The microRNA-302b-inhibited insulin-like growth factor-binding protein 2 signaling pathway induces glioma cell apoptosis by targeting nuclear factor IA.
MicroRNAs are small noncoding RNAs that post-transcriptionally control the expression of genes involved in glioblastoma multiforme (GBM) development. Although miR-302b functions as a tumor suppressor, its role in GBM is still unclear. Therefore, this study comprehensively explored the roles of miR-302b-mediated gene networks in GBM cell death. We found that miR-302b levels were significantly higher in primary astrocytes than in GBM cell lines. miR-302b overexpression dose dependently reduced U87-MG cell viability and induced apoptosis through caspase-3 activation and poly(ADP ribose) polymerase degradation. A transcriptome microarray revealed 150 downregulated genes and 380 upregulated genes in miR-302b-overexpressing cells. Nuclear factor IA (NFIA), higher levels of which were significantly related to poor survival, was identified as a direct target gene of miR-302b and was involved in miR-302b-induced glioma cell death. Higher NFIA levels were observed in GBM cell lines and human tumor sections compared with astrocytes and non-tumor tissues, respectively. NFIA knockdown significantly enhanced apoptosis. We found high levels of insulin-like growth factor-binding protein 2 (IGFBP2), another miR-302b-downregulated gene, in patients with poor survival. We verified that NFIA binds to the IGFBP2 promoter and transcriptionally enhances IGFBP2 expression levels. We identified that NFIA-mediated IGFBP2 signaling pathways are involved in miR-302b-induced glioma cell death. The identification of a regulatory loop whereby miR-302b inhibits NFIA, leading to a decrease in expression of IGFBP-2, may provide novel directions for developing therapies to target glioblastoma tumorigenesis.
Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
Chin-Cheng
CC
Lee
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Peng-Hsu
PH
Chen
Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Kuo-Hao
KH
Ho
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Chwen-Ming
CM
Shih
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Chia-Hsiung
CH
Cheng
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Cheng-Wei
CW
Lin
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Kur-Ta
KT
Cheng
Department of Neurosurgery, Taipei City Hospital Ren-Ai Branch, Taipei, Taiwan.
Ann-Jeng
AJ
Liu
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Ku-Chung
http://orcid.org/0000-0002-4696-3924
KC
Chen
D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D051839:NFI Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D059467:Transcriptome
C577903:IGFBP2 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; C532169:MIRN302A microRNA, human; D035683:MicroRNAs; D051839:NFI Transcription Factors