Intronic miR-744 Inhibits Glioblastoma Migration by Functionally Antagonizing Its Host Gene MAP2K4

摘要: Background: The second intron of Mitogen-Activated Protein Kinase 4 (MAP2K4), an important hub in the pro-invasive MAPK pathway, harbors miR-744. There is accumulating evidence that intronic micro-RNAs (miRNAs) are capable either supporting or restraining functional pathways their host genes, thereby creating intricate regulative networks. We thus hypothesized miR-744 regulates glioma migration by interacting with its host’s pathways. Methods: Patients’ tumor specimens were obtained stereotactically. MiR-744 was overexpressed U87, T98G, and primary glioblastoma (GBM) cell lines. Cell mobility studied using Boyden chamber assays. mRNA expression quantified SDS-PAGE qRT-PCR. Interactions 3’UTRs analyzed luciferase reporter assays, SMAD2/3, p38, beta-Catenin activities TOP/FOPflash gene Results: As compared to a normal brain, levels dramatically decreased GBM samples Astrocytoma WHO grade II/III exhibited intermediate levels. Re-expression lines induced focal growth impaired mobility. Luciferase activity 3’UTR constructs revealed factors TGFB1 DVL2 as direct targets reduced TGFB1, DVL2, MAP2K4, mitigated downstream SMAD2/3 beta-Catenin. knock-down repressed MAP2K4 expression. Conclusion: acts intrinsic brake on host. It impedes through simultaneously targeting SMAD-, beta-Catenin, signaling networks, strongly mitigating pro-migratory effects MAP2K4. glioma, re-expression might attenuate invasiveness.