Role Of Astrocyte Elevated Gene-1 Research Articles

The Role Of Astrocyte Elevated Gene-1 (AEG-1), A Novel Multifunctional Protein, In Chemotherapy-Induced Peripheral Neuropathy

The Role Of Astrocyte Elevated Gene-1 (AEG-1), A Novel Multifunctional Protein, In Chemotherapy-Induced Peripheral Neuropathy

The Role of Astrocyte Elevated Gene-1 (AEG-1), a Novel Multifunctional Protein, in Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent dose-limiting side effect of chemotherapy treatment, often resulting in the discontinuation of treatment for cancer patients. Taxanes, such as Paclitaxel, are a class of chemotherapeutics associated with high prevalence of CIPN development in patients. Taxanes are known to activate peripheral macrophages, generating a neurotoxic inflammatory response that contributes to the development and maintenance of neuropathy. Astrocyte Elevated Gene-1 (AEG-1) is a multifunctional protein that operates in a variety of intracellular signaling pathways. It has been shown to regulate macrophage activation and mediate cellular inflammation through direct interaction with NFκB, a transcriptional regulator of proinflammatory cytokine (PIC) expression. Our goal is to investigate if AEG-1 contributes to the development and maintenance of Paclitaxel-Induced Peripheral Neuropathy (PIPN) and associated neuroinflammation in dorsal root ganglia (DRG). Twelve- to 24-week old AEG-1 global knockout (KO) and wildtype (WT) male and female mice on C57BL/6J background were used in a model of CIPN produced by administration of four 8 mg/kg, i.p. injections of paclitaxel. Mechanical hypersensitivity and cold sensitivity were assessed via Von Frey filaments and acetone test, respectively. mRNA expression was quantified via qRT-PCR. Plasma level concentrations of paclitaxel were assessed via mass spectrometry. AEG-1 KO mice displayed protection from paclitaxel-induced mechanical hypersensitivity and cold sensitivity, unlike their WT counterparts. Paclitaxel increased the expression of AEG-1 and multiple PIC (TNFα, IL1-β, IL-6) in the DRGs of male WT mice. However, these cytokine levels were unchanged in paclitaxel treated AEG-1 KO male mice. Plasma concentration levels of paclitaxel did not differ between AEG-1 KO or WT mice at any time following drug administration. Our data suggest that AEG-1 plays a significant role in the development and maintenance of paclitaxel-induced mechanical and cold hypersensitivity. And that the expression of AEG-1 mediates paclitaxel-induced neuroinflammation in the DRGs. Grant support from 1R01CA221260-01.

Multifunctional Role of Astrocyte Elevated Gene-1 (AEG-1) in Cancer: Focus on Drug Resistance.

Simple SummaryChemotherapy is a major mode of treatment for cancers. However, cancer cells adapt to survive in stressful conditions and in many cases, they are inherently resistant to chemotherapy. Additionally, after initial response to chemotherapy, the surviving cancer cells acquire new alterations making them chemoresistant. Genes that help adapt the cancer cells to cope with stress often contribute to chemoresistance and one such gene is Astrocyte elevated gene-1 (AEG-1). AEG-1 levels are increased in all cancers studied to date and AEG-1 contributes to the development of highly aggressive, metastatic cancers. In this review, we provide a comprehensive description of the mechanism by which AEG-1 augments tumor development with special focus on its ability to regulate chemoresistance. We also discuss potential ways to inhibit AEG-1 to overcome chemoresistance.Cancer development results from the acquisition of numerous genetic and epigenetic alterations in cancer cells themselves, as well as continuous changes in their microenvironment. The plasticity of cancer cells allows them to continuously adapt to selective pressures brought forth by exogenous environmental stresses, the internal milieu of the tumor and cancer treatment itself. Resistance to treatment, either inherent or acquired after the commencement of treatment, is a major obstacle an oncologist confronts in an endeavor to efficiently manage the disease. Resistance to chemotherapy, chemoresistance, is an important hallmark of aggressive cancers, and driver oncogene-induced signaling pathways and molecular abnormalities create the platform for chemoresistance. The oncogene Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) is overexpressed in a diverse array of cancers, and its overexpression promotes all the hallmarks of cancer, such as proliferation, invasion, metastasis, angiogenesis and chemoresistance. The present review provides a comprehensive description of the molecular mechanism by which AEG-1 promotes tumorigenesis, with a special emphasis on its ability to regulate chemoresistance.

Silencing of Astrocyte elevated gene-1 (AEG-1) inhibits proliferation, migration, and invasiveness, and promotes apoptosis in pancreatic cancer cells.

To investigate the role of Astrocyte elevated gene-1 (AEG-1) in the development and progress of pancreatic cancer, short hairpin RNA (shRNA) was inserted into the RNA interference vector to knock-down the endogenous AEG-1 in two pancreatic cancer cell lines: AsPC-1 and PANC-1. Our results showed that silencing of AEG-1 suppressed the proliferation, colony formation ability, and cell stemness of AsPC-1 and PANC-1 cells, and inhibited their G1-to-S phase transition. Results from apoptosis assay showed that knock-down of AEG-1 led to cell apoptosis. The expression of anti-apoptotic Bcl-2 was downregulated and that of the pro-apoptotic Bax and cleaved caspase-3 was upregulated in AEG-1-silenced pancreatic cancer cells. Further, the capability of AEG-1-silenced cells to migrate and to invade through the Matrigel-coated membrane was weaker, and the expression of matrix metallopeptidase 2 (MMP-2) and MMP-9 were decreased. Moreover, the AKT-β-catenin signaling pathway was inhibited in the cells with knock-down of AEG-1. In addition, the growth of xenograft tumors formed by AsPC-1 and PANC-1 cells was suppressed by AEG-1 shRNA. In conclusion, our study demonstrates that pancreatic cancer cells require AEG-1 to maintain their survival and metastasis, suggesting AEG-1 as a potential target for the treatment of pancreatic cancers.

Upregulation of neuronal astrocyte elevated gene-1 protects nigral dopaminergic neurons in vivo

The role of astrocyte elevated gene-1 (AEG-1) in nigral dopaminergic (DA) neurons has not been studied. Here we report that the expression of AEG-1 was significantly lower in DA neurons in the postmortem substantia nigra of patients with Parkinson’s disease (PD) compared to age-matched controls. Similarly, decreased AEG-1 levels were found in the 6-hydroxydopamine (6-OHDA) mouse model of PD. An adeno-associated virus-induced increase in the expression of AEG-1 attenuated the 6-OHDA-triggered apoptotic death of nigral DA neurons. Moreover, the neuroprotection conferred by the AEG-1 upregulation significantly intensified the neurorestorative effects of the constitutively active ras homolog enriched in the brain [Rheb(S16H)]. Collectively, these results demonstrated that the sustained level of AEG-1 as an important anti-apoptotic factor in nigral DA neurons might potentiate the therapeutic effects of treatments, such as Rheb(S16H) administration, on the degeneration of the DA pathway that characterizes PD.

Astrocyte elevated gene-1 participates in the production of pro-inflammatory cytokines in dental pulp cells via NF-κB signalling pathway.

To identify the role of astrocyte elevated gene-1 (AEG-1) and the mechanism underlying the inflammatory response in dental pulp cells. Astrocyte elevated gene-1 expression was detected at different stages of pulpitis in a rat model using immunohistochemistry. RT-qPCR and Western blot were used to assess AEG-1 expression in human dental pulp cells stimulated by lipopolysaccharide (LPS). The LPS-induced expression of inflammatory cytokine genes was quantified by RT-qPCR in cells transfected with AEG-1 or negative control (NC) siRNA. Immunofluorescence and Western blot were utilized to evaluate the activation of NF-κB signalling in AEG-1 knockdown cells. AEG-1 expression was also investigated by Western blot in dental pulp cells pre-treated with inhibitors of NF-κB and PI-3K signalling before the addition of LPS. Data were analysed statistically using one-way anova. The exposure of dental pulp tissue to LPS resulted in acute inflammation with necrosis and AEG-1 expression in the pulp tissue beneath the perforation. In LPS-stimulated dental pulp cells, AEG-1 mRNA and protein were significantly up-regulated (P<0 .05) in a time- and dose-dependent manner. In AEG-1 knockdown cells, the synthesis of IL-1, IL-6 and TNF-α mRNA was suppressed significantly (P<0.05) upon LPS induction. AEG-1 knockdown also inhibited nuclear translocation of p65. Suppression of NF-κB and PI-3K abrogated the LPS-induced up-regulation of AEG-1. Astrocyte elevated gene-1 participated in inflammatory cytokine synthesis via NF-κB signalling in the dental pulp. Both NF-κB and PI-3K signalling are involved in LPS-induced AEG-1 expression in dental pulp cells.

A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH).

AEG-1 might be a key molecule regulating initiation and progression of NASH. AEG-1 inhibitory strategies might be developed as a potential therapeutic intervention in NASH patients. (Hepatology 2017;66:466-480).

Expression of astrocyte elevated gene-1 protein in ameloblastomas, keratocystic odontogenic tumors, and dentigerous cysts.

Benign epithelial odontogenic tumors such as ameloblastoma and keratocystic odontogenic tumor (KCOT) may exhibit an aggressive clinical course reminiscent of malignancies. Recent studies have indicated that astrocyte elevated gene-1 (AEG-1) is highly expressed in a variety of malignant neoplasms and its overexpression is associated with tumor invasion, metastasis, and poor survival. However, the role of AEG-1 in odontogenic tumors and cysts is still undiscovered. Immunohistochemical staining of AEG-1 was performed in 42 cases of ameloblastoma, 29 cases of KCOT, and 19 cases of dentigerous cyst. Correlations between AEG-1 expression and clinical parameters of ameloblastomas or KCOTs were statistically analyzed. AEG-1-positive staining was found in 37 (88%) of 42 ameloblastomas and in 24 (83%) of 29 KCOTs. None of 19 dentigerous cysts were positive for AEG-1 protein. For ameloblastomas, AEG-1 protein expression was significantly higher in ameloblast-like cells than in stellate reticulum-like cells (P = 0.003). For KCOTs, AEG-1 protein was diffusely expressed in all lining epithelial cells except the superficial parakeratinized cells. Moreover, the frequency of cortical plate perforation was significantly higher in ameloblastomas with high AEG-1 expression than in ameloblastomas with low or negative AEG-1 expression (P = 0.043). Significantly higher expression of AEG-1 protein in ameloblastomas and KCOTs than in dentigerous cysts and significantly greater frequency of cortical plate perforation in high AEG-1-expressed ameloblastomas than in low or negative AEG-1-expressed ameloblastomas may imply the high potential of AEG-1 to serve as a locally invasive biomarker and a target for novel therapy.

Upregulation of AEG-1 Involves in Schwann Cell Proliferation and Migration After Sciatic Nerve Crush.

Astrocyte-elevated gene-1 (AEG-1), also known as metadherin (MTDH) and lysine-rich CEACAM1 coisolated (LYRIC), has emerged as an important oncogene that regulates key cellular processes including apoptosis, migration, invasion, proliferation, and differentiation. It was reported that AEG-1 enhanced breast cancer cells migration in a NF-κB-dependent manner. Also, AEG-1 contributed cell proliferation through the PI3K-Akt/cyclin pathway. Besides, AEG-1 is implicated in diverse physiological and pathological diseases of the central nervous system (CNS), such as brain tumors, neuroblastomas, neurodegeneration, and neuronal development. However, the role of AEG-1 in the process of peripheral nervous regeneration after injury remains virtually unknown. In this study, we investigated the spatiotemporal expression of AEG-1 in a rat sciatic nerve crush model. At its peak expression, AEG-1 was expressed mainly in Schwann cells of the distal sciatic nerve segment from injury, but had few colocalizations in axons. Besides, the peak expression of AEG-1 was in parallel with proliferating cell nuclear antigen (PCNA). In vitro, we detected the increased expression of AEG-1 during the process of tumor necrosis factor α (TNF-α)-induced Schwann cell proliferation. Meanwhile, interference of AEG-1 inhibited both proliferation and migration of Schwann cells. In conclusion, we speculated that AEG-1 is involved in biochemical and physiological responses after sciatic nerve crush (SNC).

The key role of astrocyte elevated gene-1 in CCR6-induced EMT in cervical cancer.

In recent years, astrocyte elevated gene-1 (AEG-1) has been recommended as an important mediator that is involved in the epithelial-to-mesenchymal transition (EMT) process. However, the mechanisms underlying the chemokine (C-C motif) ligand 20 (CCL20)/chemokine (C-C motif) receptor 6 (CCR6)-AEG-1 pathway-mediated EMT in cervical cancer (CC) have not been well featured till now. We used immunohistochemistry and immunoblotting to assess the expression of AEG-1 in 94 cervical cancer tissues and cells. Subsequently, cervical cancer SiHa cells were treated with si-AEG-1 and then subjected to in vitro assays. We observed that AEG-1 proteins were highly expressed in cervical cancer tissues and closely correlated with International Federation of Gynecology and Obstetrics (FIGO) stage and metastasis. Importantly, we validated the expression of AEG-1, p-Erk1/2, p-Akt, vimentin, N-cadherin, and matrix metalloproteinase 2 (MMP2) increased in SiHa with CCL20 treatment in a concentration-dependent manner. When cells were treated with si-AEG-1, the expression of p-Erk1/2, p-Akt, vimentin, N-cadherin, and MMP2 was also downregulated. Using the cell cycle assay, the knockdown of AEG-1 inhibited the entry of G1 into S phase. In conclusion, AEG-1 mediates CCL20/CCR6-induced EMT development via both Erk1/2 and Akt signaling pathway in cervical cancer, which indicates that CCL20/CCR6-AEG-1-EMT pathway could be suggested as a useful target to affect the progression of cervical cancer.

Astrocyte Elevated Gene-1 (AEG-1) Regulates Lipid Homeostasis

Astrocyte elevated gene-1 (AEG-1), also known as MTDH (metadherin) or LYRIC, is an established oncogene. However, the physiological function of AEG-1 is not known. To address this question, we generated an AEG-1 knock-out mouse (AEG-1KO) and characterized it. Although AEG-1KO mice were viable and fertile, they were significantly leaner with prominently less body fat and lived significantly longer compared with wild type (WT). When fed a high fat and cholesterol diet (HFD), WT mice rapidly gained weight, whereas AEG-1KO mice did not gain weight at all. This phenotype of AEG-1KO mice is due to decreased fat absorption from the intestines, not because of decreased fat synthesis or increased fat consumption. AEG-1 interacts with retinoid X receptor (RXR) and inhibits RXR function. In enterocytes of AEG-1KO mice, we observed increased activity of RXR heterodimer partners, liver X receptor and peroxisome proliferator-activated receptor-α, key inhibitors of intestinal fat absorption. Inhibition of fat absorption in AEG-1KO mice was further augmented when fed an HFD providing ligands to liver X receptor and peroxisome proliferator-activated receptor-α. Our studies reveal a novel role of AEG-1 in regulating nuclear receptors controlling lipid metabolism. AEG-1 may significantly modulate the effects of HFD and thereby function as a unique determinant of obesity.

Abstract 72: Analyzing the role of Astrocyte Elevated Gene-1 (AEG-1) in hepatocarcinogenesis using a knockout mouse model

Abstract The oncogene Astrocyte Elevated Gene-1 (AEG-1) is overexpressed in a wide variety of human cancers. In vitro and in vivo nude mouse xenograft studies have established the tumor-promoting role of AEG-1. Activation of multiple signaling pathways, such as NF-κB, PI3K/Akt, Wnt/β-catenin and MEK/ERK, has been attributed to mediate oncogenesis by AEG-1. To better understand the role AEG-1 plays in the onset and progression of cancer and to identify key mechanism(s) of AEG-1 action, we generated a novel AEG-1 knockout mouse (AEG-1-/-). We studied hepatocarcinogenesis in this model because AEG-1 is overexpressed in more than 90% of human hepatocellular carcinoma (HCC) patients and is believed to play a key regulatory role in progression of the disease. AEG-1-/- mice were viable with normal development. We first compared the aging associated phenotype of WT and AEG-1-/- mice. At 16 months of age spontaneous tumor development in lungs and liver was observed in some cohorts of untreated WT mice (n=20). Such tumorigenesis was not detected in any of the AEG-1-/- mice. Additionally, age-associated inflammatory infiltrates were observed in the internal organs of WT but not AEG-1-/- mice. To initiate HCC, WT and AEG-1-/- mice were treated with diethylnitrosamine (DEN) at 2 weeks of age. At 32 weeks WT mice showed a marked hepatocarcinogenic response while AEG-1-/- mice exhibited profound resistance to tumor formation. The hepatocarcinogenic response was further evaluated by DEN initiation followed by daily phenobarbital treatment. WT mice exhibited an intensified hepatocarcinogenic response evidenced by large necrotic liver tumors at 28 weeks of age with a 52% rate of lung metastasis. AEG-1-/- mice remained remarkably resistant even to this combinatorial treatment with no distant metastasis. No difference in the activation of Akt, ERK and β-catenin signaling was observed between WT and AEG-1-/- mice indicating that these pathways may not be regulated by AEG-1 under physiological conditions. However, marked inhibition of NF-κB activation was observed in AEG-1-/- mice. Lipopolysaccharide (LPS)-induced NF-κB luciferase reporter activity, nuclear translocation of p65 subunit of NF-κB and induction of IL-1β and IL-6 were markedly attenuated in primary hepatocytes and macrophages isolated from AEG-1-/- versus WT mice. Chronic inflammation and NF-κB activation play a causal role in hepatocarcinogenesis. Inhibition of NF-κB activation in hepatocytes and macrophages profoundly abrogates HCC development in mouse models. Our findings in AEG-1-/- mice confirm a fundamental role of AEG-1 in NF-κB activation. Here we demonstrate that lack of AEG-1 protects from generalized inflammation thereby suppressing spontaneous as well as experimental tumorigenesis. AEG-1-/-mice might be a useful model to study inflammation and cancer in diverse organ systems. Citation Format: Chadia L. Robertson, Jyoti Srivastava, Ayesha Siddiq, Rachel Gredler, Devaraja Rajasekaran, Maaged Akiel, Xue-Ning Shen, Knarik Arkun, Shobha Ghosh, Mark A. Subler, Jolene Windle, Paul B. Fisher, Devanand Sarkar. Analyzing the role of Astrocyte Elevated Gene-1 (AEG-1) in hepatocarcinogenesis using a knockout mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 72. doi:10.1158/1538-7445.AM2014-72

Association of the human astrocyte elevated gene-1 promoter variants with susceptibility to hepatocellular carcinoma

Central role of astrocyte elevated gene-1 (AEG-1) in regulating diverse aspects of hepatocellular carcinoma (HCC) pathogenesis and association of its overexpression with HCC progression has been demonstrated. The positive regulatory regions of AEG-1 promoter contain several putative transcription factor binding sites critical for basal promoter activity. In this study, the aim was to explore the association of AEG-1 promoter variant with HCC. In this study, the human AEG-1 promoter including the region -538 to -42 was explored in 53 HCC patients and 108 healthy controls. The polymerase chain reaction-sequencing method was used for investigating AEG-1 promoter polymorphisms. A novel mutation in AEG-1 promoter in human HCC patients at a potential AP-2 binding site was explored. An A>C mutation was observed in -483 of AEG-1 promoter in 4 out of 53 HCC patients but not in 108 control individuals. Sequencing data showed genetic variations in 11 HCC patients and 3 healthy controls. Among them, one novel SNP was found in activator protein-1 (AP2), a transcription factor binding site (-483 A to C) that may be associated with the susceptibility to HCC (P = 0.012) but no associations were found for other observed variations. This mutation could be tumor-specific. AEG-1 promoter variant -483 A>C may be associated with the susceptibility to HCC in Iranian population. To our knowledge, this is the first study that has reported this association with the susceptibility to HCC. Therefore, further studies need to be conducted in larger sample sizes and other populations to validate these findings.

Astrocyte elevated gene-1 (AEG-1) shRNA sensitizes Huaier polysaccharide (HP)-induced anti-metastatic potency via inactivating downstream P13K/Akt pathway as well as augmenting cell-mediated immune response

Astrocyte elevated gene-1 (AEG-1) is an important force in the development and progression of hepatocellular carcinoma (HCC). To extend our study, we examined here the role of AEG-1 in anti-metastatic effects of Huaier polysaccharide (HP) on the human HCC MHCC97-H cell line. AEG-1 shRNA contributed to the anti-proliferation effect of HP on MHCC97-H cells. Furthermore, results of Transwell insert chambers showed that low expression of AEG-1 could effectively facilitate HP to suppress MHCC97-H cell migration and invasion. We achieved this by reducing phosphoinositide 3-kinases (P13K) and phosphorylated Akt (pAkt) expression as well as enhancing natural killer (NK) cell activity. Taken together, our data strongly suggested that AEG-1 shRNA could block the carcinogenesis and progression of MHCC97-H cells and highlight the therapeutic potential of HP in HCC treatment, at least by part, by inhibiting the activation of the PI3K/Akt pathway and enhancing the NK cell-mediated immune response. These findings may provide a new strategy for HCC treatment.

Expression of AEG-1 in human T-cell lymphoma enhances the risk of progression

The aim of this study was to examine the expression and role of astrocyte elevated gene-1 (AEG-1) in biological processes of T-cell non-Hodgkin's lymphoma (T-NHL). AEG-1 expression in T-NHL patients was characterized with immunohistochemistry. The expression of AEG-1, survivin, Bcl-2 and Bax in Jurkat and Hut-78 cells was detected by real-time PCR and western blotting. Cell proliferation, cell cycle and apoptosis were measured by MTT and flow cytometry. MMP-2/-9 activity was detected by gelatin zymography. Of the studied tumors, 104 (80.62%) exhibited cytoplasmic AEG-1 immunostaining. AEG-1-siRNA in Jurkat and Hut-78 cells suppressed cell proliferation and induced cell apoptosis, inhibited survivin and Bcl-2/Bax protein expression as well as MMP-2/-9 activity. Downregulation of AEG-1 using siRNA could provide a potential approach for gene therapy against T-NHL, and the antitumor effects may be associated with inhibition of survivin and Bcl-2/Bax protein expression and MMP-2/-9 activity.

Abstract 1324: Unraveling novel functions of the oncogene Astrocyte elevated gene-1 (AEG-1) contributing to hepatocarcinogenesis employing a transgenic mouse model

Abstract In vitro tissue culture and nude mice xenograft models have firmly established the role of Astrocyte elevated gene-1 (AEG-1) as a positive regulator of tumorigenesis, including hepatocarcinogenesis. To better appreciate the role of AEG-1 in hepatocarcinogenesis and to dissect the underlying molecular mechanism, we have created a transgenic mouse with hepatocyte-specific expression of AEG-1 (Alb/AEG1). Wild-type (WT) and Alb/AEG-1 mice were challenged with a hepatocarcinogen, N-nitrosodiethylamine (DEN), at 2 weeks of age. At 28 weeks of age, Alb/AEG-1 mice, but not WT mice, developed multinodular HCC with steatotic features and highly elevated serum liver enzymes. Affymetrix microarray analyses identified modulation of expression of genes associated with invasion, metastasis, angiogenesis and fatty acid synthesis in DEN-treated Alb/AEG-1 mice versus their WT counterparts. Hepatocytes isolated from Alb/AEG-1 mice demonstrated profound chemoresistance and dramatically evaded reduction in cell viability upon growth factor deprivation, which was associated with activation of multiple pro-survival signaling pathways. Compared to the WT hepatocytes, Alb/AEG-1 hepatocytes demonstrated marked resistance towards senescence, which was associated with abrogation of activation of a DNA damage response. Conditioned media (CM) from Alb/AEG-1 hepatocytes, but not form WT hepatocytes, induced marked angiogenesis. Mass spectrometric analysis of CM revealed noticeable increases in coagulation factors by AEG-1, which are known to play a significant role in regulating tumor invasion, angiogenesis and metastasis. siRNA-mediated knockdown of coagulation factor XII resulted in profound inhibition of AEG-1-induced angiogenesis. Our studies reveal novel aspects of AEG-1 functions, such as induction of steatosis, inhibition of senescence, a known anti-cancer mechanism, and activation of coagulation pathway to augment an aggressive hepatocarcinogenic phenotype. The Alb/AEG-1 mouse will be a useful model to decipher AEG-1 function in the context of hepatocarcinogenesis and to evaluate the efficacy of novel therapeutic strategies directed towards HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1324. doi:1538-7445.AM2012-1324

RETRACTED ARTICLE: Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity

Astrocyte-elevated gene-1 (AEG-1) has been reported to be upregulated in several malignancies and play a critical role in Ha-ras-mediated oncogenesis through the phosphatidylinositol 3-kinase/AKT signaling pathway. However, the role of AEG-1 in prostate cancer (PC) has never been reported. We now show that AEG-1 is overexpressed in clinical PC tissue samples and cultured PC cells compared to benign prostatic hyperplasia tissue samples and normal prostate epithelial cells. Interestingly, AEG-1 knockdown induced cell apoptosis through upregulation of forkhead box (FOXO) 3a activity. This alteration of FOXO3a activity was dependent on reduction of AKT activity in LNCaP and PC-3 cells with high constitutive AKT activity, but not in DU145 cells with low constitutive AKT activity, although AEG-1 knockdown had no impact on phosphatase and tensin homolog expression in these cells. AEG-1 knockdown also attenuated the constitutive activity of the nuclear factor kappaB (NF-kappaB) and the activator protein 1 (AP-1) with a corresponding depletion in the expression of NF-kappaB and AP-1-regulated genes (interleukin (IL)-6, IL-8 and matrix metalloproteinase-9) and significantly decreased cell invasion properties of PC-3 and DU145 cells. Overall, our findings suggest that aberrant AEG-1 expression plays a dominant role as a positive auto-feedback activator of AKT and as a suppressor of FOXO3a in PC cells. AEG-1 may therefore represent a novel genetic biomarker to serve as an attractive molecular target for new anticancer agents to prevent PC cell progression and metastasis.