title: 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.
authors.affiliation: Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Kwak
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Kim
authors.forename: K-R
authors.initials: KR
authors.lastname: Chun
authors.forename: Y M
authors.initials: YM
authors.lastname: Woo
authors.forename: S-J
authors.initials: SJ
authors.lastname: Park
authors.forename: J-A
authors.initials: JA
authors.lastname: Jeong
authors.forename: S H
authors.initials: SH
authors.lastname: Jo
authors.forename: T H
authors.initials: TH
authors.lastname: Kim
authors.forename: H S
authors.initials: HS
authors.lastname: Min
authors.forename: J S
authors.initials: JS
authors.lastname: Chae
authors.forename: E-J
authors.initials: EJ
authors.lastname: Choi
authors.forename: G
authors.initials: G
authors.lastname: Kim
authors.forename: S-H
authors.initials: SH
authors.lastname: Shin
authors.forename: H-S
authors.initials: HS
authors.lastname: Gwak
authors.forename: S-K
authors.initials: SK
authors.lastname: Kim
authors.forename: E-K
authors.initials: EK
authors.lastname: Hong
authors.forename: G-K
authors.initials: GK
authors.lastname: Lee
authors.forename: K-H
authors.initials: KH
authors.lastname: Choi
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.forename: H
authors.initials: H
authors.lastname: Yoo
authors.forename: J B
authors.initials: JB
authors.lastname: Park
authors.forename: S-H
authors.initials: SH
authors.lastname: Lee
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C524940:MIRN21 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C485561:SPRY2 protein, human; D006820:Hyaluronic Acid; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018631:ras Proteins