OncomiR-138 targets genes involved in senescence and its inhibition induces growth arrest of malignant gliomas.

Abstract

Glioblastoma Multiforme (GBM) is the most aggressive types of brain cancer with a median lifespan of 12 months. Recent studies have reported elevated expression of miR-138 in Glioma Stem cells (GSCs) and demonstrated that knocking miR-138 down prevented tumor progression, though the exact downstream mechanism was unknown. This study aimed at elucidating the downstream mechanisms upon functional inhibition of miR-138 in glioma cells through identification of differentially regulated genes.

Upon knock down using AntagomiR-138, U87MG cells displayed a senescent phenotype, suggesting senescence as a plausible downstream consequence. To further evaluate the observed phenotype, SA-β-gal staining and cell cycle analysis were performed and both yield positive results towards senescence. Microarray validation showed up regulation of senescence associated genes, which include cytokines and chemokines upon miR-138 knock down and the increased phosphorylated p38 MAPK detection upon miR-138 knock down, suggest an oncogene-induced senescence relayed by an interleukin-dependent inflammatory network involving p38 MAPK pathway. This pathway is further strengthened by the identification of miR-138 direct targets, affirming their role in causing miR-138 knock down induced senescence.

Identification of senescence as a downstream consequence of miR-138 inhibition will aid in developing a pro-senescence therapeutic drug for GBM.