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AEG-1 expression characteristics in human non-small cell lung cancer and its relationship with apoptosis

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Abstract

Expression of astrocyte-elevated gene-1 (AEG-1), a novel oncoprotein, has been shown to promote cell growth and inhibit apoptosis, but the underlying molecular mechanisms and its functional significance in non-small cell lung cancer (NSCLC) remain to be elucidated. In the present study, statistical analysis displayed a significant correlation of AEG-1 expression with clinical staging (P = 0.048), differentiation (P = 0.019) and lymph node metastasis (P = 0.032). Simultaneously, the overall survival time in patients with higher AEG-1 expression was obviously shorter than that in patients with lower expression of AEG-1 (P < 0.001). Furthermore, we found that AEG-1 could inhibit apoptotic cell death in L-78 cells, as assessed by MTT, TUNEL and flow cytometry assay. After treating L-78 cells with AEG-1 siRNA, caspase-3 protein was significantly up-regulated and Bcl-2 protein was markedly decreased in L-78 cells, which was verified by the immunohistochemistry results about AEG-1, caspase-3 and Bcl-2. Furthermore, PI3K p110 protein and phosphorylated Akt were also largely attenuated by the treatment of AEG-1 siRNA. In conclusion, our results indicated that AEG-1 played a crucial role in the carcinogenesis of NSCLC and could inhibit apoptosis via activating cell survival signaling (enhancing the level of anti-apoptotic protein Bcl-2 and the activation of PI3K/Akt pathway).

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References

  1. Su ZZ, Kang DC, Chen Y, et al. 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. 2002;21:3592–602.

    Article  PubMed  CAS  Google Scholar 

  2. Su ZZ, Chen Y, Kang DC, et al. Customized rapid subtraction hybridization (RaSH) gene microarrays identify overlapping expression changes in human fetal astrocytes resulting from human immunodeficiency virus-1 infection or tumor necrosis factor-alpha treatment. Gene. 2003;306:67–78.

    Article  PubMed  CAS  Google Scholar 

  3. Kang DC, Su ZZ, Sarkar D, et al. Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1. Gene. 2005;353:8–15.

    Article  PubMed  CAS  Google Scholar 

  4. Brown DM, Ruoslahti E. Metadherin, a cell surface protein in breast tumors that mediate lung metastasis. Cancer Cell. 2004;5:365–74.

    Article  PubMed  CAS  Google Scholar 

  5. Kikuno N, Shiina H, Urakami S, et al. Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity. Oncogene. 2007;26:7647–55.

    Article  PubMed  CAS  Google Scholar 

  6. Yoo BK, Emdad L, Su ZZ, et al. Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J Clin Invest. 2009;119:465–77.

    Article  PubMed  CAS  Google Scholar 

  7. Yu C, Chen K, Zheng H, et al. Overexpression of astrocyte elevated gene-1 (AEG-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis. Carcinogenesis. 2009;30:894–901.

    Article  PubMed  CAS  Google Scholar 

  8. Lee SG, Jeon HY, Su ZZ, et al. Astrocyte elevated gene-1 contributes to the pathogenesis of neuroblastoma. Oncogene. 2009;28:2476–84.

    Article  PubMed  CAS  Google Scholar 

  9. Hu G, Chong RA, Yang Q, et al. MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor prognosis breast cancer. Cancer Cell. 2009;15:9–20.

    Article  PubMed  CAS  Google Scholar 

  10. Emdad L, Sarkar D, Lee SG, et al. Astrocyte elevated gene-1 (AEG-1): a novel target for human glioma therapy. Mol Cancer Ther. 2010;9:79–88.

    Article  PubMed  CAS  Google Scholar 

  11. Song L, Li W, Zhang H, et al. Overexpression of AEG-1 significantly associates with tumor aggressiveness and poor prognosis in human non-small cell lung cancer. J Pathol. 2009;219:317–26.

    Article  PubMed  CAS  Google Scholar 

  12. Han YH, Kim SZ, Kim SH, et al. Arsenic trioxide inhibits the growth of Calu-6 cells via inducing a G2 arrest of the cell cycle and apoptosis accompanied with the depletion of GSH. Cancer Lett. 2008;18:40–55.

    Article  CAS  Google Scholar 

  13. Franke TF, Hornik CP, Segev L, et al. PI3K/Akt and apoptosis: size matters. Oncogene. 2003;22:8983–98.

    Article  PubMed  CAS  Google Scholar 

  14. Franke TF, Yang SI, Chan TO, et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell. 1995;81:727–36.

    Article  PubMed  CAS  Google Scholar 

  15. del Peso L, González-García M, Page C, et al. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science. 1997;278:687–99.

    Article  PubMed  Google Scholar 

  16. Cardone MH, Roy N, Stennicke HR, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998;282:1318–21.

    Article  PubMed  CAS  Google Scholar 

  17. Dan HC, Sun M, Kaneko S, et al. Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J Biol Chem. 2004;279:5405–12.

    Article  PubMed  CAS  Google Scholar 

  18. Lee SG, Su ZZ, Emdad L, et al. Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenicHa-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc Natl Acad Sci USA. 2006;103:17390–5.

    Article  PubMed  CAS  Google Scholar 

  19. Lee SG, Su ZZ, Emdad L, et al. Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling. Oncogene. 2008;27:1114–21.

    Article  PubMed  CAS  Google Scholar 

  20. Ke Z, Zhang X, Ma L, et al. Expression of DPC4/Smad4 in non-small-cell lung carcinoma and its relationship with angiogenesis. Neoplasma. 2008;55:323–9.

    PubMed  CAS  Google Scholar 

  21. Emdad L, Sarkar D, Su ZZ, et al. Astrocyte elevated gene-1: recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration. Pharmacol Ther. 2007;114:155–70.

    Article  PubMed  CAS  Google Scholar 

  22. Li J, Zhang N, Song LB, et al. Astrocyte elevated gene-1 is a novel prognostic marker for breast cancer progression and overall patient survival. Clin Cancer Res. 2008;14:3319–26.

    Article  PubMed  CAS  Google Scholar 

  23. Jian-bo X, Hui W, Yu-long H, et al. Astrocyte-elevated gene-1 overexpression is associated with poor prognosis in gastric cancer. Med Oncol. 2011;28:455–62.

    Article  PubMed  Google Scholar 

  24. Song H, Li C, Li R, et al. Prognostic significance of AEG-1 expression in colorectal carcinoma. Int J Colorectal Dis. 2010;25:1201–9.

    Article  PubMed  Google Scholar 

  25. Emdad L, Sarkar D, Su ZZ, et al. Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. Cancer Res. 2006;66:1509–16.

    Article  PubMed  CAS  Google Scholar 

  26. Hermine O, Haioun C, Lepage E, et al. Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin’s lymphoma. Grouped’Etude des Lymphomes de l’Adulte (GELA). Blood. 1996;87:265–72.

    PubMed  CAS  Google Scholar 

  27. Wang W, Abbruzzese JL, Evans DB, et al. The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res. 1999;5:119–27.

    PubMed  CAS  Google Scholar 

  28. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.

    Article  PubMed  CAS  Google Scholar 

  29. Johnson DE. Programmed cell death regulation: basic mechanisms and therapeutic opportunities. Leukemia. 2000;14:1340–4.

    Article  PubMed  CAS  Google Scholar 

  30. Cho SG, Choi EJ. Apoptotic signaling pathways: caspases and stress-activated protein kinases. J Biochem Mol Biol. 2002;35:24–7.

    Article  PubMed  CAS  Google Scholar 

  31. Higuchi M, Honda T, Proske RJ, et al. Regulation of reactive oxygen species-induced apoptosis and necrosis by caspase 3-like proteases. Oncogene. 1998;17:2753–60.

    Article  PubMed  CAS  Google Scholar 

  32. Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003;22:8590–607.

    Article  PubMed  CAS  Google Scholar 

  33. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91:231–9.

    Article  PubMed  CAS  Google Scholar 

  34. Yao R, Cooper GM. Requirement for phosphatidyl-inositol-3 kinase in the prevention of apoptosis by the nerve growth factor. Science. 1995;267:2003–6.

    Article  PubMed  CAS  Google Scholar 

  35. Pugazhenthi S, Nesterova A, Sable C, et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem. 2000;275:10761–6.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by Foundation of China National Natural Science (30900650/H1615), Foundation of China National Natural Science (81172232/H1615), Foundation of Guangdong Natural Science (9451008901002146), the Fund for the Preceptorial Program of Higher Education, China, Grant number: 20090171120070, and Guangzhou science and technology program[2010]122010u1-E00621.

Conflict of interest

All authors declare that there is no conflict of interest in this scientific work.

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Authors and Affiliations

  1. Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Road 58, Guangzhou, 510080, Province Guangdong, People’s Republic of China

    Zun-fu Ke, Shuhua Li & Lian-tang Wang

  2. Department of Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Province Guangdong, People’s Republic of China

    Xiaopeng Mao

  3. Department of Pathology, Guang Dong Medical College, Dongguan, 523808, People’s Republic of China

    Cao Zeng

  4. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Province Guangdong, People’s Republic of China

    Shanyang He

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  1. Zun-fu Ke
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Correspondence to Lian-tang Wang.

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Zun-fu Ke and Xiaopeng Mao have the same attribution to this article.

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Ke, Zf., Mao, X., Zeng, C. et al. AEG-1 expression characteristics in human non-small cell lung cancer and its relationship with apoptosis. Med Oncol 30, 383 (2013). https://doi.org/10.1007/s12032-012-0383-9

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  • DOI: https://doi.org/10.1007/s12032-012-0383-9

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