AEG-1/MTDH/LYRIC in liver cancer

Abstract

Hepatocellular carcinoma (HCC) is a highly virulent malignancy with diverse etiology. Identification of a common mediator of aggressive progression of HCC would be extremely beneficial not only for diagnostic/prognostic purposes but also for developing targeted therapies. AEG-1/MTDH/LYRIC gene is amplified in human HCC patients, and overexpression of AEG-1/MTDH/LYRIC has been identified in a high percentage of both hepatitis B virus and hepatitis C virus positive HCC cases, suggesting its key role in regulating hepatocarcinogenesis. Important insights into the molecular mechanisms mediating oncogenic properties of AEG-1/MTDH/LYRIC, especially regulating chemoresistance, angiogenesis, and metastasis, have been obtained from studies using HCC model. Additionally, analysis of HCC model has facilitated the identification of AEG-1/MTDH/LYRIC downstream genes and interacting proteins, thereby unraveling novel players regulating HCC development and progression leading to the development of novel interventional strategies. Characterization of a hepatocyte-specific AEG-1/MTDH/LYRIC transgenic mouse (Alb/AEG-1) has revealed novel aspects of AEG-1/MTDH/LYRIC function in in vivo contexts. Combination of AEG-1/MTDH/LYRIC inhibition and chemotherapy has documented significant efficacy in abrogating human HCC xenografts in nude mice indicating the need for developing effective AEG-1/MTDH/LYRIC inhibition strategies to obtain objective response and survival benefits in terminal HCC patients.

Keywords: AEG-1; Hepatocellular carcinoma; LSF; SND1; Transgenic mouse model.

Figure 7.1

AEG-1/MTDH/LYRIC promotes hepatocarcinogenesis. In HCC genomic amplification (8q22 gain), downregulation of miRNA-375 and stabilization of AEG-1/MTDH/LYRIC protein by monoubiquitination have been identified as potential mechanisms of AEG-1/MTDH/LYRIC overexpression. Microarray analysis identified AEG-1/MTDH/LYRIC downstream genes (left box). AEG-1/MTDH/LYRIC increases LEF-1 with resultant activation of β-catenin pathway. AEG-1/MTDH/LYRIC induces the transcription factor late SV40 factor (LSF) which transcriptionally regulates osteopontin (OPN), matrix metalloproteinase-9 (MMP9), and thymidylate synthase (TS). AEG-1/MTDH/LYRIC downregulates insulin-like growth factor-binding protein-7 (IGFBP7), an inducer of senescence. Right box shows AEG-1/MTDH/LYRIC-interacting proteins identified in HCC cells. AEG-1/MTDH/LYRIC interacts with staphylococcal nuclease domain containing-1 (SND1) and together these two proteins increase RNA-induced silencing complex (RISC) activity that facilitates oncogenic miRNA-mediated degradation of tumor suppressor mRNAs. AEG-1/MTDH/LYRIC interacts with the translational machinery that potentially facilitates association of specific mRNAs, such as multidrug resistance 1 (MDR1) and coagulation factor XII (FXII), to polysome increasing their translation. The net effects of these events are augmentation of hallmarks of cancer.