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AEG-1 Is a Target of Perifosine and Is Over-Expressed in Gastric Dysplasia and Cancers

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Abstract

Background

Perifosine, an alkylphospholipid, is an Akt inhibitor which inhibits the growth of diverse cancer cells. We have reported its inhibitory effects on the growth of gastric cancer cells recently, but its molecular mechanisms are still largely unknown.

Aims

The purpose of this study was to investigate the effect and regulatory mechanism of perifosine in gastric cancer.

Methods

Cell viability was determined by sulforhodamine B assay after transiently transfected with AEG-1 specific siRNAs. qRT-PCR and western blot assay were used to determine the mRNA expression and proteins levels of cell signaling molecules examined. Immunohistochemistry was used to detect the AEG-1 expression in 87 gastric carcinomas, 60 dysplasia, and 47 normal gastric mucosa.

Results

Perifosine decreased AEG-1 gene expression along with inhibition of Akt/GSK3β/C-MYC signaling pathway. Knockdown of AEG-1 using siRNA led to significant down-regulation of cyclin D1 expression at both mRNA level and protein level, and inhibited the growth of gastric cancer cells. AEG-1 expression was elevated in gastric dysplasia and cancer tissues compared to normal gastric mucosa (P < 0.01). AEG-1 over-expression correlated with diffuse type of gastric cancer and advanced tumor stages.

Conclusions

Perifosine inhibits the growth of gastric cancer cells possibly through inhibition of the Akt/GSK3β/C-MYC signaling pathway—mediated down-regulation of AEG-1 that subsequently down-regulated cyclin D1. AEG-1 may play an important role in the carcinogenesis and progression of gastric cancer and could be a therapeutic target of perifosine.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 30873099, 81102458, 81172004) (X. Wang), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) (X. Wang), the Nanjing Pharmaceutical Technology Development Project (YKK09050) (W. Huang), “Medical ZhongDianRenCai Project” of Jiangsu Province (RC2011059) (L. Yang), and ‘‘Six RenCai Gaofeng’’ Funding for the Young Academic Leader of Jiangsu Province (2012) (L. Yang). We thank Dr. Heath Elrod for editing of the manuscript.

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Pathology, Nanjing Medical University Affiliated Nanjing Hospital (Nanjing First Hospital), Nanjing, 210006, Jiangsu, China

    Wenbin Huang

  2. Department of Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China

    Li Yang, Song Liang & Dongxiao Liu

  3. Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China

    Xi Chen, Zhuo Ma, Sulan Zhai, Ping Li & Xuerong Wang

Authors
  1. Wenbin Huang
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  2. Li Yang
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  3. Song Liang
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  4. Dongxiao Liu
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  5. Xi Chen
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  6. Zhuo Ma
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  7. Sulan Zhai
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  8. Ping Li
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  9. Xuerong Wang
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Corresponding author

Correspondence to Xuerong Wang.

Additional information

Wenbin Huang and Li Yang contributed equally to this work.

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Huang, W., Yang, L., Liang, S. et al. AEG-1 Is a Target of Perifosine and Is Over-Expressed in Gastric Dysplasia and Cancers. Dig Dis Sci 58, 2873–2880 (2013). https://doi.org/10.1007/s10620-013-2735-5

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  • DOI: https://doi.org/10.1007/s10620-013-2735-5

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