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

Abstract

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.

Acidic extracellular pH induces autophagy to promote anoikis resistance of hepatocellular carcinoma cells via downregulation of miR-3663-3p

“…Autophagy is involved in HCC metastasis by facilitating anoikis resistance and lung colonization by HCC cells [17]. AEG-1 is a key contributor to anoikis resistance and metastasis by inducing autophagy in HCC [22]. These reports provide evidence for autophagy triggered by different mechanisms to enhance anoikis resistance of tumor cells, but whether it happens in an acidic TME is unknown.…”

“…Autophagy contributes to the survival of tumor cells, which are lack of appropriate matrix contact, either during early carcinoma formation or in the later stages of dissemination and metastasis [21,22]. To induce anoikis, we cultured HCC cells in attachment-free conditions on poly-HEMA coated plates.…”

The Double-Edge Sword of Autophagy in Cancer: From Tumor Suppression to Pro-tumor Activity

“…Also, astrocyte elevated gene 1 (AEG-1) protein has a high correlation with metastasis in hepatocarcinoma. AEG-1 induces resistance to anoikis by activating autophagy (129). Another molecule that induces resistance to anoikis by activating autophagy is miR-30a.…”

Stresses in the metastatic cascade: molecular mechanisms and therapeutic opportunities

“…A gain-of-function genomic screen identified tropomyosin receptor kinase B (TrkB), a neurotrophic tyrosine kinase receptor, as a potent inhibitor of anoikis and promoter of metastasis (Douma et al 2004). MTDH has been shown to promote anoikis resistance by enhancing autophagy through the protein kinase RNA like ER kinase (PERK)-eIF2α-ATF4-CHOP signaling axis in hepatocellular carcinoma (Zhu et al 2020). Moreover, pancreatic cancer cells with hyperactivated STAT3 signaling were found to be more anoikis-resistant and with higher metastatic potential (Fofaria and Srivastava 2015).…”