Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas
Abstract
Gliomas are associated with high mortality because of their exceedingly invasive character. As these tumors acquire their invasiveness from low-grade tumors, it is very important to understand the detailed molecular mechanisms of invasion onset. Recent evidences suggest the significant role of microRNAs in tumor invasion. Thus, we hypothesized that deregulation of microRNAs may be important for the malignant progression of gliomas. We found that the aberrant expression of miR-21 is responsible for glioma invasion by disrupting the negative feedback circuit of Ras/MAPK signaling, which is mediated by Spry2. Upregulation of miR-21 was triggered by tumor microenvironmental factors such as hyaluronan and growth factors in glioma cells lacking functional phosphatase and tensin homolog (PTEN), but not harboring wild-type PTEN. Consistently with these in vitro results, Spry2 protein levels were significantly decreased in 79.7% of invasive WHO grade II-IV human glioma tissues, but not in non-invasive grade I and normal tissues. The Spry2 protein levels were not correlated with their mRNA levels, but inversely correlated with miR-21 levels. Taken together, these results suggest that the post-transcriptional regulation of Spry2 by miR-21 has an essential role on the malignant progression of human gliomas. Thus, Spry2 may be a novel therapeutic target for treating gliomas.
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miR-21 targets Spry2, a negative feedback regulator of Ras, and consequently amplifies Ras/MAPK signaling particularly in conjunction with dysfunctional PTEN.
“Studies have found that miR-21 targets Spry2, a negative feedback regulator of Ras, and consequently amplifies Ras/MAPK signaling particularly in conjunction with dysfunctional PTEN.”
From miR-21 as a diagnostic and prognostic biomarker in glioma: tissue and serum expression analysis in a Pakistani cohort (2026) · cites this paper as [40]
miR-21 overexpression may promote glioma growth via overactivation of Ras/MAPK.
“Therefore, miR-21 overexpression may promote glioma growth via overactivation of Ras/MAPK [40].”
From miR-21 as a diagnostic and prognostic biomarker in glioma: tissue and serum expression analysis in a Pakistani cohort (2026) · cites this paper as [40]
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MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators
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“Recently, it was reported that glioma invasion is induced by increased miR-21 expression, but the mechanism by which this occurs remains unclear (Gabriely et al., 2008).”
BackgroundMicroRNA-21 targets Sprouty2 and promotes cellular outgrowths
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Sprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis
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Dendrimer-Based Drug Delivery Systems for Brain Targeting
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“Similarly, miR-21 promotes Ras/MAPK activation by targeting Spry2, a negative regulator of Ras, particularly when PTEN is dysfunctional, leading to proliferation, invasion, and metastasis [40].”
- Authors
- Kwak, H.-J., Kim, Y.-J., Chun, K.-R., Woo, Y. M., Park, S.-J., Jeong, J.-A., Jo, S. H., Kim, T. H., Min, H. S., Chae, J. S., Choi, E.-J., Kim, G., Shin, S.-H., Gwak, H.-S., Kim, S.-K., Hong, E.-K., Lee, G.-K., Choi, K.-H., Kim, J. H., Yoo, H., Park, J. B., & Lee, S.-H.
- Affiliations
- National Cancer Center (KR)
- Korea Advanced Institute of Science and Technology (KR)
- Korea University (KR)
- Corresponding author
- Park, J B
- Lee, S-H
- Venue
- Oncogene
- Published
- 2011-01-31
- Volume
- 30
- Issue
- 21
- Pages
- 2433-2442
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2058328925
- Cited by
- 151
- References
- 6
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 10 · 2020: 10 · 2019: 6 · 2018: 8 · 2017: 8 · 2016: 12 · 2015: 10 · 2014: 14 · 2013: 15 · 2012: 17
- FWCI
- 6.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- SPRY2, miR-21, glioma, tumor invasion, RAS/MAPK pathway, PTEN, hyaluronic acid, microRNA regulation, post-transcriptional regulation, malignant progression, therapeutic target
- MeSH terms
- Cell Movement, Glioma, Humans, Hyaluronic Acid, Immunohistochemistry, Membrane Proteins, Neoplasm Invasiveness, Blotting, Western, Signal Transduction, Down-Regulation, Gene Expression Regulation, Neoplastic, ras Proteins, Reverse Transcriptase Polymerase Chain Reaction, Mitogen-Activated Protein Kinases, RNA Interference, MicroRNAs, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, HEK293 Cells
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