huang
- Department of Pharmacology and Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Dah-Yuu Lu
- Graduate Institute of Neural and Cognitive Sciences, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan.
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19
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Osthole suppresses the migratory ability of human glioblastoma multiforme cells via inhibition of focal adhesion kinase-mediated matrix metalloproteinase-13 expression. Int J Mol Sci 2014; 15:3889-903. [PMID: 24599080 PMCID: PMC3975374 DOI: 10.3390/ijms15033889] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 02/24/2014] [Accepted: 02/25/2014] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most common type of primary and malignant tumor occurring in the adult central nervous system. GBM often invades surrounding regions of the brain during its early stages, making successful treatment difficult. Osthole, an active constituent isolated from the dried C. monnieri fruit, has been shown to suppress tumor migration and invasion. However, the effects of osthole in human GBM are largely unknown. Focal adhesion kinase (FAK) is important for the metastasis of cancer cells. Results from this study show that osthole can not only induce cell death but also inhibit phosphorylation of FAK in human GBM cells. Results from this study show that incubating GBM cells with osthole reduces matrix metalloproteinase (MMP)-13 expression and cell motility, as assessed by cell transwell and wound healing assays. This study also provides evidence supporting the potential of osthole in reducing FAK activation, MMP-13 expression, and cell motility in human GBM cells.
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20
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Abstract
Malignant gliomas are characterized by a diffuse infiltration into the surrounding brain parenchyma. Infiltrating glioma cells exist in close proximity with components of the tumor microenvironment, including the extracellular matrix (ECM). Whereas levels of collagens in the normal adult brain are low, in glioma, collagen levels are elevated and play a vital role in driving tumor progression. This article provides a comprehensive overview of the nature of collagens found in gliomas and offers unique insight into the mechanisms by which cancer cells interact with this ECM via cellular factors such as integrins, discoidin domain receptors, and mannose receptors. Also discussed are the major remodeling pathways of brain tumor collagen, mediated primarily by matrix metalloproteinases, and the reciprocal relationship between these enzymes and the collagen receptors. Finally, a concluding perspective is offered on how the biophysical properties of the collagen ECM, in particular, mechanical stiffness and compliance, influence malignant outcome. A better understanding of the complex molecular interactions between glioma cells and the collagen ECM will provide new avenues to combat the rampant tumor progression and chemoresistance in brain cancer patients.
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Affiliation(s)
- Leo S Payne
- Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom.
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