MicroRNA-21 Knockdown Disrupts Glioma Growth In vivo and Displays Synergistic Cytotoxicity with Neural Precursor Cell–Delivered S-TRAIL in Human Gliomas
Published version of a preprint
Abstract
Despite the development of new glioma therapies that allow for tumor-targeted in situ delivery of cytotoxic drugs, tumor resistance to apoptosis remains a key impediment to effective treatment. Mounting evidence indicates that microRNAs (miRNA) might play a fundamental role in tumorigenesis, controlling cell proliferation and apoptosis. In gliomas, microRNA-21 (miR-21) levels have been reported to be elevated and their knockdown is associated with increased apoptotic activity. We hypothesized that suppression of miR-21 might sensitize gliomas for cytotoxic tumor therapy. With the use of locked nucleic acid (LNA)-antimiR-21 oligonucleotides, bimodal imaging vectors, and neural precursor cells (NPC) expressing a secretable variant of the cytotoxic agent tumor necrosis factor–related apoptosis inducing ligand (S-TRAIL), we show that the combined suppression of miR-21 and NPC-S-TRAIL leads to a synergistic increase in caspase activity and significantly decreased cell viability in human glioma cells in vitro. This phenomenon persists in vivo, as we observed complete eradication of LNA-antimiR-21–treated gliomas subjected to the presence of NPC-S-TRAIL in the murine brain. Our results reveal the efficacy of miR-21 antagonism in murine glioma models and implicate miR-21 as a target for therapeutic intervention. Furthermore, our findings provide the basis for developing combination therapies using miRNA modulation and cytotoxic tumor therapies. [Cancer Res 2007;67(19):8994–9000]
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The 2'-O-MOE miR-21 ASO induced many proapoptotic and cell cycle arrest genes but did not significantly and consistently change the viability of glioma cell lines.
“We note that, though 2′-O-MOE miR-21 ASO induced many proapoptotic and cell cycle arrest genes (Fig. 2C; also see Table S1 in the supplemental material), it did not significantly and consistently change the viability of glioma cell lines, which was reported for other, less potent miR-21 inhibitors (5, 8).”
From MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators (2008) · cites this paper as [8]
An LNA-DNA anti-miR-21 oligonucleotide was previously shown to reduce tumors in an intracranial U87 glioma model.
“In contrast, an LNA-DNA anti-miR-21 oligonucleotide was previously shown to reduce tumors in an intracranial U87 glioma model (8).”
From MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators (2008) · cites this paper as [8]
miR-21 knockdown in glioblastoma cells significantly repressed tumor formation in vivo.
“Recently, a study determined that miR-21 knockdown in glioblastoma cells significantly repressed tumor formation in vivo (12).”
From MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells (2008) · cites this paper as [12]
Cites
Silencing of microRNAs in vivo with ‘antagomirs’
Krützfeldt, J., Rajewsky, N., Braich, R., Rajeev, K. G., Tuschl, T., Manoharan, M., & Stoffel, M. (2005) · Nature · doi:10.1038/nature04303 · Cited by 3,949 · see citing works
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MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators
Gabriely, G., Wurdinger, T., Kesari, S., Esau, C. C., Burchard, J., Linsley, P. S., & Krichevsky, A. M. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00479-08 · Cited by 888 · see citing works
Self-citationMicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells
Papagiannakopoulos, T., Shapiro, A., & Kosik, K. S. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1305 · Cited by 705 · see citing works
MicroRNA-21 down-regulates the expression of tumor suppressor PDCD4 in human glioblastoma cell T98G
Chen, Y., Liu, W., Chao, T., Zhang, Y., Yan, X., Gong, Y., Qiang, B., Yuan, J., Sun, M., & Peng, X. (2008) · Cancer Letters · doi:10.1016/j.canlet.2008.06.034 · Cited by 217 · see citing works
Abels, E. R., Maas, S. L. N., Nieland, L., Wei, Z., Cheah, P. S., Tai, E., Kolsteeg, C.-J., Dusoswa, S. A., Ting, D. T., Hickman, S., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.036 · Cited by 199 · see citing works
Self-citationDownregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo
Gaur, A. B., Holbeck, S. L., Colburn, N. H., & Israel, M. A. (2011) · Neuro-Oncology · doi:10.1093/neuonc/nor033 · Cited by 180 · see citing works
Costa, P. M., Cardoso, A. L., Nóbrega, C., Pereira de Almeida, L. F., Bruce, J. N., Canoll, P., & Pedroso de Lima, M. C. (2013) · Human Molecular Genetics · doi:10.1093/hmg/dds496 · Cited by 80 · see citing works
Targeting miR-21 in glioma: a small RNA with big potential
Moore, L. M., & Zhang, W. (2010) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2010.527334 · Cited by 51 · see citing works
Inhibition of miR-21 in glioma cells using catalytic nucleic acids
Belter, A., Rolle, K., Piwecka, M., Fedoruk-Wyszomirska, A., Naskręt-Barciszewska, M. Z., & Barciszewski, J. (2016) · Scientific Reports · doi:10.1038/srep24516 · Cited by 36 · see citing works
- Authors
- Corsten, M. F., Miranda, R., Kasmieh, R., Krichevsky, A. M., Weissleder, R., & Shah, K.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Brigham and Women's Hospital (US)
- Venue
- Cancer Research
- Published
- 2007-10-01
- Volume
- 67
- Issue
- 19
- Pages
- 8994-9000
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2127207254
- Cited by
- 406
- References
- 1
- Citations by year
- 2025: 5 · 2024: 6 · 2023: 3 · 2022: 11 · 2021: 12 · 2020: 12 · 2019: 10 · 2018: 8 · 2017: 16 · 2016: 20 · 2015: 22 · 2014: 27 · 2013: 40 · 2012: 40
- FWCI
- 15.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01CA069246, P50CA086355, R21CA116141)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- miR-21, glioma, neural progenitor cells, tumor necrosis factor-related apoptosis-inducing ligand, LNA antisense oligonucleotides, apoptosis sensitization, caspase activity, combination therapy, anticancer drug delivery, local drug delivery, tumor growth inhibition
- MeSH terms
- Animals, Brain Neoplasms, Genetic Vectors, Glioblastoma, Humans, Mice, Nude, Neurons, Stem Cells, Transfection, Lentivirus, Oligonucleotides, Antisense, Caspases, MicroRNAs, Cell Line, Tumor, Cell Growth Processes, Mice, TNF-Related Apoptosis-Inducing Ligand
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