Carcinogenesis Advance Access published online on March 20, 2009
Carcinogenesis, doi:10.1093/carcin/bgp064
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Overexpression of Astrocyte Elevated Gene-1 (AEG-1) Is Associated with Esophageal Squamous Cell Carcinoma (ESCC) Progression and Pathogenesis
1 State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China
2 Department of Neurosurgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
3 Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510065, China
4 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
* To whom all correspondence should be addressed: Dr. Li-Bing Song, State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R.China, Phone: +86(20)87343192. Fax: +86(20)87343171. Email: lb.song1{at}gmail.com
Dr. Jun Li, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou, Guangdong 510080, P.R.China. Phone: +86(20)87335793. Fax: +86(20)87331209. E-mail:junli99{at}gmail.com
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 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 that patients with high AEG-1 levels exhibited shorter survival time (P < 0.001). Multivariate analysis indicated that AEG-1 expression may 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 shRNAi 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 p27Kip1 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.
Key Words: AEG-1 • Esophageal Squamous Cell Carcinoma • Prognosis • Biomarker • Proliferation
These authors contributed equally to this work. Received December 20, 2008; revised March 16, 2009; accepted March 16, 2009.
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