MicroRNA-7 upregulates death receptor 5 and primes resistant brain tumors to caspase-mediated apoptosis. Issue 2 (25th July 2017)

• Record Type: Journal Article
• Authors: Bhere, Deepak; Tamura, Kaoru; Wakimoto, Hiroaki; Choi, Sung Hugh; Purow, Benjamin; Debatisse, Jeremy; Shah, Khalid
• Is Part Of: Neuro-oncology. Volume 20:Issue 2(2018)
• Page Start: 215
• Page End: 224
• Publication Date: 2017-07-25
• Subjects: glioblastoma -- stem cell therapy -- microRNA -- cancer -- death receptor -- apoptosis; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/nox138
• Languages: English
• ISSNs: 1522-8517

Abstract

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.