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

Abstract

Astrocyte elevated gene-1 (AEG-1) is a key contributor to hepatocellular carcinoma (HCC) development and progression. To enhance our understanding of the role of AEG-1 in hepatocarcinogenesis, a transgenic mouse with hepatocyte-specific expression of AEG-1 (Alb/AEG1) was developed. Treating Alb/AEG-1, but not Wild type (WT) mice, with N-nitrosodiethylamine (DEN), resulted in multinodular HCC with steatotic features and associated modulation of expression of genes regulating invasion, metastasis, angiogenesis and fatty acid synthesis. Hepatocytes isolated from Alb/AEG-1 mice displayed profound resistance to chemotherapeutics and growth factor deprivation with activation of pro-survival signaling pathways. Alb/AEG-1 hepatocytes also exhibited marked resistance towards senescence, which correlated with abrogation of activation of a DNA damage response. Conditioned media (CM) from Alb/AEG-1 hepatocytes induced marked angiogenesis with elevation in several coagulation factors. Among these factors, AEG-1 facilitated association of Factor XII (FXII) mRNA with polysomes resulting in increased translation. siRNA-mediated knockdown of FXII resulted in profound inhibition of AEG-1-induced angiogenesis. Conclusion We uncover novel aspects of AEG-1 functions, including induction of steatosis, inhibition of senescence and activation of coagulation pathway to augment aggressive hepatocarcinogenesis. The Alb/AEG-1 mouse provides an appropriate model to scrutinize the molecular mechanism of hepatocarcinogenesis and to evaluate the efficacy of novel therapeutic strategies targeting HCC.

Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC)

“…Overexpression of AEG-1 in the poorly aggressive HCC cell line HepG3, which expresses a low level of AEG-1, significantly increases in vitro proliferation, invasion, anchorage-independent growth and chemoresistance, and in vivo tumorigenesis, angiogenesis, and metastasis in nude mice (7, 9 -11). These observations were further corroborated in a transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) that develops highly aggressive metastatic HCC in a diethylnitrosamine-induced HCC model (12,13). Conversely, knockdown of AEG-1 in highly aggressive QGY-7703 cells, expressing high levels of AEG-1, significantly abrogates in vivo tumorigenesis (7,10).…”

The emerging role of astrocyte-elevated gene-1 in hepatocellular carcinoma (Review)

“…Additionally, transgenic mice with hepatocyte-specific expression of AEG-1 (Alb/ AEG-1) were treated with N-nitrosodiethylamine, a hepatocarcinogen. A significant increase in the ratio of liver weight to body weight and the presence of more nodules of different sizes were noted in the Alb/AEG-1 mice when compared to these parameters in the WT mice (49). Based on the above studies, we regard AEG-1 as an accelerator of the growth of HCC.…”

“…Moreover, overexpression of AEG-1 was found to lead to increased production of angiogenic factors, such as vascular endothelial growth factor (VEGF), placental growth factor (PIGF) and fibroblast growth factor-α (FGFα) in human HCC cells, which are essential for angiogenesis and metastasis (16). In addition, Alb/AEG-1 mice treated with N-nitrosodiethylamine, presented with multinodular HCC with steatotic features and associated modulation of expression of genes regulating invasion and metastasis (TSPAN8 and Lcn2) (49). In concludion, AEG-1 promotes the metastasis of HCC by multiple steps, and plays a pivotal role in the poor prognosis of HCC.…”

“…Recent studies have documented that AEG-1 contributes to broadspectrum resistance to various chemotherapeutics including 5-fluorouracil (5-Fu), doxorubicin, paclitaxel, cisplatin and 4-hydroxycyclophosphamide (4-HC) (16,21,(55)(56)(57). Hepatocytes isolated from Alb/AEG-1 mice also displayed profound resistance to chemotherapeutics (49). Furthermore, microarray analysis of HCC revealed that AEG-1 upregulated several genes implicated in chemoresistance including drug-metabolizing enzymes, such as dihydropryimidine dehydrogenase (DPYD), cytochrome P450B6 (CYP2B6) and dyhydrodiol dehydrogenase (ARK1C2), ATP-binding cassette transporter ABCC11/MRP8 and the transcription factor LSF/ TFCP2 (16).…”

Astrocyte elevated gene-1 (AEG-1): a new potential therapeutic target for the treatment of nonalcoholic steatohepatitis (NASH)

“…In a recent article published in Hepatology by Srivastava et al entitled "A novel role of Astrocyte Elevated Gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH)" (4), the investigators discovered that AEG-1 is an important regulator in regulating the development of NASH. They generated a transgenic mouse with hepatocytespecific overexpression of AEG-1 (Alb/AEG-1) and investigated its oncogenic functions (5). Interestingly, they discovered that Alb/AEG-1 mice spontaneously developed NASH, suggesting that AEG-1 prevents the spontaneous development of NASH.…”