Astrocyte elevated gene 1 (AEG‐1) promotes anoikis resistance and metastasis by inducing autophagy in hepatocellular carcinoma

• Published in: Journal of cellular physiology Vol. 235; no. 6; pp. 5084 - 5095
• Main Authors: Zhu, Hai‐Dan, Liu, Lian, Deng, Huan, Li, Zheng‐Bo, Sheng, Jia‐Qi, He, Xing‐Xing, Tian, De‐An, Li, Pei‐Yuan
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.06.2020
• Subjects: Activating Transcription Factor 4 - genetics; AEG‐1; Animals; Anoikis; Anoikis - genetics; Autophagy; Autophagy - genetics; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell culture; Cell Line, Tumor; Cell Proliferation - genetics; eIF-2 Kinase - genetics; Flow Cytometry; Gene Expression Regulation, Neoplastic - genetics; Hepatocellular carcinoma; Heterografts; Humans; Kinases; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Membrane Proteins - genetics; Metastases; Metastasis; Mice; Neoplasm Metastasis; Phagocytosis; Protein kinase; Ribonucleic acid; RNA; RNA-Binding Proteins - genetics; RNA-mediated interference; Signal Transduction - genetics; Survival; Suspension culture; Tumor cells; Tumors; Xenografts; Xenotransplantation; anoikis; AEG-1; autophagy; metastasis; hepatocellular carcinoma
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.29377

Astrocyte elevated gene 1 (AEG‐1) is overexpressed in hepatocellular carcinoma (HCC) and is strongly associated with tumor metastasis. Anoikis resistance and autophagy may play an important role in the survival of circulating tumor cells. However, the relationship among AEG‐1, anoikis resistance, autophagy, and metastasis in HCC is still not clear. The results of this study indicate that AEG‐1 expression is increased in HCC cell lines grown in suspension culture. AEG‐1 could enhance anoikis resistance to promote the survival of detached HCC cells. Moreover, the anoikis resistance appears to be partly dependent on autophagy. Regulating AEG‐1 expression changed the autophagy levels to modulate anoikis resistance, likely acting via the protein kinase RNA‐like ER kinase (PERK)‐eIF2α‐ATF4‐CHOP signaling axis. Finally, inhibiting autophagy by RNA interference prevented the AEG‐1‐promoted metastasis of HCC xenografts to the liver and lungs of nude mice. Taken together, AEG‐1 is a key contributor to anoikis resistance and metastasis by inducing autophagy in vitro and in vivo, and it may be a potential target for therapeutic intervention in HCC. Our study indicates that astrocyte elevated gene 1 (AEG‐1) plays a central role in mediating a PERK‐eIF2α‐ATF4‐CHOP–dependent cytoprotective autophagic response that enables hepatocellular carcinoma (HCC) cells to resist anoikis after extracellular matrix (ECM) detachment. Furthermore, AEG‐1‐induced autophagy contributes to HCC metastasis in vivo. This study provides a better understanding of the relationship among AEG‐1, endoplasmic reticulum (ER) stress, autophagy, anoikis resistance, and HCC metastasis, which may lead to the discovery of new targets for HCC treatment.