Abstract
Background
Astrocyte elevated gene-1 (AEG-1), as an HIV-1 or TNF-α-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.
Methods
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.
Results
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).
Conclusions
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.
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Abbreviations
- AEG-1:
-
Astrocyte-elevated gene-1
- HIV-1:
-
Human immunodeficiency virus type 1
- TNF-α:
-
Tumor necrosis factor-α
- PI3K:
-
Phosphoinositide 3-kinase
- NF–κB:
-
Nuclear factor–kappa B
- AP-1:
-
Activator protein 1
- ERK:
-
Extracellular signal-regulated protein kinase
References
Jemal A, Siegel R, Ward E et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249
Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767
Vogelstein B, Fearon ER, Hamilton SR et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532
Carvalho B, Postma C, Mongera S et al (2009) Multiple putative oncogenes at the chromosome 20q amplicon contribute to colorectal adenoma to carcinoma progression. Gut 58:79–89
Su ZZ, Kang DC, Chen Y et al (2002) Identification and cloning of human astrocyte genes displaying elevated expression after infection with HIV-1 or exposure to HIV-1 envelope glycoprotein by rapid subtraction hybridization, RaSH. Oncogene 21:3592–3602
Lee SG, Su ZZ, Emdad L et al (2006) Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc Natl Acad Sci USA 14:17390–17395
Emdad L, Sarkar D, Su ZZ et al (2006) Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. Cancer Res 66:1509–1516
Emdad L, Sarkar D, Su ZZ et al (2007) Astrocyte elevated gene-1: recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration. Pharmacol Ther 114:155–170
Sarkar D, Park ES, Emdad L et al (2008) Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1. Cancer Res 68:1478–1484
Hu G, Chong RA, Yang Q et al (2009) MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell 15:9–20
Li J, Zhang N, Song LB et al (2008) Astrocyte elevated gene-1 is a novel prognostic marker for breast cancer progression and overall patient survival. Clin Cancer Res 14:3319–3326
Yu C, Chen K, Zheng H et al (2009) Overexpression of astrocyte elevated gene-1 (aeg-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis. Carcinogenesis 30:894–901
Liu H, Song X, Liu C et al (2009) Knockdown of astrocyte elevated gene-1 inhibits proliferation and enhancing chemo-sensitivity to cisplatin or doxorubicin in neuroblastoma cells. J Exp Clin Cancer Res 28:19
Kikuno N, Shiina H, Urakami S et al (2007) Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity. Oncogene 26:7647–7655
Yoo BK, Emdad L, Su ZZ et al (2009) Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J Clin Invest 119:465–477
Brown DM, Ruoslahti E (2004) Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell 5:365–374
Samowitz WS, Slattery ML, Sweeney C et al (2007) APC mutations and other genetic and epigenetic changes in colon cancer. Mol Cancer Res 5:165–170
Olschwang S, Hamelin R, Laurent-Puig P et al (1997) Alternative genetic pathways in colorectal carcinogenesis. Proc Natl Acad Sci USA 94:12122–12127
Mayer RJ (1999) Third international conference on biology, prevention and treatment of gastrointestinal malignancies. Cologne, 23-26 September 1998. Ann Oncol 10:281–287
Rex DK, Kahi CJ, Levin B et al (2006) Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and US Multi-Society Task Force on Colorectal Cancer. CA Cancer J Clin 56:160–167
Verdecchia A, De Angelis R, Capocaccia R et al (1998) The cure for colon cancer: results from the EUROCARE study. Int J Cancer 77:322–329
Hu G, Wei Y, Kang Y (2009) The multifaceted role of MTDH/AEG-1 in cancer progression. Clin Cancer Res 15:5615–5620
Song L, Li W, Zhang H, Liao W et al (2009) Over-expression of AEG-1 significantly associates with tumour aggressiveness and poor prognosis in human non-small cell lung cancer. J Pathol 219:317–326
Li J, Yang L, Song L, Xiong H et al (2009) Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1. Oncogene 28:3188–3196
Renehan AG, O'Dwyer ST, Haboubi NJ et al (2002) Early cellular events in colorectal carcinogenesis. Colorectal Dis 4:76–89
Valera V, Yokoyama N, Walter B et al (2005) Clinical significance of Ki-67 proliferation index in disease progression and prognosis of patients with resected colorectal carcinoma. Br J Surg 92:1002–1007
Salminen E, Palmu S, Vahlberg T et al (2005) Increased proliferation activity measured by immunoreactive Ki67 is associated with survival improvement in rectal/recto sigmoid cancer. World J Gastroenterol 11:3245–3249
Yu HG, Yu LL, Yang Y et al (2003) Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis. Oncology 65:37–45
Scaife CL, Kuang J, Wills JC et al (2002) Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis: implications for metastasis. Cancer Res 62:6870–6878
Lee HR, Cheong HJ, Kim SJ et al (2008) Sulindac enhances arsenic trioxide-mediated apoptosis by inhibition of NF-kappaB in HCT116 colon cancer cells. Oncol Rep 20:41–47
Midgley R, Kerr D (1999) Colorectal cancer. Lancet 353:391–399
Yoo BK, Gredler R, Vozhilla N et al (2009) Identification of genes conferring resistance to 5-fluorouracil. Proc Natl Acad Sci USA 106:12938–12943
Acknowledgements
We would like to thank Aiwen Hou for her support and help in the preparation of this manuscript. We thank Jing Bai and Qiuju Xu for their technical assistance. This research is funded by Natural Science Foundation of Heilongjiang Province (No. D2009-21) and Innovation Fund for Excellent Graduates of Harbin Medical University (No. HCXB2010018).
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Hongtao Song and Cong Li contributed equally to this manuscript.
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Song, H., Li, C., Li, R. et al. Prognostic significance of AEG-1 expression in colorectal carcinoma. Int J Colorectal Dis 25, 1201–1209 (2010). https://doi.org/10.1007/s00384-010-1009-3
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DOI: https://doi.org/10.1007/s00384-010-1009-3