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Open AccessArticle

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

1
Department of Anesthesiology, University Hospital, LMU Munich, 81377 Munich, Germany
2
Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, LMU Munich, 81377 Munich, Germany
3
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; https://doi.org/10.3390/cancers10110400
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
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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.

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