Modulation of MicroRNAs 34a and 21 Affects Viability, Senescence, and Invasion in Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is an aggressive and invasive brain tumor. Current interventional strategies have been minimally successful. Three key characteristics of GBMs are (1) enhanced resistance to apoptosis, (2) increased proliferation rate, and (3) increased invasion potential, making them difficult to treat. MicroRNAs (miRs) have demonstrated beneficial therapeutic intervention; particularly miRs 34a and 21, which have been implicated in regulation of apoptosis, senescence, and invasion of GBM tumor cells. MiR21 is anti-apoptotic and pro-proliferative, whereas miR34a is proapoptotic and an anti-invasive regulator in tumor cells. Our study investigates the effects of modulating both miR34a and miR21, in addition to comparing the two individual treatments. Using targeted cationic liposomes that bind to the epidermal growth factor receptor (EGFR), we delivered miR34a and/or anti-sense oligonucleotide to miR21 (ASO21) to GBM tumor cell lines, U87MG and A172, in vitro. Our data demonstrate that co-delivery of miR34a and ASO21 results in enhanced reduction in viability and invasion, while increasing senescence in vitro. Additionally, there were significant decreases in pro-invasion and -proliferation gene markers, as well as an increase in pro-apoptotic markers. In vivo results demonstrate that the combination of miR34a and ASO21 reduced tumor volume and proliferation of the A172 tumor cells. Accumulation of rhodamine encapsulated EGFR-targeted cationic liposomes was observed throughout the primary tumor bed after systemic injection. To our knowledge, we are the first to modulate multiple miRs, while using a targeted cationic liposomal delivery for miR-based therapy. These results demonstrate a potential clinically relevant, miR therapeutic strategy for GBM.