Astrocyte elevated gene-1 (AEG-1): A key driver of hepatocellular carcinoma (HCC)

Abstract

An array of human cancers, including hepatocellular carcinoma (HCC), overexpress the oncogene Astrocyte elevated gene-1 (AEG-1). It is now firmly established that AEG-1 is a key driver of carcinogenesis, and enhanced expression of AEG-1 is a marker of poor prognosis in cancer patients. In-depth studies have revealed that AEG-1 positively regulates different hallmarks of HCC progression including growth and proliferation, angiogenesis, invasion, migration, metastasis and resistance to therapeutic intervention. By interacting with a plethora of proteins as well as mRNAs, AEG-1 regulates gene expression at transcriptional, post-transcriptional, and translational levels, and modulates numerous pro-tumorigenic and tumor-suppressive signal transduction pathways. Even though extensive research over the last two decades using various in vitro and in vivo models has established the pivotal role of AEG-1 in HCC, effective targeting of AEG-1 as a therapeutic intervention for HCC is yet to be achieved in the clinic. Targeted delivery of AEG-1 small interfering ribonucleic acid (siRNA) has demonstrated desired therapeutic effects in mouse models of HCC. Peptidomimetic inhibitors based on protein-protein interaction studies has also been developed recently. Continuous unraveling of novel mechanisms in the regulation of HCC by AEG-1 will generate valuable knowledge facilitating development of specific AEG-1 inhibitory strategies. The present review describes the current status of AEG-1 in HCC gleaned from patient-focused and bench-top studies as well as transgenic and knockout mouse models. We also address the challenges that need to be overcome and discuss future perspectives on this exciting molecule to transform it from bench to bedside.

Keywords: Astrocyte elevated gene-1; Hepatocellular carcinoma; Metastasis; Mouse models; Targeting strategies.

Fig. 1

Current treatment recommendations in different stages of HCC. The staging system is based on the BCLC algorithm introduced in 1999. The lenvatinib clinical trial did not include patients with 50% or higher occupation of the liver with tumors or invasion of the bile duct or main portal vein. None of the second-line therapies were tested in patients after lenvatinib therapy.

Fig. 2

Cartoon showing important structural features of human AEG-1 mediating its function. Please see text for details. TMD: transmembrane domain; NSL: nuclear localization signal; LHD: lung-homing domain. K⁶³-linked polyubiquitin interaction region is required for interaction with upstream ubiquitinated activators of NF-κB, such as RIP1 and TRAF2. Numbers indicate amino acids (a.a.).

Fig. 3

Schematic presentation of the mechanisms of AEG-1 regulation and AEG-1 downstream events in HCC. For details, please see the main text.

Fig. 4

Mechanisms by which AEG-1 induces NASH. AEG-1 binds to RXR using LXXLL motif which inhibits PPARα and decreases fatty acid β-oxidation. AEG-1 binds to specific mRNAs increasing translation of lipogenic enzymes thus increasing de novo lipogenesis. These two events lead to increased steatosis. AEG-1 activates NF-κB by multiple mechanisms. It binds to p65 subunit of NF-κB and functions as a bridging factor between NF-κB and basal transcription machinery. It interacts with upstream ubiquitinated molecules of NF-κB pathway such as TRAF2 and RIP1. It is directly phosphorylated by IKKβ which is necessary for subsequent IKKβ-mediated phosphorylation of IκBα leading to its proteasomal degradation and translocation of NF-κB to the nucleus. NF-κB activation leads to increased inflammation. Thus AEG-1 increases both steatotic and inflammatory components of NASH. Image created using tools from Biorender.