Next Article in Journal
Dosimetric Comparison of Proton Radiation Therapy, Volumetric Modulated Arc Therapy, and Three-Dimensional Conformal Radiotherapy Based on Intracranial Tumor Location
Next Article in Special Issue
Finding the Right Way to Target EGFR in Glioblastomas; Lessons from Lung Adenocarcinomas
Previous Article in Journal
Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells
Previous Article in Special Issue
Reduction of Human Glioblastoma Spheroids Using Cold Atmospheric Plasma: The Combined Effect of Short- and Long-Lived Reactive Species

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

Department of Anesthesiology, University Hospital, LMU Munich, 81377 Munich, Germany
Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, 81377 Munich, Germany
Department of Neurosurgery, University Hospital, LMU Munich, 81377 Munich, Germany
Author to whom correspondence should be addressed.
These authors contributed equally.
Cancers 2018, 10(11), 400;
Received: 1 September 2018 / Revised: 16 October 2018 / Accepted: 24 October 2018 / Published: 25 October 2018
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
Background: The second intron of Mitogen-Activated Protein Kinase 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 of either supporting or restraining functional pathways of their host genes, thereby creating intricate regulative networks. We thus hypothesized that miR-744 regulates glioma migration by interacting with its host’s pathways. Methods: Patients’ tumor specimens were obtained stereotactically. MiR-744 was overexpressed in U87, T98G, and primary glioblastoma (GBM) cell lines. Cell mobility was studied using migration and Boyden chamber assays. Protein and mRNA expression was quantified by SDS-PAGE and qRT-PCR. Interactions of miR-744 and 3’UTRs were analyzed by luciferase reporter assays, and SMAD2/3, p38, and beta-Catenin activities by TOP/FOPflash reporter gene assays. Results: As compared to a normal brain, miR-744 levels were dramatically decreased in GBM samples and in primary GBM cell lines. Astrocytoma WHO grade II/III exhibited intermediate expression levels. Re-expression of miR-744 in U87, T98G, and primary GBM cell lines induced focal growth and impaired cell mobility. Luciferase activity of 3’UTR reporter constructs revealed the pro-invasive factors TGFB1 and DVL2 as direct targets of miR-744. Re-expression of miR-744 reduced levels of TGFB1, DVL2, and the host MAP2K4, and mitigated activity of TGFB1 and DVL2 downstream targets SMAD2/3 and beta-Catenin. TGFB1 knock-down repressed MAP2K4 expression. Conclusion: MiR-744 acts as an intrinsic brake on its host. It impedes MAP2K4 functional pathways through simultaneously targeting SMAD-, beta-Catenin, and MAPK signaling networks, thereby strongly mitigating pro-migratory effects of MAP2K4. MiR-744 is strongly repressed in glioma, and its re-expression might attenuate tumor invasiveness. View Full-Text
Keywords: glioblastoma; migration; microRNAs; MAP2K4 glioblastoma; migration; microRNAs; MAP2K4
Show Figures

Figure 1

MDPI and ACS Style

Hübner, M.; Hinske, C.L.; Effinger, D.; Wu, T.; Thon, N.; Kreth, F.-W.; Kreth, S. Intronic miR-744 Inhibits Glioblastoma Migration by Functionally Antagonizing Its Host Gene MAP2K4. Cancers 2018, 10, 400.

AMA Style

Hübner M, Hinske CL, Effinger D, Wu T, Thon N, Kreth F-W, Kreth S. Intronic miR-744 Inhibits Glioblastoma Migration by Functionally Antagonizing Its Host Gene MAP2K4. Cancers. 2018; 10(11):400.

Chicago/Turabian Style

Hübner, Max, Christian L. Hinske, David Effinger, Tingting Wu, Niklas Thon, Friedrich-Wilhelm Kreth, and Simone Kreth. 2018. "Intronic miR-744 Inhibits Glioblastoma Migration by Functionally Antagonizing Its Host Gene MAP2K4" Cancers 10, no. 11: 400.

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

Back to TopTop