MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

Abstract

(2015) MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation, Autophagy, 11:12, 2213-2232, DOI: 10.1080/15548627.2015 LG, low glucose; MAP1LC3B/LC3B, microtubuleassociated protein 1 light chain 3B; MU, mutation; NC, negative control; NSC, neural stem cell; oe, overexpressing; OS, overall survival; PFS, progression-free survival; qRT-PCR, quantitative real-time reverse transcription polymerase chain reaction; SNAI2, Slug (snail family zinc finger 2); SNAI1, snail (snail family zinc finger 1); TEM, transmission electron microscopy; TMZ, temozolomide; VIM, vimentin; WT, wild type; ZEB1, zinc finger E-box binding homeobox 1.The epithelial-to-mesenchymal (-like) transition (EMT), a crucial embryonic development program, has been linked to the regulation of glioblastoma (GBM) progression and invasion. Here, we investigated the role of MIR517C/miR-517c, which belongs to the C19MC microRNA cluster identified in our preliminary studies, in the pathogenesis of GBM. We found that MIR517C was associated with improved prognosis in patients with GBM. Furthermore, following treatment with the autophagy inducer temozolomide (TMZ) and low glucose (LG), MIR517C degraded KPNA2 (karyopherin alpha 2 [RAG cohort 1, importin alpha 1]) and subsequently disturbed the nuclear translocation of TP53 in the GBM cell line U87 in vitro. Interestingly, this microRNA could inhibit autophagy and reduce cell migration and infiltration in U87 cells harboring wild-type (WT) TP53, but not in U251 cells harboring mutant (MU) TP53. Moreover, the expression of epithelial markers (i.e., CDH13/T-cadherin and CLDN1 [claudin 1]) increased, while the expression of mesenchymal markers (i.e., CDH2/N-cadherin, SNAI1/Snail, and VIM [vimentin]) decreased, indicating that the EMT status was blocked by MIR517C in U87 cells. Compared with MIR517C overexpression, MIR517C knockdown promoted infiltration of U87 cells to the surrounding structures in nude mice in vivo. The above phenotypic changes were also observed in TP53 +/+ and TP53 -/-HCT116 colon cancer cells. In summary, our study provided support for a link between autophagy and EMT status in WT TP53 GBM cells and provided evidence for the signaling pathway (MIR517C-KPNA2-cytoplasmic TP53) involved in attenuating autophagy and eliminating the increased migration and invasion during the EMT.

Decorin‐mediated inhibition of the migration of U87MG glioma cells involves activation of autophagy and suppression of TGF‐β signaling

“…TMZ induces massive DNA damages and triggers cell apoptosis of glioma cells . TMZ was reported to also activate autophagy in U87MG cells . We observed a similar effect as indicated by MDC staining (Fig.…”

<p>Meg3 Induces EMT and Invasion of Glioma Cells via Autophagy</p>

“…44 Lu et al found that CQ blocked autophagy-induced cell migration and GBM infiltration. 45 Furthermore, some relevant clinical studies of CQ in the treatment of brain tumor have been reported. In a double-blinded clinical trial involving 30 patients with glioblastoma multiforme (NCT00224978) (a Phase III clinical trial), randomizing eligible patients with surgically confirmed glioblastoma to receive conventional chemotherapy and radiotherapy plus placebo or 150 mg/day CQ per os, the result showed CQ-receiving patients exhibited an imp roved mid-term survival as compared with their control counterparts.…”

Clustered miRNAs and their role in biological functions and diseases

“…Understanding the precise mechanism of autophagy and senescence and their interrelationship is important to understand their roles in healthy cells and in disease (Lin & Baehrecke, ; Lecot et al, ). miRNA clusters are likely to regulate autophagy, as they target many autophagy pathway genes such as unc‐51 like autophagy activating kinase 1 ( ULK)1 , TP53 and slu7 homolog splicing factor ( SLU7) (Chen et al, ; Lu et al, ). Ulk1 along with Beclin‐1 , is important for reticulocyte clearance of mitochondria via autophagy‐related protein 5 (Atg5)/Atg7‐independent autophagy (Honda et al, ).…”