Unknown

Dataset Information

0

MicroRNA-7 upregulates death receptor 5 and primes resistant brain tumors to caspase-mediated apoptosis.


ABSTRACT: Background:MicroRNAs (miRs) are known to play a pivotal role in tumorigenesis, controlling cell proliferation and apoptosis. In this study, we investigated the potential of miR-7 to prime resistant tumor cells to apoptosis in glioblastoma (GBM). Methods:We created constitutive and regulatable miR-7 expression vectors and utilized pharmacological inhibition of caspases and genetic loss of function to study the effect of forced expression of miR-7 on death receptor (DR) pathways in a cohort of GBM with established resistance to tumor necrosis factor apoptosis inducing ligand (TRAIL) and in patient-derived primary GBM stem cell (GSC) lines. We engineered adeno-associated virus (AAV)-miR-7 and stem cell (SC) releasing secretable (S)-TRAIL and utilized real time in vivo imaging and neuropathology to understand the effect of the combined treatment of AAV-miR-7 and SC-S-TRAIL in vitro and in mouse models of GBM from TRAIL-resistant GSC. Results:We show that expression of miR-7 in GBM cells results in downregulation of epidermal growth factor receptor and phosphorylated Akt and activation of nuclear factor-kappaB signaling. This leads to an upregulation of DR5, ultimately priming resistant GBM cells to DR-ligand, TRAIL-induced apoptotic cell death. In vivo, a single administration of AAV-miR-7 significantly decreases tumor volumes, upregulates DR5, and enables SC-delivered S-TRAIL to eradicate GBM xenografts generated from patient-derived TRAIL-resistant GSC, significantly improving survival of mice. Conclusions:This study identifies the unique role of miR-7 in linking cell proliferation to death pathways that can be targeted simultaneously to effectively eliminate GBM, thus presenting a promising strategy for treating GBM.

SUBMITTER: Bhere D 

PROVIDER: S-EPMC5777493 | BioStudies | 2018-01-01T00:00:00Z

REPOSITORIES: biostudies

Similar Datasets

1000-01-01 | S-EPMC4554544 | BioStudies
1000-01-01 | S-EPMC6362213 | BioStudies
2013-01-01 | S-EPMC3676868 | BioStudies
1000-01-01 | S-EPMC3641324 | BioStudies
2011-01-01 | S-EPMC3255792 | BioStudies
2017-01-01 | S-EPMC5796532 | BioStudies
2015-01-01 | S-EPMC4270944 | BioStudies
2020-01-01 | S-EPMC7183418 | BioStudies
2010-01-01 | S-EPMC3035906 | BioStudies
2015-01-01 | S-EPMC4688186 | BioStudies