|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Wang, H, Pan, J-Q, Luo, L, Ning, X-J, Ye, Z-P, Yu, Z, Li, W-S|
|Date Published||2015 Feb 11|
|Keywords||Animals, Base Sequence, Brain Neoplasms, Carcinogenesis, Cell Line, Tumor, Disease Progression, Glioblastoma, Humans, Mice, Nude, MicroRNAs, Molecular Sequence Data, Neoplasm Invasiveness, Neovascularization, Pathologic, NF-kappa B, Phenotype, Prognosis, RNA-Binding Proteins, S-Phase Kinase-Associated Proteins, Signal Transduction, Smad Proteins, Transforming Growth Factor beta, Up-Regulation|
BACKGROUND: Inflammatory cytokines and transforming growth factor-β (TGF-β) are mutually inhibitory. However, hyperactivation of nuclear factor-κB (NF-κB) and TGF-β signaling both emerge in glioblastoma. Here, we report microRNA-148a (miR-148a) overexpression in glioblastoma and that miR-148a directly suppressed Quaking (QKI), a negative regulator of TGF-β signaling.
METHODS: We determined NF-κB and TGF-β/Smad signaling activity using pNF-κB-luc, pSMAD-luc, and control plasmids. The association between an RNA-induced silencing complex and QKI, mitogen-inducible gene 6 (MIG6), S-phase kinase-associated protein 1 (SKP1), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was tested with microribonucleoprotein immunoprecipitation and real-time PCR. Xenograft tumors were established in the brains of nude mice.
RESULTS: QKI suppression induced an aggressive phenotype of glioblastoma cells both in vitro and in vivo. Interestingly, we found that NF-κB induced miR-148a expression, leading to enhanced-strength and prolonged-duration TGF-β/Smad signaling. Notably, these findings were consistent with the significant correlation between miR-148a levels with NF-κB hyperactivation and activated TGF-β/Smad signaling in a cohort of human glioblastoma specimens.
CONCLUSIONS: These findings uncover a plausible mechanism for NF-κB-sustained TGF-β/Smad activation via miR-148a in glioblastoma, and may suggest a new target for clinical intervention in human cancer.
|Alternate Journal||Mol. Cancer|
|PubMed Central ID||PMC4429406|