SNAI1 is Involved in the Proliferation and Migration of Glioblastoma Cells

Han, Shuai D.; Kim, Jihoon; Han, Myoung‐Eun; Sim, Hey-Eun; Kim, Ki-Sun; Yoon, Sik; Baek, Sun‐Yong; Kim, Bong-Seon; Oh, Sae‐Ock

doi:10.1007/s10571-010-9643-4

Cited by 104 publications

(94 citation statements)

References 33 publications

(41 reference statements)

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“…[4][5][6] In GBM, members of the SNAI-family, e.g., ZEB1 and ZEB2, act as EMT activators, enhancing the invasiveness of GBM cells in vitro and in vivo. 7,8 Moreover, EMT processes in GBM cells are also linked to stem-like status, 8 which may cause cellular dedifferentiation of noncancer stem cells, allowing the cells to acquire selfrenewal and tumor-initiating ability. 9,10 Increasing evidence has shown that IR and TMZ inhibit tumor growth in GBM by inducing a type of programmed cell death that is dependent of autophagy.…”

Section: Introductionmentioning

confidence: 99%

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

Xiao

Liu

et al. 2015

Autophagy

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(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.

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Section: Introductionmentioning

confidence: 99%

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

Xiao

Liu

et al. 2015

Autophagy

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“…40,56 Snail/Slug proteins have already been involved in GBM invasion. 57,58 We demonstrate the regulation of Snail/Slug, in parallel to increased PY142 b-catenin, upon stimulation of GBM cells with HGF. Statistical studies indicate that both nuclear Snail/ Slug and nuclear PY142 b-catenin peak in astrocytomas of grade III.…”

Section: Resultsmentioning

confidence: 79%

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

et al. 2015

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Glioblastoma multiforme (GBM) is a fast growing brain tumor characterized by extensive infiltration into the surrounding tissue and one of the most aggressive cancers. GBM is the most common glioma (originating from glialderived cells) that either evolves from a low grade astrocytoma or appears de novo. Wnt/b-catenin and Hepatocyte Growth Factor (HGF)/c-Met signaling are hyperactive in human gliomas, where they regulate cell proliferation, migration and stem cell behavior. We previously demonstrated that b-catenin is phosphorylated at Y142 by recombinant c-Met kinase and downstream of HGF signaling in neurons. Here we studied phosphoY142 (PY142) b-catenin and dephospho S/T b-catenin (a classical Wnt transducer) in glioma biopsies, GBM cell lines and biopsyderived glioma cell cultures. We found that PY142 b-catenin mainly localizes in the nucleus and signals through transcriptional activation in GBM cells. Tissue microarray analysis confirmed strong nuclear PY142 b-catenin immunostaining in astrocytoma and GBM biopsies. By contrast, active b-catenin showed nuclear localization only in GBM samples. Western blot analysis of tumor biopsies further indicated that PY142 and active b-catenin accumulate independently, correlating with the expression of Snail/Slug (an epithelial-mesenchymal transition marker) and Cyclin-D1 (a regulator of cell cycle progression), respectively, in high grade astrocytomas and GBMs. Moreover, GBM cells stimulated with HGF showed increasing levels of PY142 b-catenin and Snail/Slug. Importantly, the expression of mutant Y142F b-catenin decreased cell detachment and invasion induced by HGF in GBM cell lines and biopsy-derived cell cultures. Our results identify PY142 b-catenin as a nuclear b-catenin signaling form that downregulates adhesion and promotes GBM cell invasion.

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“…Some transcriptional repressors such as SNAI-1/2, zinc finger E-box binding homeobox-1 (ZEB-1) and ZEB-2 are able to bind directly to the Ecadherin promoter and repress its transcription. Overexpression of these proteins supports mesenchymal transformation and the change of behavioural characteristics and promotes the continuous acquisition of malignant features by tumor cells [18,19]. Crucial transcription factors involved in EMT are TWIST-1 and signal transducers and activators of transcription-3/-5 (STAT-3/-5).…”

Section: Molecular Principles Of Emtmentioning

confidence: 99%

“…It has been reported that knockdown of SNAI-1 results in decreased invasion and migration of glioma cells. Moreover, SNAI-1 induces expression of matrix metalloprotease-2 (MMP-2), another contributor to EMT progression [18].…”

Section: Molecular Principles Of Emtmentioning

confidence: 99%