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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Cabrita MA, Christofori G . (2008). Sprouty proteins, masterminds of receptor tyrosine kinase signaling. Angiogenesis 11: 53–62.
Chan JA, Krichevsky AM, Kosik KS . (2005). MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65: 6029–6033.
Conti A, Aguennouz M, La Torre D, Tomasello C, Cardali S, Angileri FF et al. (2009). miR-21 and 221 upregulation and miR-181b downregulation in human grade II-IV astrocytic tumors. J Neurooncol 93: 325–332.
Croce CM . (2009). Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10: 704–714.
Friedman RC, Farh KK, Burge CB, Bartel DP . (2009). Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19: 92–105.
Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A et al. (2007). Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21: 2683–2710.
Gabriely G, Wurdinger T, Kesari S, Esau CC, Burchard J, Linsley PS et al. (2008). MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol 28: 5369–5380.
Hirschhorn JN . (2009). Genomewide association studies--illuminating biologic pathways. N Engl J Med 360: 1699–1701.
Kim MS, Kwak HJ, Lee JW, Kim HJ, Park MJ, Park JB et al. (2008). 17-Allylamino-17-demethoxygeldanamycin down-regulates hyaluronic acid-induced glioma invasion by blocking matrix metalloproteinase-9 secretion. Mol Cancer Res 6: 1657–1665.
Kim MS, Park MJ, Kim SJ, Lee CH, Yoo H, Shin SH et al. (2005). Emodin suppresses hyaluronic acid-induced MMP-9 secretion and invasion of glioma cells. Int J Oncol 27: 839–846.
Kim VN, Nam JW . (2006). Genomics of microRNA. Trends Genet 22: 165–173.
Krichevsky AM, Gabriely G . (2009). miR-21: a small multi-faceted RNA. J Cell Mol Med 13: 39–53.
Lo TL, Fong CW, Yusoff P, McKie AB, Chua MS, Leung HY et al. (2006). Sprouty and cancer: the first terms report. Cancer Lett 242: 141–150.
Merzak A, Koocheckpour S, Pilkington GJ . (1994). CD44 mediates human glioma cell adhesion and invasion in vitro. Cancer Res 54: 3988–3992.
National Cancer Institute (2005). REMBRANDT home page. http://rembrandt.nci.nih.gov. Accessed 29 September 2009.
Negrini M, Nicoloso MS, Calin GA . (2009). MicroRNAs and cancer--new paradigms in molecular oncology. Curr Opin Cell Biol 21: 470–479.
Nicoloso MS, Spizzo R, Shimizu M, Rossi S, Calin GA . (2009). MicroRNAs--the micro steering wheel of tumour metastases. Nat Rev Cancer 9: 293–302.
Park JB, Kwak HJ, Lee SH . (2008). Role of hyaluronan in glioma invasion. Cell Adh Migr 2: 202–207.
Park MJ, Kim MS, Park IC, Kang HS, Yoo H, Park SH et al. (2002). PTEN suppresses hyaluronic acid-induced matrix metalloproteinase-9 expression in U87MG glioblastoma cells through focal adhesion kinase dephosphorylation. Cancer Res 62: 6318–6322.
Roversi G, Pfundt R, Moroni RF, Magnani I, Van Reijmersdal S, Pollo B et al. (2006). Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines. Oncogene 25: 1571–1583.
Sayed D, Rane S, Lypowy J, He M, Chen IY, Vashistha H et al. (2008). MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths. Mol Biol Cell 19: 3272–3282.
Shaw AT, Meissner A, Dowdle JA, Crowley D, Magendantz M, Ouyang C et al. (2007). Sprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis. Genes Dev 21: 694–707.
TCGARN (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455: 1061–1068.
Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M et al. (2008). MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456: 980–984.
Toole BP . (2004). Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 4: 528–539.
Acknowledgements
This work was supported by the National Cancer Center Grants (1010171, 1010172, and 1110120) and the National Research Foundation Grant (2010-0016811). JHK was supported by the National Cancer Center Grant (1110110) and the National Research Foundation Grant (2010-0016704).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
Kwak, HJ., Kim, YJ., Chun, KR. et al. Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas. Oncogene 30, 2433–2442 (2011). https://doi.org/10.1038/onc.2010.620
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2010.620
Keywords
This article is cited by
-
Recent insights into the microRNA-dependent modulation of gliomas from pathogenesis to diagnosis and treatment
Cellular & Molecular Biology Letters (2022)
-
Development of a miRNA-controlled dual-sensing system and its application for targeting miR-21 signaling in tumorigenesis
Experimental & Molecular Medicine (2020)
-
Regulation of breast cancer metastasis signaling by miRNAs
Cancer and Metastasis Reviews (2020)
-
RETRACTED ARTICLE: Knockdown of FOXO3a induces epithelial-mesenchymal transition and promotes metastasis of pancreatic ductal adenocarcinoma by activation of the β-catenin/TCF4 pathway through SPRY2
Journal of Experimental & Clinical Cancer Research (2019)
-
Oligonucleotide Therapeutics as a New Class of Drugs for Malignant Brain Tumors: Targeting mRNAs, Regulatory RNAs, Mutations, Combinations, and Beyond
Neurotherapeutics (2019)