NF-?B induces miR-148a to sustain TGF-?/Smad signaling activation in glioblastoma.

ABSTRACT:

Background

Inflammatory cytokines and transforming growth factor-? (TGF-?) are mutually inhibitory. However, hyperactivation of nuclear factor-?B (NF-?B) and TGF-? 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-? signaling.

Methods

We determined NF-?B and TGF-?/Smad signaling activity using pNF-?B-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-?B induced miR-148a expression, leading to enhanced-strength and prolonged-duration TGF-?/Smad signaling. Notably, these findings were consistent with the significant correlation between miR-148a levels with NF-?B hyperactivation and activated TGF-?/Smad signaling in a cohort of human glioblastoma specimens.

Conclusions

These findings uncover a plausible mechanism for NF-?B-sustained TGF-?/Smad activation via miR-148a in glioblastoma, and may suggest a new target for clinical intervention in human cancer.

SUBMITTER: Wang H 

PROVIDER: S-EPMC4429406 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature