MiR-338-3p regulates neuronal maturation and suppresses glioblastoma proliferation

• Published in: PloS one Vol. 12; no. 5; p. e0177661
• Main Authors: Howe, 6th, James R, Li, Emily S, Streeter, Sarah E, Rahme, Gilbert J, Chipumuro, Edmond, Russo, Grace B, Litzky, Julia F, Hills, L Benjamin, Rodgers, Kyla R, Skelton, Patrick D, Luikart, Bryan W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11-05-2017; Public Library of Science (PLoS)
• Subjects: 3' Untranslated regions; Animal models; Animals; Antidepressants; Axons; Backbone; Biology and Life Sciences; Biotechnology; Bipolar disorder; Brain; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Brain tumors; Cancer; Cell cycle; Cell Differentiation; Cell growth; Cell Line, Tumor; Cell Proliferation; Cell Shape; Cell survival; Cells (biology); Circuits; Cloning; Colorectal carcinoma; Conditioning; Construction; Cyclin-dependent kinase 5; Dendrites; Dentate Gyrus - metabolism; Dentate Gyrus - pathology; Disease-Free Survival; Fluorescence; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genetics; Glial Fibrillary Acidic Protein - metabolism; Glioblastoma - genetics; Glioblastoma - pathology; Glioblastomas; Hepatitis; Hippocampus; Humans; Hyperactivity; In vivo methods and tests; Infections; Injection; Learning; Liver; Maturation; Medicine; Medicine and Health Sciences; Memory; Mental disorders; Mice; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Modulation; Morphogenesis; Nervous system; Neural stem cells; Neurobiology; Neurodegenerative diseases; Neurogenesis; Neurons; Neurons - metabolism; Neurons - pathology; Neurosciences; Physiology; Psychiatry; Reproducibility of Results; Ribonucleic acid; RNA; Rodents; Sensors; Separation; Signal transduction; Spine; Stimulation; Survival; Tissues; Treatment Outcome; Tumor suppressor genes; Viruses; Lebanon; United States > US; New Hampshire
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0177661

Neurogenesis is a highly-regulated process occurring in the dentate gyrus that has been linked to learning, memory, and antidepressant efficacy. MicroRNAs (miRNAs) have been previously shown to play an important role in the regulation of neuronal development and neurogenesis in the dentate gyrus via modulation of gene expression. However, this mode of regulation is both incompletely described in the literature thus far and highly multifactorial. In this study, we designed sensors and detected relative levels of expression of 10 different miRNAs and found miR-338-3p was most highly expressed in the dentate gyrus. Comparison of miR-338-3p expression with neuronal markers of maturity indicates miR-338-3p is expressed most highly in the mature neuron. We also designed a viral "sponge" to knock down in vivo expression of miR-338-3p. When miR-338-3p is knocked down, neurons sprout multiple primary dendrites that branch off of the soma in a disorganized manner, cellular proliferation is upregulated, and neoplasms form spontaneously in vivo. Additionally, miR-338-3p overexpression in glioblastoma cell lines slows their proliferation in vitro. Further, low miR-338-3p expression is associated with increased mortality and disease progression in patients with glioblastoma. These data identify miR-338-3p as a clinically relevant tumor suppressor in glioblastoma.