Genome Editing Reveals Glioblastoma Addiction to MicroRNA-10b.

ABSTRACT: Glioblastoma (GBM) brain tumor remains among the most lethal and incurable human diseases. Oncogenic microRNA-10b (miR-10b) is strongly and universally upregulated in GBM, and its inhibition by antisense oligonucleotides (ASOs) reduces the growth of heterogeneous glioma cells; therefore, miR-10b represents a unique therapeutic target for GBM. Here we explored the effects of miR-10b gene editing on GBM. Using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system, we investigated effects of miR-10b gene editing on the growth of cultured human glioma cells, tumor-initiating stem-like cells, and mouse GBM xenografts, as well as the oncogene-induced transformation of normal astrocytes. We show that GBM is strictly "addicted" to miR-10b and that miR-10b gene ablation is lethal for glioma cell cultures and established intracranial tumors. miR-10b loss-of-function mutations lead to the death of glioma, but not other cancer cell lines. We have not detected escaped proliferative clones of GBM cells edited in the miR-10b locus. Finally, neoplastic transformation of normal astrocytes was abolished by the miR-10b-editing vectors. This study demonstrates the feasibility of gene editing for brain tumors in vivo and suggests virus-mediated miR-10b gene ablation as a promising therapeutic approach that permanently eliminates the key regulator essential for tumor growth and survival.

SUBMITTER: El Fatimy R 

PROVIDER: S-EPMC5368404 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature