miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma

Abstract

Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma-initiating cells (GICs), which contribute to tumor recurrence following initial response to therapy. Here, we identified miR-182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Repression of Bcl2-like12 (Bcl2L12), cMet, and hypoxia-inducible factor 2α (HIF2A) is of central importance to miR-182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we synthesized miR-182-based spherical nucleic acids (182-SNAs); i.e., gold nanoparticles covalently functionalized with mature miR-182 duplexes. Intravenously administered 182-SNAs penetrated the blood-brain/blood-tumor barriers (BBB/BTB) in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM.

miRNA-182 and the regulation of the glioblastoma phenotype - toward miRNA-based precision therapeutics

“…Unlike miR-9, our studies suggest that miR-182 also influences the apoptotic response of glioma cells to a variety of anti-cancer agents, including TMZ and RTK inhibitors, by downregulating the caspase and p53 inhibitor Bcl2L12. 2 In addition, we demonstrated that miR-182 expression provoked a more differentiated state in multipotent GICs, which is evidenced by decreased expression of stem cell markers Oct4, CD44, Nanog and Sox2, and by elevated levels of microtubule-associated protein 2 (MAP2) and glial fibrillary acidic protein (GFAP) expression. Furthermore, miR-182 is expressed at lower levels in CD133-positive, GSC-enriched GICs compared to CD133-negative non-stem cells.…”

“…43 With respect to the regulation of differentiation processes, the miR-182-repressed transcriptome was enriched for a stem cell specific signature, mirrored phenotypically by reduced sphere size and expansion, and enhanced differentiation along neuronal and astroglial axes. 2 In further support of a tumor suppressive role of miR-182 in GBM, our studies in orthotopic xenograft models using transformed glioma cells and mesenchymal GICs harboring low levels of endogenous miR-182 showed that ectopic expression of miR-182 increases animal subject survival, and slows tumor growth, as determined by measurement of tumor weights, and by bioluminescence imaging of luciferase-modified tumors. 2 Thus, our studies point to miR-182 as a critical tumor suppressor and prognostic factor in GBM, which integrates cell death, growth and differentiation processes in GBM.…”

“…Furthermore, miR-182 is expressed at lower levels in CD133-positive, GSC-enriched GICs compared to CD133-negative non-stem cells. 2 To define miR-182-dependent transcriptional effects, we transduced patient-derived GICs, of the mesenchymal subtype, harboring lowlevel expression of endogenous miR-182, with miR-182 or control (Co)-miR lentivirus. Cultures were subjected to whole genome expression profiling.…”

MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics

“…Kouri et al. 135 used gold nanoparticles to develop a novel construct of RNA‐based spherical nucleic acids (SNA) functionalized with mature miR‐182 sequences (182‐SNA). SNAs exhibit high cellular uptake, high stability, high resistance to nuclease degradation, low activation of the innate immune system, and no significant acute or long‐term toxicity in animal models.…”

“…The constructs disseminated throughout the glioma parenchyma where glioma cells displayed robust cellular uptake of the 182‐SNAs. This was accompanied by potent downregulation of target proteins as well as enhanced sensitivity toward chemotherapy‐induced apoptosis, resulting in significantly reduced tumor burden and increased survival time with no significant adverse side effects 135, 136.…”