Astrocyte elevated gene-1 promotes hepatocarcinogenesis: Novel insights from a mouse model†‡

Astrocyte elevated gene-1 (AEG-1), also known as metadherin (MTDH) and lysine-rich CECAM-1 co-isolated protein (LYRIC), is now established as a positive regulator of tumorigenesis (1). Using immunohistochemistry in a large cohort of patient samples, elevated AEG-1 protein expression has been documented in a variety of cancers (1). AEG-1 expression gradually increases with disease progression and displays a negative correlation with patient survival. The AEG-1 gene is located in human chromosome 8q22, which is amplified in breast and liver cancers (2, 3). AEG-1 is a downstream gene in the Ha-Ras signaling pathway that activates PI3K/Akt and leads to transcriptional upregulation of AEG-1 by c-Myc (4). AEG-1 is a target of miRNA-375, a tumor suppressor in diverse cancers (5). Thus AEG-1 expression might be increased by a variety of mechanisms during carcinogenesis. Gain- and loss-of-function studies in diverse cell lines confirm the importance of AEG-1 in the development and progression of cancer. In multiple cancer cell lines that express low levels of AEG-1 and are poorly aggressive, AEG-1 overexpression results in a significant increase in in vitro proliferation, anchorage-independent growth, migration and invasion and in vivo tumorigenesis, metastasis and angiogenesis in nude mice xenograft models (1). As a corollary, RNAi-mediated inhibition of AEG-1 in aggressive cell lines expressing high levels of AEG-1 significantly inhibits aforementioned in vitro and in vivo oncogenic phenotypes. AEG-1 overexpression results in activation of multiple pro-survival signal transduction pathways, and profoundly contributes to chemoresistance and tumor angiogenesis, major hallmarks of aggressive cancers (1). Thus AEG-1 plays a fundamental role in aggressive progression of the carcinogenic process. The molecular mechanism by which AEG-1 induces these profound changes is gradually being clarified. AEG-1 is a 582 amino acids protein with a transmembrane domain and multiple nuclear localization signals (NLS) (1). In cancer cells, AEG-1 is detected in the cytoplasm as well as on the cell membrane and in the nucleus (2). Depending upon location, AEG-1 interacts with different protein complexes regulating diverse functions. AEG-1 interacts with NF-κB and CBP promoting NF-κB-mediated transcription (6) while it interacts with YY1 along with CBP to repress transcription (7). In the cytoplasm, AEG-1 is a component of the RNA-induced silencing complex (RISC) and assists oncomiR-mediated degradation of tumor suppressor mRNAs (8). AEG-1 facilitates translation of specific mRNAs, such as the mRNA for the multidrug resistance gene (MDR1), which contributes to chemoresistance (9). The membrane-located AEG-1 promotes interaction of cancer cells with lung endothelium thus augmenting metastasis (3). The identification of the diverse interacting partners indicates that AEG-1 may be a scaffold protein mediating formation of multi-protein complexes in different intracellular compartments. AEG-1 plays an important role in hepatocarcinogenesis (2). AEG-1 mRNA and protein overexpression as well as amplification of AEG-1 gene was detected in a large percentage of Hepatocellular carcinoma (HCC) patients (2). To better comprehend the role of AEG-1 in hepatocarcinogenesis and to decipher the underlying molecular mechanism(s) in an in vivo context, we have generated a transgenic mouse with hepatocyte-specific expression of AEG-1 (Alb/AEG-1). We document that compared to wild-type (WT) mice, the hepatocarcinogenic process is significantly amplified in Alb/AEG-1 mice. We unravel novel aspects of AEG-1, including induction of steatosis, protection from senescence and activation of coagulation pathways, which contribute to its tumor promoting functions. This is the first study analyzing AEG-1 function in vivo and Alb/AEG-1 mouse provides a useful model to further understand the hepatocarcinogenic process and evaluate emerging novel therapies for this invariably fatal disease.