Suppression of microRNA-9 by mutant EGFR signaling upregulates FOXP1 to enhance glioblastoma tumorigenicity.

ABSTRACT: The EGF receptor (EGFR) is amplified and mutated in glioblastoma, in which its common mutation (?EGFR, also called EGFRvIII) has a variety of activities that promote growth and inhibit death, thereby conferring a strong tumor-enhancing effect. This range of activities suggested to us that ?EGFR might exert its influence through pleiotropic effectors, and we hypothesized that microRNAs might serve such a function. Here, we report that ?EGFR specifically suppresses one such microRNA, namely miR-9, through the Ras/PI3K/AKT axis that it is known to activate. Correspondingly, expression of miR-9 antagonizes the tumor growth advantage conferred by ?EGFR. Silencing of FOXP1, a miR-9 target, inhibits ?EGFR-dependent tumor growth and, conversely, de-repression of FOXP1, as a consequence of miR-9 inhibition, increases tumorigenicity. FOXP1 was sufficient to increase tumor growth in the absence of oncogenic ?EGFR signaling. The significance of these findings is underscored by our finding that high FOXP1 expression predicts poor survival in a cohort of 131 patients with glioblastoma. Collectively, these data suggest a novel regulatory mechanism by which ?EGFR suppression of miR-9 upregulates FOXP1 to increase tumorigenicity.

SUBMITTER: Gomez GG 

PROVIDER: S-EPMC3947420 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature