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.

Role of MTDH, FOXM1 and microRNAs in Drug Resistance in Hepatocellular Carcinoma

“…MTDH has also been shown to play a critical role in DNA damage response (DDR) in a transgenic mouse model with hepatocyte-specific expression of MTDH (Alb/MTDH) [36,37]. Compared to control hepatocytes, reduced reactive oxygen species (ROS) levels and delayed activation of ATM, ATR, CHK1 and CHK2 have been observed in Alb/MTDH hepatocytes following isolation and culture.…”

“…HCC in both wild-type mice or in Arf(−/−)Rosa26-FOXM1 Tg mice was induced by diethylnitrosamine/phenobarbital. These HCC-bearing mice were then injected daily with the cell-penetrating ARF (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44) peptide inhibitor to pharmacologically reduce FOXM1 activity. After 4 weeks of this treatment, HCC regions displayed reduced tumor cell proliferation and angiogenesis within the HCC region but not in the adjacent normal liver tissue.…”

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

“…AEG-1 is ubiquitously lowly expressed in all normal tissues, with higher expression detected in the skeletal muscle and heart and in endocrine glands such as the thyroid and adrenal gland (22). AEG-1 is markedly upregulated in HCC (16,24), breast (25), gastric (26), gallbladder (27), colorectal (28), prostate (23) and renal (29) cancer, esophageal squamous cell carcinoma (ESSC) (30), non-small cell lung cancer (NSCLC) (31), pancreatic ductal adenocarcinoma (32), tongue carcinoma (33), melanoma (22), glioblastoma multiforme (GBM) (34), acute myeloid leukemia (35), neuroblastoma (36), oligodendroglioma (37) andosteosarcoma (38), cervical (39) and ovarian carcinoma (40).…”

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

“…AEG-1 exerts its function by modulating a variety of signal transduction pathways and altering global gene expression profiles (15). Two particular aspects of AEG-1 function, pertinent to this study, are highlighted here.…”