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Title: MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy

Abstract

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 only of 14.6 months, despite the aggressive standard post-surgery treatment approaches of radiotherapy concomitant with chemotherapy with temozolomide. Altered cell metabolism has been identified as an emerging cancer hallmark, including in GB, thus offering a new target for cancer therapies. On the other hand, abnormal expression levels of miRNAs, key regulators of multiple molecular pathways, have been correlated with pathological manifestations of cancer, such as chemoresistance, proliferation, and resistance to apoptosis. In this work, we hypothesized that gene therapy based on modulation of a miRNA with aberrant expression in GB and predicted to target crucial metabolic enzymes might impair tumor cell metabolism. We found that the increase of miR-144 levels, shown to be downregulated in U87 and DBTRG human GB cell lines, as well as in GB tumor samples, promoted the downregulation of mRNA of enzymes involved in bioenergetic pathways, with consequent alterations in cell metabolism, impairment of migratory capacity, and sensitization of DBTRG cells to a chemotherapeutic drug, the dichloroacetate (DCA). Taken together, our findings provide evidence thatmore » the miR-144 plus DCA combined therapy holds promise to overcome GB-acquired chemoresistance, therefore deserving to be explored toward its potential application as a complementary therapeutic approach to the current treatment options for this type of brain tumor.« less

Authors:
ORCiD logo [1];  [2];  [2];  [3];  [3];  [4];  [5];  [6];  [7];  [2]
  1. Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal, Institute for Interdisciplinary Research of the University of Coimbra, 3030-789 Coimbra, Portugal
  2. Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal, Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3000-456 Coimbra, Portugal
  3. Institute for Developmental Biology and Neurobiology, Johannes Gutenberg University of Mainz, 55128 Mainz, Germany
  4. Neuropathology Laboratory, Neurology Service, University Hospital of Coimbra, 3004-561 Coimbra, Portugal
  5. Neurosurgery Service, University Hospital of Coimbra, 3004-561 Coimbra, Portugal
  6. Neurosurgery Service, University Hospital of Coimbra, 3004-561 Coimbra, Portugal, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
  7. Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
Publication Date:
Sponsoring Org.:
USDOE Office of Energy Efficiency and Renewable Energy (EERE), Transportation Office. Fuel Cell Technologies Office
OSTI Identifier:
1563047
Grant/Contract Number:  
POCI-01-0145-FEDER-016390; POCI-01-0145-FEDER-007440
Resource Type:
Published Article
Journal Name:
Human Molecular Genetics
Additional Journal Information:
Journal Name: Human Molecular Genetics Journal Volume: 28 Journal Issue: 16; Journal ID: ISSN 0964-6906
Publisher:
Oxford University Press
Country of Publication:
United Kingdom
Language:
English

Citation Formats

Cardoso, Ana M. S., Sousa, Madalena, Morais, Catarina M., Oancea-Castillo, Liliana R., Régnier-Vigouroux, Anne, Rebelo, Olinda, Tão, Hermínio, Barbosa, Marcos, Pedroso, Maria C. de Lima, and Jurado, Amália S. MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy. United Kingdom: N. p., 2019. Web. doi:10.1093/hmg/ddz099.
Cardoso, Ana M. S., Sousa, Madalena, Morais, Catarina M., Oancea-Castillo, Liliana R., Régnier-Vigouroux, Anne, Rebelo, Olinda, Tão, Hermínio, Barbosa, Marcos, Pedroso, Maria C. de Lima, & Jurado, Amália S. MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy. United Kingdom. doi:10.1093/hmg/ddz099.
Cardoso, Ana M. S., Sousa, Madalena, Morais, Catarina M., Oancea-Castillo, Liliana R., Régnier-Vigouroux, Anne, Rebelo, Olinda, Tão, Hermínio, Barbosa, Marcos, Pedroso, Maria C. de Lima, and Jurado, Amália S. Tue . "MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy". United Kingdom. doi:10.1093/hmg/ddz099.
@article{osti_1563047,
title = {MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy},
author = {Cardoso, Ana M. S. and Sousa, Madalena and Morais, Catarina M. and Oancea-Castillo, Liliana R. and Régnier-Vigouroux, Anne and Rebelo, Olinda and Tão, Hermínio and Barbosa, Marcos and Pedroso, Maria C. de Lima and Jurado, Amália S.},
abstractNote = {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 only of 14.6 months, despite the aggressive standard post-surgery treatment approaches of radiotherapy concomitant with chemotherapy with temozolomide. Altered cell metabolism has been identified as an emerging cancer hallmark, including in GB, thus offering a new target for cancer therapies. On the other hand, abnormal expression levels of miRNAs, key regulators of multiple molecular pathways, have been correlated with pathological manifestations of cancer, such as chemoresistance, proliferation, and resistance to apoptosis. In this work, we hypothesized that gene therapy based on modulation of a miRNA with aberrant expression in GB and predicted to target crucial metabolic enzymes might impair tumor cell metabolism. We found that the increase of miR-144 levels, shown to be downregulated in U87 and DBTRG human GB cell lines, as well as in GB tumor samples, promoted the downregulation of mRNA of enzymes involved in bioenergetic pathways, with consequent alterations in cell metabolism, impairment of migratory capacity, and sensitization of DBTRG cells to a chemotherapeutic drug, the dichloroacetate (DCA). Taken together, our findings provide evidence that the miR-144 plus DCA combined therapy holds promise to overcome GB-acquired chemoresistance, therefore deserving to be explored toward its potential application as a complementary therapeutic approach to the current treatment options for this type of brain tumor.},
doi = {10.1093/hmg/ddz099},
journal = {Human Molecular Genetics},
number = 16,
volume = 28,
place = {United Kingdom},
year = {2019},
month = {5}
}

Journal Article:
Free Publicly Available Full Text
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DOI: 10.1093/hmg/ddz099

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