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1.  Astrocyte Elevated Gene-1 (AEG-1): a novel target for human glioma therapy 
Molecular cancer therapeutics  2010;9(1):79-88.
Malignant gliomas including glioblastoma multiforme (GBM) and anaplastic astrocytomas are the most common primary brain tumors. Despite multimodal treatment including surgery, chemotherapy and radiation, median survival for patients with GBMs is only 12–15 months. Identifying molecules critical for glioma progression is crucial for devising effective targeted therapy. In the present study, we investigated the potential contribution of Astrocyte Elevated Gene-1 (AEG-1) in gliomagenesis and explored the possibility of AEG-1 as a therapeutic target for malignant glioma. We analyzed the expression levels of AEG-1 in 9 normal brain tissues and 98 brain tumor patient samples by Western blot analysis and immunohistochemistry. AEG-1 expression was significantly elevated in > 90% of diverse human brain tumor samples including GBMs and astrocytic tumors, and also in human glioma cell lines as compared to normal brain tissues and normal astrocytes. Knockdown of AEG-1 by siRNA inhibited cell viability, cloning efficiency, invasive ability of U87 human glioma cells and 9L rat gliosarcoma cells. We also found that matrix metalloproteases (MMP-2 and MMP-9) are involved in AEG-1-mediated invasion of glioma cells. In an orthotopic nude mouse brain tumor model using primary human GBM12 tumor cells, AEG-1 siRNA significantly suppressed glioma cell growth in vivo. Taken together these provocative results indicate that AEG-1 may play a crucial role in the pathogenesis of glioma and that AEG-1 could represent a viable potential target for malignant glioma therapy.
doi:10.1158/1535-7163.MCT-09-0752
PMCID: PMC3165052  PMID: 20053777
AEG-1; brain tumor; glioma; invasion; angiogenesis
2.  Oncogene AEG-1 promotes glioma-induced neurodegeneration by increasing glutamate excitotoxicity 
Cancer research  2011;71(20):6514-6523.
Aggressive tumor growth, diffuse tissue invasion and neurodegeneration are hallmarks of malignant glioma. Although glutamate excitotoxicity is considered to play a key role in glioma-induced neurodegeneration, the mechanism(s) controlling this process is poorly understood. AEG-1 is an oncogene overexpressed in multiple types of human cancers including >90% of brain tumors. AEG-1 also promotes gliomagenesis particularly in the context of tumor growth and invasion, two primary characteristics of glioma. In the present study, we investigated the contribution of AEG-1 to glioma-induced neurodegeneration. Pearson correlation coefficient analysis in normal brain tissues and glioma patient samples indicated a strong negative correlation between expression of AEG-1 and a primary glutamate transporter of astrocytes EAAT2. Gain and loss of function studies in normal primary human fetal astrocytes and T98G glioblastoma multiforme cells revealed that AEG-1 repressed EAAT2 expression at a transcriptional level by inducing YY1 activity to inhibit CBP function as a coactivator on the EAAT2 promoter. In addition, AEG-1-mediated EAAT2 repression caused a reduction of glutamate uptake by glial cells, resulting in induction of neuronal cell death. These findings were also confirmed in glioma patient samples demonstrating that AEG-1 expression negatively correlated with NeuN expression. Taken together, our findings suggest that AEG-1 contributes to glioma-induced neurodegeneration, a hallmark of this fatal tumor, through regulation of EAAT2 expression.
doi:10.1158/0008-5472.CAN-11-0782
PMCID: PMC3193553  PMID: 21852380
AEG-1; glioma; EAAT2; glutamate; glioma-induced neurodegeneration
3.  Expression patterns of astrocyte elevated gene-1 (AEG-1) during development of the mouse embryo 
Gene expression patterns : GEP  2010;10(7-8):361-367.
Expression of astrocyte elevated gene-1 (AEG-1) is elevated in multiple human cancers including brain tumors, neuroblastomas, melanomas, breast cancers, non-small cell lung cancers, liver cancers, prostate cancers, and esophageal cancers. This gene plays crucial roles in tumor cell growth, invasion, angiogenesis and progression to metastasis. In addition, over-expression of AEG-1 protects primary and transformed cells from apoptosis-inducing signals by activating PI3K-Akt signaling pathways. These results suggest that AEG-1 is intimately involved in tumorigenesis and may serve as a potential therapeutic target for various human cancers. However, the normal physiological functions of AEG-1 require clarification. We presently analyzed the expression pattern of AEG-1 during mouse development. AEG-1 was expressed in mid-to-hindbrain, fronto-nasal processes, limbs, and pharyngeal arches in the early developmental period from E8.5 to E9.5. In addition, at stages of E12.5-E18.5 AEG-1 was localized in the brain, and olfactory and skeletal systems suggesting a role in neurogenesis, as well as in skin, including hair follicles, and in the liver, which are organ sites in which AEG-1 has been implicated in tumor development and progression. AEG-1 co-localized with Ki-67, indicating a role in cell proliferation, as previously revealed in tumorigenesis. Taken together, these results suggest that AEG-1 may play a prominent role during normal mouse development in the context of cell proliferation as well as differentiation, and that temporal regulation of AEG-1 expression may be required during specific stages and in specific tissues during development.
doi:10.1016/j.gep.2010.08.004
PMCID: PMC3165053  PMID: 20736086
AEG-1; development; mouse embryo; cell proliferation; cancer
4.  Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression 
Hepatocellular carcinoma (HCC) is a highly aggressive vascular cancer characterized by diverse etiology, activation of multiple signal transduction pathways, and various gene mutations. Here, we have determined a specific role for astrocyte elevated gene-1 (AEG1) in HCC pathogenesis. Expression of AEG1 was extremely low in human hepatocytes, but its levels were significantly increased in human HCC. Stable overexpression of AEG1 converted nontumorigenic human HCC cells into highly aggressive vascular tumors, and inhibition of AEG1 abrogated tumorigenesis by aggressive HCC cells in a xenograft model of nude mice. In human HCC, AEG1 overexpression was associated with elevated copy numbers. Microarray analysis revealed that AEG1 modulated the expression of genes associated with invasion, metastasis, chemoresistance, angiogenesis, and senescence. AEG1 also was found to activate Wnt/β-catenin signaling via ERK42/44 activation and upregulated lymphoid-enhancing factor 1/T cell factor 1 (LEF1/TCF1), the ultimate executor of the Wnt pathway, important for HCC progression. Inhibition studies further demonstrated that activation of Wnt signaling played a key role in mediating AEG1 function. AEG1 also activated the NF-κB pathway, which may play a role in the chronic inflammatory changes preceding HCC development. These data indicate that AEG1 plays a central role in regulating diverse aspects of HCC pathogenesis. Targeted inhibition of AEG1 might lead to the shutdown of key elemental characteristics of HCC and could lead to an effective therapeutic strategy for HCC.
doi:10.1172/JCI36460
PMCID: PMC2648696  PMID: 19221438
5.  Knockdown of astrocyte elevated gene-1 inhibits proliferation and enhancing chemo-sensitivity to cisplatin or doxorubicin in neuroblastoma cells 
Background
Astrocyte elevated gene-1 (AEG-1) was originally characterized as a HIV-1-inducible gene in primary human fetal astrocyte. Recent studies highlight a potential role of AEG-1 in promoting tumor progression and metastasis. The aim of this study was to investigate if AEG-1 serves as a potential therapeutic target of human neuroblastoma.
Methods
We employed RNA interference to reduce AEG-1 expression in human neuroblastoma cell lines and analyzed their phenotypic changes.
Results
We found that the knockdown of AEG-1 expression in human neuroblastoma cells significantly inhibited cell proliferation and apoptosis. The specific downregulation induced cell arrest in the G0/G1 phase of cell cycle. In the present study, we also observed a significant enhancement of chemo-sensitivity to cisplatin and doxorubicin by knockdown of AEG-1.
Conclusion
Our study suggests that overexpressed AEG-1 enhance the tumorogenic properties of neuroblastoma cells. The inhibition of AEG-1 expression could be a new adjuvant therapy for neuroblastoma.
doi:10.1186/1756-9966-28-19
PMCID: PMC2654547  PMID: 19216799
6.  The multifaceted role of MTDH/AEG-1 in cancer progression 
Cancer is the result of the progressive acquisition of multiple malignant traits through the accumulation of genetic or epigenetic alterations. Recent studies have established a functional role of MTDH (Metadherin)/AEG-1 (Astrocyte Elevated Gene 1) in several crucial aspects of tumor progression, including transformation, evasion of apoptosis, invasion, metastasis and chemoresistance. Overexpression of MTDH/AEG-1 is frequently observed in melanoma, glioma, neuroblastoma, and carcinomas of breast, prostate, liver and esophagus and is correlated with poor clinical outcomes. MTDH/AEG-1 functions as a downstream mediator of the transforming activity of oncogenic Ha-Ras and c-Myc. Furthermore, MTDH/AEG-1 overexpression activates the PI3K/Akt, NFκB, and Wnt/β-catenin signaling pathways to stimulate proliferation, invasion, cell survival and chemoresistance. The lung-homing domain of MTDH/AEG-1 also mediates the adhesion of tumor cells to the vasculature of distant organs and promotes metastasis. These findings suggest that therapeutic targeting of MTDH/AEG-1 may simultaneously suppress tumor growth, block metastasis and enhance the efficacy of chemotherapeutic treatments.
doi:10.1158/1078-0432.CCR-09-0049
PMCID: PMC2747034  PMID: 19723648
7.  Progress of cancer research on astrocyte elevated gene-1/Metadherin (Review) 
Oncology Letters  2014;8(2):493-501.
Tumor development is initiated by an accumulation of numerous genetic and epigenetic alterations that promote tumor initiation, invasion and metastasis. Astrocyte elevated gene-1 [AEG-1; also known as Metadherin (MTDH) and Lysine-rich CEACAM1 co-isolated (LYRIC)] has emerged in recent years as a potentially crucial mediator of tumor malignancy, and a key converging point of a complex network of oncogenic signaling pathways. AEG-1/MTDH has a multifunctional role in tumor development that has been found to be involved in the following signaling cascades: i) The Ha-Ras and PI3K/Akt pathways; ii) the nuclear factor-κB signaling pathway; iii) the ERK/mitogen-activated protein kinase and Wnt/β-catenin pathways; and iv) the Aurora-A kinase signaling pathway. Studies have established that AEG-1/MTDH is crucial in tumor progression, including transformation, the evasion of apoptosis, invasion, angiogenesis and metastasis. In addition, recent clinical studies have convincingly associated AEG-1/MTDH with tumor progression and poor prognosis in a number of cancer types, including hepatocellular, esophageal squamous cell, gallbladder and renal cell carcinomas, breast, non-small cell lung, prostate, gastric and colorectal cancers, and glioma, melanoma, neuroblastoma and osteosarcoma. AEG-1/MTDH may be used as a biomarker to identify subgroups of patients who require more intensive treatments and who are likely to benefit from AEG-1/MTDH-targeted therapies. The therapeutic targeting of AEG-1/MTDH may simultaneously block metastasis, suppress tumor growth and enhance the efficacy of chemotherapeutic treatments.
doi:10.3892/ol.2014.2231
PMCID: PMC4081432  PMID: 25009642
astrocyte elevated gene-1; metadherin; neoplasms; metastasis; chemoresistance
8.  Astrocyte elevated gene-1 and breast cancer (Review) 
Oncology Letters  2011;2(3):399-405.
Astrocyte elevated gene-1 (AEG-1), also known as MTDH and Lyric, is a novel gene that was first cloned by subtraction hybridization in 2002 and has recently been shown to play a role as a crucial oncogene that acts as a promoter of tumor malignancy. Overexpression and inhibition studies both in in vitro and in vivo models have partly shown the oncogenic roles of AEG-1 in a number of crucial aspects of tumor development and progression, including transformation, evasion of apoptosis, proliferation, cell survival, migration, invasion, metastasis, angiogenesis and chemoresistance through the activation of numerous signaling pathways, such as the nuclear factor κB, PI3K/AKT, Wnt/β-catenin and mitogen-activated protein kinase signaling pathways. However the potential roles of AEG-1, particularly in specific organs or tissues, such as breast tissue, require further clarification. Studies have found that in normal human breast tissue, AEG-1 is always expressed at low levels or is absent, while it is widely overexpressed in many breast cancer cell lines and breast tumors. The present review evaluates the current literature with regards to AEG-1 relative to breast cancer development and progression and highlights new perspectives relative to this molecule, indicating its potential to become a new target for the clinical treatment of breast cancer.
doi:10.3892/ol.2011.268
PMCID: PMC3410483  PMID: 22866094
astrocyte elevated gene-1; metastasis; angiogenesis; prognosis; breast cancer
9.  AEG-1/MTDH/LYRIC: Signaling Pathways, Downstream Genes, Interacting Proteins, and Regulation of Tumor Angiogenesis 
Advances in cancer research  2013;120:75-111.
Astrocyte elevated gene-1 (AEG-1), also known as metadherin (MTDH) and lysine-rich CEACAM1 coisolated (LYRIC), was initially cloned in 2002. AEG-1/MTDH/LYRIC has emerged as an important oncogene that is overexpressed in multiple types of human cancer. Expanded research on AEG-1/MTDH/LYRIC has established a functional role of this molecule in several crucial aspects of tumor progression, including transformation, proliferation, cell survival, evasion of apoptosis, migration and invasion, metastasis, angiogenesis, and chemoresistance. The multifunctional role of AEG-1/MTDH/LYRIC in tumor development and progression is associated with a number of signaling cascades, and recent studies identified several important interacting partners of AEG-1/MTDH/LYRIC in regulating cancer promotion and other biological functions. This review evaluates the current literature on AEG-1/MTDH/LYRIC function relative to signaling changes, interacting partners, and angiogenesis and highlights new perspectives of this molecule, indicating its potential as a significant target for the clinical treatment of various cancers and other diseases.
doi:10.1016/B978-0-12-401676-7.00003-6
PMCID: PMC3928810  PMID: 23889988
10.  Astrocyte Elevated Gene-1 (AEG-1): a multifunctional regulator of normal and abnormal physiology 
Pharmacology & therapeutics  2011;130(1):1-8.
Since its initial identification and cloning in 2002, Astrocyte Elevated Gene-1 (AEG-1), also known as metadherin (MTDH), 3D3 and LYsine-RIch CEACAM1 co-isolated (LYRIC), has emerged as an important oncogene that is overexpressed in all cancers analyzed so far. Examination of a large cohort of patient samples representing diverse cancer indications has revealed progressive increase in AEG-1 expression with stages and grades of the disease and an inverse relationship between AEG-1 expression level and patient prognosis. AEG-1 functions as a bona fide oncogene by promoting transformation. In addition, it plays a significant role in invasion, metastasis, angiogenesis and chemoresistance, all important hallmarks of an aggressive cancer. AEG-1 is also implicated in diverse physiological and pathological processes, such as development, inflammation, neurodegeneration, migraine and Huntington disease. AEG-1 is a highly basic protein with a transmembrane domain and multiple nuclear localization signals and it is present in the cell membrane, cytoplasm, nucleus, nucleolus and endoplasmic reticulum. In each location, AEG-1 interacts with specific proteins thereby modulating diverse intracellular processes the combination of which contributes to its pleiotrophic properties. The present review provides a snapshot of the current literature along with future perspectives on this unique molecule.
doi:10.1016/j.pharmthera.2011.01.008
PMCID: PMC3043119  PMID: 21256156
Astrocyte elevated gene-1 (AEG-1); Oncogene; Metastasis; Chemoresistance; Angiogenesis; Neurodegeneration
11.  High expression of astrocyte elevated gene-1 (AEG-1) is associated with progression of cervical intraepithelial neoplasia and unfavorable prognosis in cervical cancer 
Background
Astrocyte elevated gene-1(AEG-1) plays an important role in the development and progression of certain types of human cancers. However, the expression dynamics of AEG-1 in cervical cancer and its clinical/prognostic significance are unclear.
Method
In present study, the methods of tissue microarrays (TMA) and immunohistochemistry (IHC) were utilized to investigate AEG-1 expression in cervical intraepithelial neoplasia (CIN) and cervical cancer. Receiver operating characteristic (ROC) curve analysis, χ2 test, Kaplan-Meier plots, and multivariate Cox regression analysis were used to analyze the data.
Results
The expression level of AEG-1 was increased from CIN I to CIN III. High expression of AEG-1 could be observed in 61.1% (55/90) of cervical cancer. Moreover, high expression of AEG-1 correlated with tumor size and lymph node metastasis (all P <0.05). More importantly, high expression of AEG-1 was closely associated with cervical cancer patient shortened survival time as evidenced by univariate and multivariate analysis (P <0.05).
Conclusions
Our data suggest for the first time that high expression of AEG-1 is associated significantly with progression of cervical cancer. AEG-1 overexpression, as examined by IHC, has the potential to be used as an immunomarker to predict prognosis of cervical cancer patients.
doi:10.1186/1477-7819-11-297
PMCID: PMC3866971  PMID: 24256614
AEG-1; Cervical cancer; Tissue microarrays; Prognosis
12.  Astrocyte elevated gene-1 regulates osteosarcoma cell invasion and chemoresistance via endothelin-1/endothelin A receptor signaling 
Oncology Letters  2012;5(2):505-510.
Astrocyte elevated gene-1 (AEG-1) and endothelin-1 (ET-1)/endothelin A receptor (ETAR) signaling have been demonstrated to be important in osteosarcoma (OS) progression. In the present study, we explored the interaction between AEG-1 and ET-1/ETAR signaling in OS cells, and investigated the mechanism(s) through which the functional interaction may impact OS cell invasion and chemoresistance. Overexpression and knockdown of AEG-1 were performed in Saos-2 and MG-63 OS cells, respectively. Overexpression of AEG-1 in Saos-2 cells significantly increased ET-1 expression (at both the mRNA and protein levels), cell invasion, MMP-2 expression and cell survival against cisplatin. These effects were eradicated using a selective phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, or a selective ETAR inhibitor, BQ123. Knockdown of AEG-1 in MG-63 cells significantly decreased ET-1 expression (at both the mRNA and protein levels), cell invasion, MMP-2 expression and cell survival against cisplatin. Exogenous ET-1 restored cell invasion and MMP-2 expression levels in MG-63 cells, in which AEG-1 had been knocked down, in the presence of LY294002, but not in the presence of BQ123. However, exogenous ET-1 only partially rescued cell survival against cisplatin-induced apoptosis in the presence of LY294002, in cells in which AEG-1 had been knocked down. In conclusion, we have demonstrated that AEG-1 regulates ET-1 expression at the transcriptional level in a PI3K-dependent manner in OS cells. Downstream of PI3K, ET-1/ETAR signaling primarily mediates the promoting effect of AEG-1 on OS cell invasion, likely through the upregulation of MMP-2 expression, thus, ET-1/ETAR signaling partially, but significantly, mediates the AEG-1-induced chemoresistance in OS cells. To the best of our knowledge, this study has provided the first evidence of a functional association between AEG-1 and ET-1/ETAR signaling in OS cells, which adds novel insights into the molecular mechanism of OS metastasis and chemoresistance.
doi:10.3892/ol.2012.1056
PMCID: PMC3573026  PMID: 23420812
astrocyte elevated gene-1; endothelin-1; endothelin A cell invasion; chemoresistance; osteosarcoma; phosphatidylinositol 3-kinase; receptor
13.  AEG-1/MTDH/LYRIC, the Beginning: Initial Cloning, Structure, Expression Profile, and Regulation of Expression 
Since its initial identification as a HIV-1-inducible gene in 2002, astrocyte elevated gene-1 (AEG-1), subsequently cloned as metadherin (MTDH) and lysine-rich CEACAM1 coisolated (LYRIC), has emerged over the past 10 years as an important oncogene providing a valuable prognostic marker in patients with various cancers. Recent studies demonstrate that AEG-1/MTDH/LYRIC is a pleiotropic protein that can localize in the cell membrane, cytoplasm, endoplasmic reticulum (ER), nucleus, and nucleolus, and contributes to diverse signaling pathways such as PI3K–AKT, NF-κB, MAPK, and Wnt. In addition to tumorigenesis, this multifunctional protein is implicated in various physiological and pathological processes including development, neurodegeneration, and inflammation. The present review focuses on the discovery of AEG-1/MTDH/LYRIC and conceptualizes areas of future direction for this intriguing gene. We begin by describing how AEG-1, MTDH, and LYRIC were initially identified by different research groups and then discuss AEG-1 structure, functions, localization, and evolution. We conclude with a discussion of the expression profile of AEG-1/MTDH/LYRIC in the context of cancer, neurological disorders, inflammation, and embryogenesis, and discuss how AEG-1/MTDH/LYRIC is regulated. This introductory discussion of AEG-1/MTDH/LYRIC will serve as the basis for the detailed discussions in other chapters of the unique properties of this intriguing molecule.
doi:10.1016/B978-0-12-401676-7.00001-2
PMCID: PMC3930353  PMID: 23889986
14.  AEG-1 expression correlates with CD133 and PPP6c levels in human glioma tissues 
Journal of Biomedical Research  2014;28(5):388-395.
Abstract
Astrocyte elevated gene-1 (AEG-1) is associated with tumor genesis and progression in a variety of human cancers. This study aimed to explore the significance of AEG-1 in glioma and investigate whether it correlated with radioresistance of glioma cells. Immunohistochemical staining showed that the intensity of AEG-1, CD133 and PPP6c protein expression in glioma tissues increased significantly, mainly in the cytoplasm. The expression rate of AEG-1, CD133 and PPP6c were 85.9% (67/78), 60.3% (47/78) and 65.8% (51/78), respectively. AEG-1 expression was correlated with age (r = 0.227, P = 0.045), clinical stage (r = 0.491, P<0.001) and clinical grade (r = 0.450, P<0.001). No correlation was found between AEG-1 expression and other clinicopathologic parameters (P>0.05). The expression of AEG-1 was positively correlated with the expression of CD133 (r = 0.240, P  =  0.035) and PPP6c (r =  0.250, P  =  0.027). In addition, retrieved data on TCGA implied co-occurrence of genomic alterations of AEG-1 and PPP6c in glioblastoma. Our findings indicate that AEG-1 is positively correlated with CD133 and AEG-1 expression. It may play an important role in the progression of glioma and may serve as potential novel marker of chemoresistance and radioresistance.
doi:10.7555/JBR.28.20140015
PMCID: PMC4197390  PMID: 25332711
glioma; AEG-1; immunohistochemistry; radioresistance
15.  Astrocyte elevated gene-1 (AEG-1) is a marker for aggressive salivary gland carcinoma 
Background
Astrocyte elevated gene-1 (AEG-1) is associated with tumorigenesis and progression in diverse human cancers. The present study was aimed to investigate the clinical and prognostic significance of AEG-1 in salivary gland carcinomas (SGC).
Methods
Real-time PCR and western blot analyses were employed to examine AEG-1 expression in two normal salivary gland tissues, eight SGC tissues of various clinical stages, and five pairs of primary SGC and adjacent salivary gland tissues from the same patient. Immunohistochemistry (IHC) was performed to examine AEG-1 protein expression in paraffin-embedded tissues from 141 SGC patients. Statistical analyses was applies to evaluate the diagnostic value and associations of AEG-1 expression with clinical parameters.
Results
AEG-1 expression was evidently up-regulated in SGC tissues compared with that in the normal salivary gland tissues and in matched adjacent salivary gland tissues. AEG-1 protein level was positively correlated with clinical stage (P < 0.001), T classification (P = 0.008), N classification (P = 0.008) and M classifications (P = 0.006). Patients with higher AEG-1 expression had shorter overall survival time, whereas those with lower tumor AEG-1 expression had longer survival time.
Conclusions
Our results suggest that AEG-1 expression is associated with SGC progression and may represent a novel and valuable predictor for prognostic evaluation of SGC patients.
doi:10.1186/1479-5876-9-205
PMCID: PMC3286424  PMID: 22133054
AEG-1; Biomarker; Prognosis; Salivary gland carcinomas
16.  Molecular mechanism of chemoresistance by Astrocyte Elevated Gene-1 (AEG-1) 
Cancer research  2010;70(8):3249-3258.
Our recent findings demonstrate that Astrocyte Elevated Gene-1 (AEG-1) is overexpressed in >90% of human hepatocellular carcinoma (HCC) samples and AEG-1 plays a central role in regulating development and progression of HCC. In the present manuscript, we elucidate a molecular mechanism of AEG-1-induced chemoresistance, an important characteristic of aggressive cancers. AEG-1 increases the expression of multidrug resistance gene 1 (MDR1) protein resulting in increased efflux and decreased accumulation of doxorubicin (DOX) promoting DOX-resistance. Suppression of MDR1, by siRNA or by chemical reagents, or inhibition of AEG-1 or a combination of both genes significantly increases in vitro sensitivity to DOX. In nude mice xenograft studies, a lentivirus expressing AEG-1 shRNA, in combination with DOX, profoundly inhibited growth of aggressive human HCC cells compared to either agent alone. We document that although AEG-1 does not affect MDR1 gene transcription, it facilitates association of MDR1 mRNA to polysomes resulting in increased translation and AEG-1 also inhibits ubiquitination and subsequent proteasome-mediated degradation of MDR1 protein. This study is the first documentation of a unique aspect of AEG-1 function, i.e., translational and post-translational regulation of proteins. Inhibition of AEG-1 might provide a means of more effectively using chemotherapy to treat HCC, which displays inherent chemoresistance with aggressive pathology.
doi:10.1158/0008-5472.CAN-09-4009
PMCID: PMC2855753  PMID: 20388796
Astrocyte Elevated Gene-1 (AEG-1); doxorubicin; Multidrug resistance gene-1 (MDR1); translation; nude mice
17.  Astrocyte elevated gene-1 (AEG-1): far more than just a gene regulated in astrocytes 
Cancer research  2009;69(22):8529-8535.
Since its original cloning by subtraction hybridization in 2002, it is now evident that Astrocyte elevated gene-1 (AEG-1) is a key contributor to the carcinogenic process in diverse organs. AEG-1 protein expression is elevated in advanced stages of many cancers, which correlates with poor survival. In specific cancers, such as breast and liver cancer, the AEG-1 gene itself is amplified further supporting a seminal role in tumorigenesis. Overexpression and inhibition studies both in in vitro and in in vivo models reveal the importance of AEG-1 in regulating multiple physiologically and pathologically relevant processes including proliferation, invasion, metastasis and gene expression. AEG-1 is a single-pass transmembrane protein with multiple nuclear localization signals and no known domains or motifs. Although pertinent roles of AEG-1 in the carcinogenic process are established, its potential function (promotion of metastasis only versus functioning as a bona fide oncogene) as well as localization (cell surface versus nucleus) remain areas requiring further clarification. The present review critically evaluates what is currently known about AEG-1 and provides new perspectives relative to this intriguing molecule that may provide a rational target for intervening in the cancer phenotype.
doi:10.1158/0008-5472.CAN-09-1846
PMCID: PMC2782420  PMID: 19903854
18.  AEG-1/MTDH/LYRIC in Liver Cancer 
Advances in cancer research  2013;120:193-221.
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.
doi:10.1016/B978-0-12-401676-7.00007-3
PMCID: PMC3924581  PMID: 23889992
19.  Astrocyte elevated gene-1 regulates astrocyte responses to neural injury: implications for reactive astrogliosis and neurodegeneration 
Background
Reactive astrogliosis is a ubiquitous but poorly understood hallmark of central nervous system pathologies such as trauma and neurodegenerative diseases. In vitro and in vivo studies have identified proinflammatory cytokines and chemokines as mediators of astrogliosis during injury and disease; however, the molecular mechanism remains unclear. In this study, we identify astrocyte elevated gene-1 (AEG-1), a human immunodeficiency virus 1 or tumor necrosis factor α-inducible oncogene, as a novel modulator of reactive astrogliosis. AEG-1 has engendered tremendous interest in the field of cancer research as a therapeutic target for aggressive tumors. However, little is known of its role in astrocytes and astrocyte-mediated diseases. Based on its oncogenic role in several cancers, here we investigate the AEG-1-mediated regulation of astrocyte migration and proliferation during reactive astrogliosis.
Methods
An in vivo brain injury mouse model was utilized to show AEG-1 induction following reactive astrogliosis. In vitro wound healing and cell migration assays following AEG-1 knockdown were performed to analyze the role of AEG-1 in astrocyte migration. AEG-1-mediated regulation of astrocyte proliferation was assayed by quantifying the levels of cell proliferation markers, Ki67 and proliferation cell nuclear antigen, using immunocytochemistry. Confocal microscopy was used to evaluate nucleolar localization of AEG-1 in cultured astrocytes following injury.
Results
The in vivo mouse model for brain injury showed reactive astrocytes with increased glial fibrillary acidic protein and AEG-1 colocalization at the wound site. AEG-1 knockdown in cultured human astrocytes significantly reduced astrocyte migration into the wound site and cell proliferation. Confocal analysis showed colocalization of AEG-1 to the nucleolus of injured cultured human astrocytes.
Conclusions
The present findings report for the first time the novel role of AEG-1 in mediating reactive astrogliosis and in regulating astrocyte responses to injury. We also report the nucleolar localization of AEG-1 in human astrocytes in response to injury. Future studies may be directed towards elucidating the molecular mechanism of AEG-1 action in astrocytes during reactive astrogliosis.
doi:10.1186/1742-2094-9-195
PMCID: PMC3488579  PMID: 22884085
AEG-1; Astrocyte; HIV-1; Reactive astrogliosis
20.  Astrocyte elevated gene 1: biological functions and molecular mechanism in cancer and beyond 
Cell & Bioscience  2011;1:36.
Since its discovery, nearly one decade of research on astrocyte elevated gene 1 (AEG-1) has witnessed expanding knowledge of this molecule, ranging from its role in cancer biology to molecular mechanisms underlying the biological functions. As a multifunctional oncoprotein, AEG-1 has been shown to overexpress in multiple types of human cancer, and the elevation of AEG-1 in tumor cells leads to enhanced phenotypes characteristic of malignant aggressiveness, including increased abilities to proliferate robustly, to invade surrounding tissues, to migrate, to induce neovascularization, and to enhance chemoresistance. The multifunctional role of AEG-1 in tumor development and progression has been found to be associated with several signaling cascades, namely, 1) activation of NF-kappa B, partially through direct interaction with p65; 2) PI3K/AKT signaling triggered by AEG-1 indirectly; 3) enhancement of the transcriptional activity of beta-catenin by indirect activation of MAPK and induction of LEF1; 4) regulation of mi/siRNA-mediated gene silencing by interacting with SND1; and 5) promotion of protective autophagy; in addition to possibly unknown mechanisms. Elevated AEG-1 expression is seen in nearly all tumor types, and in most cases AEG-1 positively correlates with tumor progression and poorer patient survival. Taken together, AEG-1 might represent a potential prognostic biomarker and therapeutic target.
doi:10.1186/2045-3701-1-36
PMCID: PMC3221637  PMID: 22060137
21.  Expression of astrocyte elevated gene-1 closely correlates with the angiogenesis of gastric cancer 
Oncology Letters  2014;7(5):1447-1454.
Previous studies have demonstrated that astrocyte elevated gene-1 (AEG-1) is overexpressed in several cancer types and that its upregulation may promote cell proliferation, cell transformation and tumor progression. The present study investigated the expression and prognostic value of AEG-1 in primary gastric cancer (GC) as well as its role in angiogenesis. The results obtained from real-time reverse transcription polymerase chain reaction and western blotting revealed the upregulation of AEG-1 mRNA (P=0.007) and protein expression (P<0.001) in the majority of cancerous tissues compared with matched adjacent non-cancerous gastric tissues. To further investigate the clinicopathological and prognostic roles of AEG-1, immunohistochemical analysis of 216 GC tissue blocks was performed. The results showed that high AEG-1 expression closely correlated with differentiation degree (P<0.001 ), T stage (P<0.001), N stage (P=0.003) and M stage (P=0.013). Consistent with the abovementioned results, AEG-1 upregulation was also found to significantly correlate with poor survival in GC patients (P<0.001). Furthermore, carcinomas with elevated AEG-1 expression demonstrated high vascular endothelial growth factor (VEGF) expression and microvessel density, which was labeled by cluster of differentiation 34. In addition, an AEG-1 siRNA assay in MGC-803 cells showed that the AEG-1 gene may promote VEGF and hypoxia-inducible factor-1α protein and mRNA expression. The results of the current study indicated that AEG-1 may serve as a valuable prognostic marker for GC and may be involved in regulating tumor angiogenesis.
doi:10.3892/ol.2014.1950
PMCID: PMC3997719  PMID: 24765154
astrocyte elevated gene-1; gastric cancer; angiogenesis; vascular endothelial growth factor; hypoxia-inducible factor-1α
22.  Astrocyte-elevated gene-1 (AEG-1) induction by hypoxia and glucose deprivation in glioblastoma 
Cancer Biology & Therapy  2011;11(1):32-39.
Glioblastomas continue to carry poor prognoses for patients despite advances in surgical, chemotherapeutic and radiation regimens. One feature of glioblastoma associated with poor prognosis is the degree of hypoxia and expression levels of hypoxia-inducible factor-1α (HIF-1α). HIF-1α expression allows metabolic adaptation to low oxygen availability, partly through upregulation of VEGF and increased tumor angiogenesis. Here, we demonstrate an induced level of astrocyte-elevated gene-1 (AEG-1) by hypoxia in glioblastoma cells. AEG-1 has the capacity to promote anchorage-independent growth and cooperates with Ha-ras in malignant transformation. In addition, AEG-1 was recently demonstrated to serve as an oncogene and can induce angiogenesis in glioblastoma. Results from in vitro studies show that hypoxic induction of AEG-1 is dependent on HIF-1α stabilization during hypoxia and that PI3K inhibition abrogates AEG-1 induction during hypoxia through loss of HIF-1α stability. Furthermore, we show that AEG-1 is induced by glucose deprivation and that prevention of intracellular reactive oxygen species (ROS) production prevents this induction. Additionally, AEG-1 knockdown results in increased ROS production and increased glucose deprivation-induced cytotoxicity. On the other hand, AEG-1 overexpression prevents ROS production and decreases glucose deprivation-induced cytotoxicity, indicating that AEG-1 induction is necessary for cells to survive this type of cell stress. These observations link AEG-1 overexpression in glioblastoma with hypoxia and glucose deprivation and targeting these physiological pathways may lead to therapeutic advances in the treatment of glioblastoma in the future.
doi:10.4161/cbt.11.1.13835
PMCID: PMC3047099  PMID: 21084864
AEG-1; glioblastoma; hypoxia; glucose deprivation; necrosis
23.  Serum anti-AEG-1 auto-antibody is a potential novel biomarker for malignant tumors 
Oncology Letters  2012;4(2):319-323.
Malignant tumors are the leading cause of mortality worldwide. The search for new biomarkers for the early diagnosis of the onset of cancer to reduce high mortality is crucial. The potential of minimal invasive testing using serum from patients renders auto-antibodies promising biomarkers for cancer diagnosis. In this study, a 181 amino acid peptide of extracellular astrocyte elevated gene-1 (AEG-1) was expressed and purified, and the peptide was used in an ELISA assay to detect anti-AEG-1 auto-antibodies (AEG-1-Abs) in 483 serum samples from different cancer patients and 230 serum samples from normal blood donors. The results showed that AEG-1-Abs at titers ≥1:50 were detected in 238 of 483 (49%) cancer patients, and the positive antibody responses in different cancer patients were as follows: 44 of 98 (45%) in breast cancer patients, 48 of 96 (50%) in hepatic carcinoma patients, 43 of 88 (49%) in rectal cancer patients, 51 of 113 (45%) in lung cancer patients, and 52 of 88 (59%) in gastric cancer patients. These results were compared with 0 of 230 (0%) in normal individuals. Moreover, AEG-1-Abs at titers ≥1:50 were also detected in 24 of 94 (26%) cancer patients in TNM stages I and II, and the positive rates of AEG-1-Abs decreased with age. These results suggest that the AEG-1-Ab response acts as a diagnostic biomarker for cancer patients with AEG-1-positive expression, and may also prove to be a possible inducer, with substantial immunity against AEG-1 by immunization boosting with AEG-1 vaccines.
doi:10.3892/ol.2012.734
PMCID: PMC3402762  PMID: 22844377
astrocyte elevated gene-1; anti-AEG-1 auto-antibody; serum; tumor biomarker; cancer
24.  Astrocyte elevated gene-1 is associated with metastasis in head and neck squamous cell carcinoma through p65 phosphorylation and upregulation of MMP1 
Molecular Cancer  2013;12:109.
Background
The survival rate of head and neck squamous cell carcinoma (HNSCC) at advanced stage is poor, despite contemporary advances in treatment modalities. Recent studies have indicated that astrocyte elevated gene-1 (AEG-1), a single transmembrane protein without any known functional domains, is overexpressed in various malignancies and is implicated in both distant metastasis and poor survival.
Results
High expression of AEG-1 in HNSCC was positively correlated with regional lymph node metastasis and a poor 5-year survival rate. Knockdown of AEG-1 in HNSCC cell lines reduced their capacity for colony formation, migration and invasion. Furthermore, decreased tumor volume and metastatic foci were observed after knockdown of AEG-1 in subcutaneous xenografts and pulmonary metastasis assays in vivo, respectively. We also demonstrated that AEG-1 increased phosphorylation of the p65 subunit of NF-κB, and regulated the expression of MMP1 in HNSCC cells. Moreover, compromised phosphorylation of the p65 (RelA) subunit of NF-κB at serine 536 was observed upon silencing of AEG-1 in both HNSCC cell lines and clinical specimens.
Conclusion
High expression of AEG-1 is associated with lymph node metastasis and its potentially associated mechanism is investigated.
doi:10.1186/1476-4598-12-109
PMCID: PMC3856534  PMID: 24063540
Astrocyte elevated gene-1 (AEG-1); Head and neck squamous cell carcinoma (HNSCC); Metastasis; Matrix metalloproteinase 1 (MMP1); p65
25.  RNA Interference-Mediated Knockdown of Astrocyte Elevated Gene-1 Inhibits Growth, Induces Apoptosis, and Increases the Chemosensitivity to 5-Fluorouracil in Renal Cancer Caki-1 Cells 
Molecules and Cells  2014;37(12):857-864.
Astrocyte elevated gene-1 (AEG-1) is a recently discovered oncogene that has been reported to be highly expressed in various types of malignant tumors, including renal cell carcinoma. However, the precise role of AEG-1 in renal cancer cell proliferation and apoptosis has not been clarified. In this study, we transfected the renal cancer cell line Caki-1 with a plasmid expressing AEG-1 short hairpin RNA (shRNA) and obtained cell colonies with stable knockdown of AEG-1. We found that AEG-1 down-regulation inhibited cell proliferation and colony formation and arrested cell cycle progression at the sub-G1 and G0/G1 phase. Western blot analysis indicated that the expression of proliferating cell nuclear antigen (PCNA), cyclin D1 and cyclin E were significantly reduced following AEG-1 down-regulation. In addition, AEG-1 knockdown led to the appearance of apoptotic bodies in renal cancer cells, and the ratio of apoptotic cells significantly increased. Expression of the anti-apoptotic factor Bcl-2 was dramatically reduced, whereas the pro-apoptotic factors Bax, caspase-3 and poly (ADP-ribose) polymerase (PARP) were significantly activated. Finally, AEG-1 knockdown in Caki-1 cells remarkably suppressed cell proliferation and enhanced cell apoptosis in response to 5-fluorouracil (5-FU) treatment, suggesting that AEG-1 inhibition sensitizes Caki-1 cells to 5-FU. Taken together, our data suggest that AEG-1 plays an important role in renal cancer formation and development and may be a potential target for future gene therapy for renal cell carcinoma.
doi:10.14348/molcells.2014.0081
PMCID: PMC4275702  PMID: 25431427
apoptosis; astrocyte elevated gene-1; chemosensitivity; proliferation; renal cancer cells

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