Original ArticlemiR-181d/MALT1 regulatory axis attenuates mesenchymal phenotype through NF-κB pathways in glioblastoma

- The miR-181d differentially expresses between proneural and mesenchymal subtype.
- As a tumor suppressor, miR-181d restrains malignant properties of glioma cells.
- The miR-181d represses NFκB transcriptional activity be directly targeting MALT1.
- The miR-181d/MALT1 regulatory axis attenuates mesenchymal phenotype.

The mesenchymal (MES) subtype of glioblastoma (GBM) indicated a more malignant phenotype and worse prognosis compared with their proneural (PN) counterpart. The plasticity between PN and MES transcriptome signatures provided an approach for clinical intervention. However, few miRNAs have been identified to participate in the shift between subtypes. Here, we utilized transcriptomic data and experimental evidences to prove that miR-181d was a novel regulator of NFκB signaling pathway by directly repressing MALT1, leading to induced PN markers and reduced MES genes. Functionally, ectopic expression of miR-181d suppressed GBM cell proliferation, colony formation and anchor-independent growth, as well as migration, invasion and tube formation. Moreover, miR-181d overexpression increased radio- and chemo-sensitivity for GBM cells. Rescue of MALT1 could partially reverse the effects of miR-181d in GBM malignant behaviors. Clinically, miR-181d could serve as a prognostic indicator for GBM patients. Taken together, we concluded that loss of miR-181d contributes to aggressive biological processes associated with MES phenotype via NFκB signaling, which broaden our insights into the underlying mechanisms in subtype transition and miRNA-based tailored medicine for GBM management.