AEG-1/MTDH-activated autophagy enhances human malignant glioma susceptibility to TGF-β1-triggered epithelial-mesenchymal transition.

// Meijuan Zou 1 , Wei Zhu 2 , Li Wang 3 , Lei Shi 3 , Rui Gao 1 , Yingwei Ou 1 , Xuguan Chen 1 , Zhongchang Wang 4 , Aiqin Jiang 5 , Kunmei Liu 6 , Ming Xiao 7 , Ping Ni 1 , Dandan Wu 1 , Wenping He 1 , Geng Sun 1 , Ping Li 1 , Sulan Zhai 1 , Xuerong Wang 1 , Gang Hu 1 1 Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210029, China 2 Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China 3 Department of Breast Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China 4 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China 5 Medical School of Nanjing University, Nanjing 210093, China 6 Ningxia Key Laboratory of Cerebrocranial Diseases, School of Laboratory Medicine, Ningxia Medical University, Yinchuan 750004, China 7 Department of Anatomy, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210029, China Correspondence to: Meijuan Zou, e-mail: zoumeijuan_njmu@163.com Keywords: transforming growth factor-β1, astrocyte elevated gene-1, protective autophagy, epithelial mesenchymal transition, malignant glioma invasion Received: June 18, 2015      Accepted: January 27, 2016      Published: February 20, 2016 ABSTRACT 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-β1-triggered epithelial-mesenchymal transition (EMT) through induction of autophagy. TGF-β1 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-β1, 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.