Int J Biol Sci 2020; 16(15):3050-3061. doi:10.7150/ijbs.48126 This issue

Research Paper

Downregulation of MEG3 promotes neuroblastoma development through FOXO1-mediated autophagy and mTOR-mediated epithelial-mesenchymal transition

Mujie Ye1,2*, Hong Lu3*, Weitao Tang1,2, Tianrui Jing4, Shiyu Chen4, Meng Wei1,2, Jingjing Zhang5, Jing Wang1,2, Jing Ma6, Duan Ma4✉, Kuiran Dong1,2✉

1. Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, 201102, China.
2. Key Laboratory of Neonatal Disease, Ministry of Health, 201102, Shanghai, China.
3. Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
4. Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, Collaborative Innovation Center of Genetics and Development, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
5. Department of Medical Imaging, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210001, China.
6. ENT institute, Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China.
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Ye M, Lu H, Tang W, Jing T, Chen S, Wei M, Zhang J, Wang J, Ma J, Ma D, Dong K. Downregulation of MEG3 promotes neuroblastoma development through FOXO1-mediated autophagy and mTOR-mediated epithelial-mesenchymal transition. Int J Biol Sci 2020; 16(15):3050-3061. doi:10.7150/ijbs.48126. Available from

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Graphic abstract

Our previous studies demonstrated that MEG3 was significantly downregulated in neuroblastoma (NB) and its expression was negatively associated with the INSS stage. Overexpression of MEG3 promoted apoptosis and inhibited proliferation in NB cells. In this study, we discovered more potential functions and molecular mechanisms of MEG3 in NB. According to the database, MEG3 positively correlated with the NB survival rate and was negatively associated with malignant clinical features. Moreover, we determined that MEG3 was mainly located in the nucleus by nuclear-cytoplasmic separation and RNA fish assays. Upregulation of MEG3 in stably transfected cell lines was accomplished, and CCK8, colony formation, and EDU assays were performed, which indicated that MEG3 significantly suppressed cell proliferation. Both wound healing and transwell experiments demonstrated that MEG3 decreased cell migration and invasion. CHIRP enrichments showed the anticancer effects of MEG3 were probably linked to autophagy and the mTOR signaling pathway. LC3 fluorescence dots and western blots showed that MEG3 attenuated autophagy by inhibiting FOXO1, but not the mTOR signaling pathway. Furthermore, MEG3 inhibited metastasis through epithelial-mesenchymal transition via the mTOR signaling pathway. Consistent with the above results, downregulation of MEG3 facilitated NB malignant phenotypes. Mechanistically, MEG3 and EZH2 regulated each other via a negative feedback loop and promoted NB progression together. In conclusion, our findings suggested that MEG3 was a tumor suppressor in NB and could be a potential target for NB treatment in the future.

Keywords: neuroblastoma, lncRNA, autophagy, epithelial-mesenchymal transition, ubiquitination