The results obtained in this study showed that expression of AEG-1 mRNA and protein was upregulated in PDAC cell lines and tissues. The results also showed that elevated expression of AEG-1 protein was associated with tumor size, clinical stage, T classification, lymph node, and distant metastases of PDAC. Expression of AEG-1 protein also associated with poor prognosis and reduced survival of patients with PDAC. Moreover, the multivariate Cox regression analysis showed that clinical stage, T classification, and AEG-1 expression were independent prognostic predictors for PDAC. Further studies would verify the results of the present study before AEG-1 could be used as a biomarker for prediction of PDAC prognosis. Such studies would also investigate the role and function of AEG-1 in PDAC.
AEG-1 is an Ha-Ras–regulated gene, which plays an essential role in promotion of tumorigenesis and cancer invasion, metastasis, and angiogenesis
. A number of studies have confirmed the potential role of AEG-1 in the development and progression of human cancers
[9–15, 24–27]. Nonetheless, it remains to be clarified whether AEG-1 expression is in parallel with the course of carcinogenesis and cancer progression or AEG-1 is the driver for tumor development and progression. In either way, AEG-1 could be used as an indicator of cancer progression, but a mechanistic study would define the role of AEG-1 in PDAC.
In the current study, expression of AEG-1 mRNA and protein was upregulated in PDAC cell lines as well as PDAC tissues. After that, AEG-1 expression was detected in PDAC tissue specimens of 105 patients. 103 out of 105 (98.09%) specimens of PDAC tissues had moderate to strong cytoplasmic staining of AEG-1 protein, whereas there was no significant staining of AEG-1 detected in the distant noncancerous pancreatic epithelial cells. This supported the role of AEG-1 in the development and progression of PDAC. Moreover, it is particularly noteworthy per the study results that AEG-1 has been found to be only localized in the cytoplasm of cancer cells. This observation coincides with the most previous reports that overexpression of AEG-1 could result in the localization of the protein in the cytoplasm
. However, Emad et al
[18, 21] found that the cytoplasm and nuclear staining of AEG-1 associated with tumor progression, metastasis and neurodegeneration. In breast cancer, nuclear staining of AEG-1 tends to become more common in lesions from patients with more advanced disease stages
. The authors found that occasional nuclear staining of AEG-1 was detected in clinical stage II samples, while stage III sections displayed noticeably increased AEG-1 nuclear localization. A large proportion of caner cells in liver metastases revealed AEG-1 translocation to the nucleus
 suggested that AEG-1 might interact with the NF-κB complex and correspond with the nuclear translocation of p65, but suspected that AEG-1 activation of NF-κB was possible by degradation of IκBα. In addition, it was recently reported that the knockdown of AEG-1 expression attenuated the constitutive activity of NF-κB in parallel with depletion in NF-κB-regulated genes
. Therefore, the present study data further support the latter possibility. However, further studies are needed to verify the role of AEG-1 at different cellular localizations in the development and signal transduction of PDAC.
Further analysis in the study showed a significant association of AEG-1 expression with advanced clinical staging, and T, N, and M classification. This suggested that AEG-1 might be useful as a biomarker to identify subsets of patients with PDAC who had more aggressive disease. Patients with high AEG-1-expressed PDAC had only a 7.84% cumulative 2-year survival rate, which was significantly lower than that in patients with low AEG-1–expressed PDAC (38.09%). The multivariate Cox regression analysis showed that clinical stage, T classification, and AEG-1 expression were independent prognostic predictors for PDAC.
The ex vivo analysis of AEG-1 expression could be a limitation of this study. An in vitro mechanistic study of AEG-1 knockout or transgenic animal models in PDAC cell would be important for further understanding of the functional significance of AEG-1 in PDAC development and progression.