Journal
ONCOTARGET
Volume 7, Issue 11, Pages 13122-13138Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7536
Keywords
transforming growth factor-beta 1; astrocyte elevated gene-1; protective autophagy; epithelial mesenchymal transition; malignant glioma invasion
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Funding
- National Natural Science Foundation of China [81402959, 81201705, 81301943, 81102458, 81172004, 81473241]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Science and Technology Development Foundation of Nanjing Medical University [2013NJMU011]
- Natural Science Foundation of Jiangsu Province [BK2012442]
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Autophagy is a tightly regulated process activated in response to metabolic stress and other microenvironmental changes. Astrocyte elevated gene 1 (AEG-1) reportedly induces protective autophagy. Our results indicate that AEG-1 also enhances the susceptibility of malignant glioma cells to TGF-beta 1-triggered epithelial-mesenchymal transition (EMT) through induction of autophagy. TGF-beta 1 induced autophagy and activated AEG-1 via Smad2/3 phosphorylation in malignant glioma cells. Also increased was oncogene cyclin D1 and EMT markers, which promoted tumor progression. Inhibition of autophagy using siRNA-BECN1 and siRNA-AEG-1 suppressed EMT. In tumor samples from patients with malignant glioma, immunohistochemical assays showed that expression levels of TGF-beta 1, AEG-1, and markers of autophagy and EMT, all gradually increase with glioblastoma progression. In vivo siRNA-AEG-1 administration to rats implanted with C6 glioma cells inhibited tumor growth and increased the incidence of apoptosis among tumor cells. These findings shed light on the mechanisms underlying the invasiveness and progression of malignant gliomas.
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