MicroRNA-1 suppresses glioblastoma in preclinical models by targeting fibronectin

Abstract

Glioblastoma (GBM) is a deadly and incurable brain tumor. Although microRNAs (miRNAs) play critical roles in regulating the cancer cell phenotype, the underlying mechanisms of how they regulate tumorigenesis are incompletely understood. We found that miR-1 is expressed at relatively low levels in brain cancer patients, especially GBM. Ectopic miR-1 expression in GBM cells inhibited proliferation and migration, increased sensitivity to apoptosis induced by the DNA alkylating agent temozolomide in vitro, and inhibited GBM tumorigenesis in vivo. Expression of miR-1 in GBM cell lines directly targets fibronectin. High fibronectin expression in GBM correlates with poor patient survival and fibronectin expression is inversely correlated with miR-1 expression. Knockout of fibronectin expression in GBM cell lines inhibited proliferation and migration, increased sensitivity to apoptosis induced by temozolomide in vitro, and markedly suppressed GBM tumor growth and promoted animal survival. In contrast, restoring fibronectin levels in GBM cells ectopically expressing miR-1 increased tumorigenicity and decreased animal survival. Therefore, these results confirm that miR-1 has tumor suppressive activity in GBM by targeting fibronectin, and that the miR-1/fibronectin pathway may be a potential drug target in this devastating cancer.

Keywords: Fibronectin; Glioblastoma; Temozolomide; Tumor suppressor; miR-1.