The EGF receptor (EGFR) is amplified and mutated in glioblastoma, in which its common mutation (DEGFR, 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 DEGFR might exert its influence through pleiotropic effectors, and we hypothesized that microRNAs might serve such a function. Here, we report that DEGFR 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 DEGFR. Silencing of FOXP1, a miR-9 target, inhibits DEGFR-dependent tumor growth and, conversely, derepression of FOXP1, as a consequence of miR-9 inhibition, increases tumorigenicity. FOXP1 was sufficient to increase tumor growth in the absence of oncogenic DEGFR 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 DEGFR suppression of miR- 9 upregulates FOXP1 to increase tumorigenicity. © 2013 American Association for Cancer Research.

Suppression of MicroRNA-9 by Mutant EGFR signaling upregulates FOXP1 to enhance glioblastoma tumorigenicity

VOLINIA, Stefano
Secondo
;
CROCE, Carlo Maria;
2014

Abstract

The EGF receptor (EGFR) is amplified and mutated in glioblastoma, in which its common mutation (DEGFR, 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 DEGFR might exert its influence through pleiotropic effectors, and we hypothesized that microRNAs might serve such a function. Here, we report that DEGFR 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 DEGFR. Silencing of FOXP1, a miR-9 target, inhibits DEGFR-dependent tumor growth and, conversely, derepression of FOXP1, as a consequence of miR-9 inhibition, increases tumorigenicity. FOXP1 was sufficient to increase tumor growth in the absence of oncogenic DEGFR 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 DEGFR suppression of miR- 9 upregulates FOXP1 to increase tumorigenicity. © 2013 American Association for Cancer Research.
Gomez, German G.; Volinia, Stefano; Croce, Carlo Maria; Zanca, Ciro; Li, Ming; Emnett, Ryan; Gutmann, David H.; Brennan, Cameron W.; Furnari, Frank B; Cavenee, Webster K.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2356318
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