Astrocyte Elevated Gene-1 Levels Research Articles

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.

MicroRNA-124 inhibits proliferation, invasion, migration and epithelial-mesenchymal transition of cervical carcinoma cells by targeting astrocyte-elevated gene-1.

MicroRNA-124 (miR-124) was reported to be attenuated in human cervical cancer (CC) specimens. However, its role in CC remains elusive. In the present study, quantitative real-time PCR (qRT-PCR) analysis demonstrated that miR-124 expression is significantly downregulated in human CC tissues and several CC cell lines. Transfection of miR-124 mimics in CC cell lines HeLa and SiHa markedly inhibits cell proliferative, migratory and invasive capacities, as well as the epithelial-mesenchymal transition (EMT) process invitro. Further studies have identified astrocyte-elevated gene-1 (AEG-1) as a direct target gene of miR-124. miR-124 downregulated AEG-1 expression through interaction with its 3'-untranslated regions (3'-UTRs), and miR-124 expression was inversely correlated with AEG-1 levels in CC specimens. Moreover, exogenous overexpression of AEG-1 significantly rescued the miR-124-induced inhibition of cell proliferation, migration and invasion, as well as the EMT process in HeLa cells. In conclusion, these findings suggested that miR-124 was able to suppress cell proliferation, invasion and migration, as well as the EMT process in cervical carcinomas through directly targeting AEG-1. miR-124 and AEG-1 may be potential therapeutic targets for the treatment of cervical carcinoma.

Abstract 269: The role of BRCA1 and AEG1 mRNA expression in advanced non-small-cell lung cancer (NSCLC) patients (p) with EGFR activating and pretreatment T790M mutations receiving the combination of erlotinib plus bevacizumab (E+B) in the BELIEF trial

Abstract The BELIEF trial (NCT01562028) examined the efficacy of E+B for the 1st line treatment of European p with advanced NSCLC harboring exon 19 deletion or exon 21 L858R epidermal growth factor receptor (EGFR) mutations with or without pretreatment T790M. Median progression-free survival (mPFS) was 13.8 months (m) (95% CI 10.3-16.2) for the 109 p enrolled in the study. mPFS was 16m (95% CI 13.1-not estimable [NE]) and 10.4m (95% CI 9.2-15.6) for the 37 T790M(+) p and 72 T790M(-) p, respectively (P = 0.089). We have previously shown that low BRCA1 levels neutralize the negative effect of pretreatment T790M and are associated with longer PFS to erlotinib. Low astrocyte elevated gene 1 (AEG1) levels are associated with longer PFS to erlotinib. A secondary objective of the BELIEF trial was the assessment of the prognostic impact of BRCA1 and AEG1 mRNA expression in the baseline tumor tissue. We assessed the baseline mRNA expression levels of BRCA1 and AEG1 and correlated them with PFS and response in the 109 EGFR-mutant NSCLC p of the BELIEF trial. BRCA1 and AEG1 mRNA levels were estimable by quantitative-real time PCR in 46 and 61 p respectively. Expression levels were divided into two groups according to their median. No statistically significant associations were found among the expression of the two biomarkers and gender, smoking status, histology, PS or type of EGFR mutation. The association of BRCA1 and AEG1 mRNA with PFS did not differ according to T790M status (interaction P = 0.81 and 0.42, respectively). Among the T790M (+) p, those with low BRCA1 mRNA had a longer mPFS of 24.6m (95% CI: 4.9-NE) compared to 15.4 m (95% CI: 2.7-NE) for p with high BRCA1 mRNA; P = 0.63. For all and T790M (-) p, BRCA1 levels did not differentiate mPFS to E+B (low vs high BRCA1 mRNA, 11.0 m [95% CI: 6.0-NE] vs 9.5 m [95% CI: 7.2-NE]; P = 0.99 and 6.9 m [95% CI: 2.1-NE] vs 9.4 m [95% CI: 4.1-NE]; P = 0.71, respectively). Similarly, among the T790M (+) p, those with low AEG1 expression had a longer mPFS of 24.6m (95% CI: 4.9-NE) compared to 15.4 m (95% CI: 5.2-NE) for those with high AEG1 mRNA; P = 0.93. For all and T790M(-) p, AEG1 levels did not differentiate mPFS to E+B (low vs high AEG1 mRNA, 10.3 m [95% CI: 8.4-24.6] vs 15.4 m [95% CI: 6.0-33.9]; P = 0.90 and 10.3m [95% CI: 8.4-NE] vs 13.3m [95% CI: 4.7-33.9] P = 0.67). No statistically or clinically significant associations were found among BRCA1, AEG1 mRNA levels and response to E+B. The BELIEF trial reconfirms our previous findings that pretreatment EGFR T790M is present in 34% of the patients. E+B is associated with a prolonged mPFS of 24.6m for EGFR-mutant p with both pretreatment EGFR T790M and low BRCA1 mRNA expression, as observed in our previous study with erlotinib alone. Similar results were observed for AEG1 levels though the interaction was not statistically significant for either biomarker. Citation Format: Rafael Rosell, Niki Karachaliou, Ana Giménez-Capitán, Carles Codony-Servat, Oliver Gautschi, Enriqueta Felip, Alessandra Curioni-Fontecedro, Solange Peters, Santiago Ponce-Aix, Martin Früh, Miklos Pless, Sanjay Popat, Sinead Cuffe, Paolo Bidoli, Adolfo Favaretto, Roswitha Kammler, Urania Dafni, Zoi Tsourti, Miguel Angel Molina-Vila, Rolf A. Stahel. The role of BRCA1 and AEG1 mRNA expression in advanced non-small-cell lung cancer (NSCLC) patients (p) with EGFR activating and pretreatment T790M mutations receiving the combination of erlotinib plus bevacizumab (E+B) in the BELIEF trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 269.

Abstract 5400: A novel combinatorial therapy for hepatocellular carcinoma (HCC)

Abstract The incidence of hepatocellular carcinoma (HCC) is rising in the US with parallel increase in mortality rate. Lack of effective therapy for advanced HCC mandates development of novel targeted therapies to counteract this fatal malady. Astrocyte elevated gene-1 (AEG-1), also known as metadherin (MTDH) and LYRIC, plays a pivotal role in hepatocarcinogenesis and serves as an ideal target for anti-HCC therapy. AEG-1 interacts with retinoid X receptor (RXR) and inhibits retinoic acid-induced gene expression and cell death. Retinoic acid has been evaluated for HCC treatment without promising result. Overexpression of AEG-1 might underlie the poor performance of retinoic acid in HCC clinical trials. We documented that combination of a lentivirus expressing AEG-1 shRNA (lenti.shAEG-1) and all-trans retinoic acid (ATRA) profoundly and synergistically inhibited subcutaneous human HCC xenografts in nude mice. We now have developed liver-targeted nanoplexes by conjugating poly(amidoamine) (PAMAM) dendrimers with polyethylene glycol (PEG) and lactobionic acid (PAMAM-PEG-Gal) which were complexed with AEG-1 siRNA (PAMAM-AEG-1si). PAMAM has a net positive charge that complexes with the net negative charge of the siRNA backbone, PEG increases stability of the nanoplexes and increases circulation time and the galactose binds to asialoglycoprotein receptors that are upregulated on liver cells. The polymer conjugate was characterized by 1H-NMR and optimal nanoplex formulations were characterized for surface charge and size using a zetasizer Nano ZS. We established orthotopic xenografts of human HCC cell QGY-7703 expressing luciferase (QGY-luc) in the livers of athymic nude mice and monitored tumor development by bioluminescence imaging (BLI). One week after tumor establishment mice were treated with PAMAM-siCon, PAMAM-siCon+ATRA, PAMAM-AEG-1si and PAMAM-AEG-1si+ATRA by 8 i.v. injections over 4 weeks, and sacrificed 2 weeks after the last injection. In the control group the tumor developed aggressively. ATRA showed little effect due to high AEG-1 levels in QGY-luc cells. PAMAM-AEG-1si showed significant reduction in tumor growth and the combination of PAMAM-AEG-1si+ATRA showed profound and synergistic inhibition so that the tumors were almost undetectable by BLI. Measurement of liver weight at the end of the experiment corroborated these findings. Analysis of AEG-1 mRNA in tumor samples showed a marked decrease in AEG-1 level by PAMAM-AEG-1si indicating efficacy of in vivo knockdown. The group treated with PAMAM-AEG-1si+ATRA nanoplexes showed increased necrosis, inhibition of proliferation and increased apoptosis when compared to other groups. Liver is an ideal organ for RNAi therapy and ATRA is an approved anti-cancer agent. Our exciting observations suggest that the combinatorial approach might be an effective way to combat HCC and need to be evaluated stringently in endogenous mouse models of HCC for a potential Phase I/II clinical trial. Citation Format: Jyoti Srivastava, Devaraja Rajasekaran, Ayesha Siddiq, Rachel Gredler, Chadia L. Robertson, Maaged A. Akiel, Xue-Ning Shen, Kareem A.N. Ebeid, Aliasger K. Salem, Paul B. Fisher, Devanand Sarkar. A novel combinatorial therapy for hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5400. doi:10.1158/1538-7445.AM2015-5400

Combination of Nanoparticle-Delivered siRNA for Astrocyte Elevated Gene-1 (AEG-1) and All-trans Retinoic Acid (ATRA): An Effective Therapeutic Strategy for Hepatocellular Carcinoma (HCC).

Hepatocellular carcinoma (HCC) is a fatal cancer with no effective therapy. Astrocyte elevated gene-1 (AEG-1) plays a pivotal role in hepatocarcinogenesis and inhibits retinoic acid-induced gene expression and cell death. The combination of a lentivirus expressing AEG-1 shRNA and all-trans retinoic acid (ATRA) profoundly and synergistically inhibited subcutaneous human HCC xenografts in nude mice. We have now developed liver-targeted nanoplexes by conjugating poly(amidoamine) (PAMAM) dendrimers with polyethylene glycol (PEG) and lactobionic acid (Gal) (PAMAM-PEG-Gal) which were complexed with AEG-1 siRNA (PAMAM-AEG-1si). The polymer conjugate was characterized by (1)H-NMR, MALDI, and mass spectrometry; and optimal nanoplex formulations were characterized for surface charge, size, and morphology. Orthotopic xenografts of human HCC cell QGY-7703 expressing luciferase (QGY-luc) were established in the livers of athymic nude mice and tumor development was monitored by bioluminescence imaging (BLI). Tumor-bearing mice were treated with PAMAM-siCon, PAMAM-siCon+ATRA, PAMAM-AEG-1si, and PAMAM-AEG-1si+ATRA. In the control group the tumor developed aggressively. ATRA showed little effect due to high AEG-1 levels in QGY-luc cells. PAMAM-AEG-1si showed significant reduction in tumor growth, and the combination of PAMAM-AEG-1si+ATRA showed profound and synergistic inhibition so that the tumors were almost undetectable by BLI. A marked decrease in AEG-1 level was observed in tumor samples treated with PAMAM-AEG-1si. The group treated with PAMAM-AEG-1si+ATRA nanoplexes showed increased necrosis, inhibition of proliferation, and increased apoptosis when compared to other groups. Liver is an ideal organ for RNAi therapy and ATRA is an approved anticancer agent. Our exciting observations suggest that the combinatorial approach might be an effective way to combat HCC.

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

Non-thyroidal illness syndrome (NTIS), characterized by low serum 3,5,3'-triiodothyronine (T3) with normal l-thyroxine (T4) levels, is associated with malignancy. Decreased activity of type I 5'-deiodinase (DIO1), which converts T4 to T3, contributes to NTIS. T3 binds to thyroid hormone receptor, which heterodimerizes with retinoid X receptor (RXR) and regulates transcription of target genes, such as DIO1. NF-κB activation by inflammatory cytokines inhibits DIO1 expression. The oncogene astrocyte elevated gene-1 (AEG-1) inhibits RXR-dependent transcription and activates NF-κB. Here, we interrogated the role of AEG-1 in NTIS in the context of hepatocellular carcinoma (HCC). T3-mediated gene regulation was analyzed in human HCC cells, with overexpression or knockdown of AEG-1, and primary hepatocytes from AEG-1 transgenic (Alb/AEG-1) and AEG-1 knock-out (AEG-1KO) mice. Serum T3 and T4 levels were checked in Alb/AEG-1 mice and human HCC patients. AEG-1 and DIO1 levels in human HCC samples were analyzed by immunohistochemistry. AEG-1 inhibited T3-mediated gene regulation in human HCC cells and mouse hepatocytes. AEG-1 overexpression repressed and AEG-1 knockdown induced DIO1 expression. An inverse correlation was observed between AEG-1 and DIO1 levels in human HCC patients. Low T3 with normal T4 was observed in the sera of HCC patients and Alb/AEG-1 mice. Inhibition of co-activator recruitment to RXR and activation of NF-κB were identified to play a role in AEG-1-mediated down-regulation of DIO1. AEG-1 thus might play a role in NTIS associated with HCC and other cancers.

Astrocyte Elevated Gene-1 Increases Invasiveness of NSCLC Through Up-Regulating MMP7

Background/Aims: The aggressive manner of non-small cell lung cancer (NSCLC) cells accounts for the majority of the lethality of the disease. Recently, increased astrocyte elevated gene-1 (AEG-1) levels have been shown to closely correlate with poor prognosis of NSCLC, whereas the underlying mechanisms are not clear. Methods: We examined the AEG-1 and matrix metalloproteinase 7 (MMP7) levels in NSCLC tissues, compared to the paired adjacent non-tumor lung tissue. We modulated AEG-1 levels in NSCLC cells, and examined its effects on MMP7 levels by RT-qPCR, on cellular protein by Western blot, and on secreted protein by ELISA. We also examined the cell invasiveness in AEG-1-modified NSCLC cells in a transwell cell migration assay. We used specific signal pathway inhibitors to treat AEG-1-modified NSCLC cells and examined its effects on MMP7. Results: AEG-1 and MMP7 levels were both significantly increased in NSCLC tissues, compared to the paired adjacent non-tumor lung tissue. The AEG-1 and MMP7 levels were strongly correlated. Overexpression of AEG-1 in NSCLC cells significantly increased MMP7 levels and cell invasiveness, while AEG-1 depletion in NSCLC cells significantly decreased MMP7 levels and cell invasiveness. Application of a specific MAPK-p42/p44 inhibitor, but not application of specific inhibitors for MAPK-p38, PI3k/Akt, or JNK signaling pathways, to AEG-1-overexpressing NSCLC cells substantially abolished the AEG-1-mediated MMP7 up regulation. Conclusion: AEG-1 promotes NSCLC cell invasiveness through MAPK-p42/p44-dependent activation of MMP7.

Astrocyte elevated gene-1 activates MMP9 to increase invasiveness of colorectal cancer

The molecular mechanism underlying the invasiveness of colorectal cancer (CRC) cells remains largely unknown. Here, we found that astrocyte elevated gene-1 (AEG-1) was significantly upregulated in CRC tissues, compared with the adjacent normal tissues from human patients. Ectopic expression of AEG-1 enhanced the invasive ability of CRC cells, while small interfering RNA (siRNA)-induced knockdown of AEG-1 inhibited the invasive ability of CRC cells. Transcription, protein levels, and secretion of matrix metalloproteinase 9 (MMP9), all increased by AEG-1 overexpression in CRC cells, and all decreased by AEG-1 inhibition. Suppression of endogenous MMP9 abrogated the effects of AEG-1 on invasiveness, without affecting AEG-1 levels. Taken together, these findings suggest that AEG-1 contributes to CRC invasiveness and metastasis by enhancing MMP9 activity. Thus, AEG-1 appears to be a novel therapeutic target for preventing the metastasis of CRC.

MiR-137 suppresses cell growth in ovarian cancer by targeting AEG-1

Astrocyte elevated gene-1 (AEG-1) is an oncogene overexpressed in multiple types of human cancers including ovarian cancer (OC). However, the underlying mechanism of AEG-1 up-regulation in OC is not well understood. In this study, we showed that miR-137 downregulated AEG-1 expression through interaction with its 3′ untranslated region (3′UTR) and that miR-137 expression was inversely correlated with AEG-1 levels in OC specimens. Similar to the downregulation of AEG-1, overexpression of miR-137 in OC cell lines decreased in vitro cell growth, clonogenicity, and also induced G1 arrest. Importantly, miR-137 overexpression suppressed in vivo tumor growth in nude mice models. Furthermore, we found that restoring the AEG-1 (without the 3′UTR) significantly rescued miR-137-induced cell growth inhibition and cell-cycle arrest. Taken together, these findings indicate that miR-137 functions as a tumor suppressor by inhibition of AEG-1. These molecules might be targets for prevention or treatment of OC.

Astrocyte elevated gene-1 overexpression in human primary gallbladder carcinomas: An unfavorable and independent prognostic factor

Astrocyte elevated gene-1 (AEG-1), as an HIV-1 or TNF-α-inducible transcript, is correlated with various aspects of tumor malignancy. However, the status of AEG-1 expression and its clinical significance in human gallbladder carcinoma (GBC) remains unknown. In the present study, we investigated AEG-1 expression in two GBC cell lines (GBC-SD and SGC-996) and GBC tissues by immunohistochemical, Western blot and real-time PCR analysis. We found that AEG-1 was highly expressed in GBC samples (63.4%, 26 of 41) compared with normal gallbladder mucosa (p=0.0003) and highly invasive GBC-SD cell lines at both the protein (p=0.0043) and mRNA levels (p=0.0001), and strongly correlated with differentiation degree (p=0.006), Nevin stage (p=0.0344), Ki-67 expression (p=0.0024) and liver infiltration (p=0.0332) in these patients. Multivariate analysis indicated that AEG-1 overexpression was an independent prognostic marker for GBC patients. Moreover, patients with high AEG-1 levels had shorter survival time (p=0.008). Our results suggest that the AEG-1 protein is a valuable marker of GBC progression and could be a potential therapeutic target.

Astrocyte elevated gene 1 (AEG-1) mRNA expression in non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations.

10541 Background: NSCLC p with EGFR mutations respond to the oral EGFR tyrosine kinase inhibitors erlotinib and gefitinib, although the duration of response in individual p is unpredictable. In our previous study, we found that erlotinib-treated p with low BRCA1 mRNA levels had a progression-free survival (PFS) of 27 months (m) vs 10 m for p with high levels (P=0.02). AEG-1 is a multifunctional oncogene that plays a role in several carcinogenic processes. Through PI3K/Akt, AEG-1 activates IKK, leading to phosphorylation and destabilization of the NF-kB inhibitor NFKBIA, which is a gatekeeper for EGFR signaling. Methods: Tumor mRNA expression levels of BRCA1 and AEG-1 were assessed by quantitative PCR in 77 erlotinib-treated p with EGFR mutations. Expression levels were dichotomized at the median. Results: PFS was longer in p with low AEG-1 expression (27 vs 12 m; P=0.003). Median survival (MS) was not reached for p with low AEG-1 levels and was 24 m for p with high levels (P=0.08). Based on these results, we generated an AEG-1/BRCA1 risk model: p with high levels of both genes were considered high-risk, p with low levels of both genes were low-risk, and p with high levels of one and low levels of the other gene were intermediate-risk. PFS was not reached in the low-risk group, while it was 18 m for the intermediate-risk group and 8 m for the high-risk group (P=0.00006) (HR for high- vs low-risk groups, 6.6; 95%CI, 2-4-18; P<0.00001). MS was not reached in the low-risk group, while it was 31 m for the intermediate-risk group and 18 m for the high-risk group (P=0.05). In the multivariate analysis for PFS, the only independent prognostic variables were bone metastases (HR, 2.7; 95%CI, 1.1-6.5; P=0.03) and the AEG-1/BRCA1 risk groups (HR for high-risk group, 7.7 (95%CI, 2.8-21.3; P<0.00001). Conclusions: The two-gene risk model based on AEG-1 and BRCA1 mRNA expression was strongly associated with clinical outcome, with significantly shorter PFS and MS in the high-risk group. This model can be useful for the proper individualized management of p with EGFR mutations.

Expression of Astrocyte Elevated Gene-1

To assess the expression of astrocyte elevated gene-1 (AEG-1) in different endometrial specimens and to investigate its relationship with clinicopathological features and its impact on patient outcome. By Western blot analysis, we investigated AEG-1 expression in paired endometrial tissues and adjacent nontumor tissues of the same patients (n = 4). Immunohistochemistry analysis was used to determine the expression levels of AEG-1 protein in 35 normal endometrium, 40 atypical endometrial hyperplasia, and 174 endometrial cancers. The correlation between AEG-1 expression and various clinicopathological characteristics of endometrial cancer patients was analyzed. Western blot analysis showed that AEG-1 expression levels were up-regulated in all 4 human primary endometrial cancer tissues compared with their matched adjacent noncancerous tissues. The frequent and strong expression of AEG-1 was gradually elevated in normal endometrial tissue, atypical hyperplasia, and endometrial cancers (P < 0.001). Although AEG-1 staining mainly emerged in the cytoplasm, a nuclear distribution was observed in both invasive and advanced endometrial cancer cells. The Ki67 (a proliferation marker) was frequently expressed in the high AEG-1-expressed area, whereas areas with low AEG-1 levels showed weak Ki67 expression. Astrocyte elevated gene-1 overexpression was positively correlated with the International Federation of Gynecology and Obstetrics stage, depth of myometrial invasion, lymph node metastasis, lymph vascular space invasion, and recurrence but not with age or histological type. Patients with high AEG-1 expression had significantly poor overall survival and disease-free survival compared with patients with AEG-1 low expression (both P < 0.001). Multivariate Cox proportional hazards regression demonstrated that high AEG-1 expression was an independent prognostic factor for both the overall survival and disease-free survival of patients with endometrial cancer (P = 0.002 and P = 0.004, respectively). Astrocyte elevated gene-1 overexpression may be associated with carcinogenesis and tumor progression in endometrial cancer. Moreover, it may be a new prognostic marker or a target for improving the treatment efficiency of patients with endometrial cancer.

Prognostic significance of AEG-1 expression in colorectal carcinoma

Astrocyte elevated gene-1 (AEG-1), as an HIV-1 or TNF-alpha-inducible transcript, is associated with various aspects of tumor malignancy. However, relatively little knowledge is available related to the role of AEG-1 in colorectal carcinoma. By immunohistochemical and western blot analysis, we investigated AEG-1 expression in normal mucosa, adenomas, and carcinomas of colorectum. By statistical analysis, we determined its relationship with clinicopathological parameters and overall survival in colorectal carcinoma. We found that AEG-1 expression levels were gradually elevated in normal tissues, low-grade adenoma, high-grade adenoma, and colorectal carcinoma, respectively. Though AEG-1 staining mainly emerged in the cytoplasm, we observed that nuclear staining of AEG-1 tends to become more common in lesions from patients with more advanced disease stages. Furthermore, there was a similar trend for Ki67 expression (as a proliferative index) from normal mucous to adenoma and carcinoma. Statistical analysis revealed that AEG-1 expression was markedly correlated with the UICC stage (P < 0.001), T classification (P = 0.002), N classification (P = 0.015), M classification (P = 0.010), Ki67 expression (P = 0.012), and histological differentiation (P = 0.037) in the colorectal cancer patients. Besides, those patients with high AEG-1 levels had shorter survival time (P < 0.001). High AEG-1 expression correlates with poor overall survival in the colorectal carcinoma patients. In addition, AEG-1 expression in colorectal carcinoma may be associated with tumor progression, indicating that AEG-1 may be a potential preventive and chemotherapeutic target in the patients.

Overexpression of astrocyte elevated gene-1 (AEG-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis

Astrocyte elevated gene-1 (AEG-1), upregulated in various types of human cancers, has been reported to be associated with the carcinogenesis of human cancer. However, the functional significance of AEG-1 in human esophageal squamous cell carcinoma (ESCC) remains unknown. In the present study, we showed the expression of AEG-1 was markedly upregulated in esophageal cancer cell lines and surgical ESCC specimens at both transcriptional and translational levels. Immunohistochemical analysis revealed that 80 of 168 (47.6%) paraffin-embedded archival ESCC specimens exhibited high levels of AEG-1 expression. Statistical analysis suggested the upregulation of AEG-1 was significantly correlated with the clinical staging of the ESCC patients (P = 0.001), T classification (P = 0.002), N classification (P = 0.034), M classification (P = 0.021) and histological differentiation (P = 0.035) and those patients with high AEG-1 levels exhibited shorter survival time (P < 0.001). Multivariate analysis indicated that AEG-1 expression might be an independent prognostic indicator of the survival of patients with ESCC. Furthermore, we found that ectopic expression of AEG-1 in ESCC cells could significantly enhance cell proliferation and anchorage-independent growth ability. Conversely, silencing AEG-1 by short hairpin RNAi caused an inhibition of cell growth and anchorage-independent growth ability on soft agar. Moreover, we demonstrated that the upregulation of AEG-1 could reduce the expression of p27(Kip1) and induce the expression of cyclin D1 through the AKT/FOXO3a pathway. Our findings suggest that the AEG-1 protein is a valuable marker of ESCC progression and that the upregulation of AEG-1 plays an important role in the development and pathogenesis of human ESCC.