Analysis of a novel regulator of hepatocellular carcinoma

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DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is a highly aggressive cancer with no currently available effective treatment. Understanding the molecular mechanism of HCC development and progression is imperative to develop novel, effective and targeted therapies for this lethal disease. Our recent findings reveal that Astrocyte Elevated Gene-1 (AEG-1) plays an important role in HCC pathogenesis. In human HCC samples AEG-1 mRNA and protein were significantly overexpressed compared to normal liver and in a subset of HCC patients AEG-1 gene itself was amplified. In 109 HCC patients, AEG-1 protein was overexpressed in >90% cases and AEG-1 expression level showed significant correlation with the stages and grades of the disease. Forced overexpression of AEG-1 in less aggressive HCC cells resulted in highly aggressive, angiogenic and metastatic tumors in nude mice. Conversely, inhibition of AEG-1 significantly abrogated growth of highly aggressive HCC cells in nude mice. In HCC cells, AEG-1 activated pro-survival signaling pathways such as MEK/ERK, PI3K/Akt, NF-?B and Wnt signaling pathways that are known to contribute to hepatocarcinogenesis and AEG-1 modulated specific genes regulating invasion, angiogenesis, chemoresistance and senescence. Additionally, AEG-1 protected primary human hepatocytes from induction of senescence. These findings strongly indicate that AEG-1 plays an important role in regulating HCC development and progression. AEG-1 is located both on the cell surface and in intracellular compartments including the nucleus. While the cell surface located AEG-1 facilitates metastasis by adhering to the endothelium, our findings indicate that the intracellular AEG-1 might contribute to the initial steps of tumorigenesis, such as immortalization and transformation, by turning on pro-survival signals and modulating gene expression. We have previously shown that AEG-1 functions as a transcriptional co-activator and presently we identify as an AEG-1 interacting partner Staphylococcal Nuclease Domain Containing-1 (SND1) which regulates gene expression by modulating transcription, mRNA splicing, RNA interference and mRNA stability. The long-term objectives of the present proposal are to identify key players regulating HCC pathogenesis and translate that knowledge for developing novel and effective targeted therapies. The immediate objectives of the present proposal are to analyze the role of AEG-1 in hepatocarcinogenesis in a transgenic mouse model; elucidate the role of AEG-1-SND1 interaction in mediating AEG-1 function as well as hepatocarcinogenesis; and establish AEG-1 as a diagnostic and prognostic marker for HCC by analyzing patient-derived HCC samples. Successful completion of the proposed studies will provide in-depth insights into structural and functional realms of AEG-1 thus facilitating development of strategies to block AEG-1 as a potential therapeutic regimen for HCC. PUBLIC HEALTH RELEVANCE: Astrocyte elevated gene-1 (AEG-1) is overexpressed in hepatocellular carcinoma (HCC) patients and plays a key role in regulating hepatocarcinogenesis by turning on pro- survival signals and modulating global gene expression. The proposed studies aim at understanding AEG-1 function by using a transgenic mouse model and analyzing AEG-1 interacting proteins and establishing AEG-1 as a diagnostic and prognostic marker for HCC.