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Akt-p53-miR-365-cyclin D1/cdc25A axis contributes to gastric tumorigenesis induced by PTEN deficiency

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  • Shui-Long Guo

    (State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology
    Institute of Geriatrics, PLA Postgraduate School of Medicine, PLA General Hospital)

  • Hui Ye

    (E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine)

  • Yan Teng

    (State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology)

  • You-Liang Wang

    (State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology)

  • Guan Yang

    (State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology)

  • Xiu-Bin Li

    (State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology)

  • Chong Zhang

    (E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine)

  • Xue Yang

    (E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine)

  • Zhong-Zhou Yang

    (MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University)

  • Xiao Yang

    (State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology
    E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine)

Abstract

Although PTEN/Akt signaling is frequently deregulated in human gastric cancers, the in vivo causal link between its dysregulation and gastric tumorigenesis has not been established. Here we show that inactivation of PTEN in mouse gastric epithelium initiates spontaneous carcinogenesis with complete penetrance by 2 months of age. Mechanistically, activation of Akt suppresses the abundance of p53, leading to decreased transcription of miR-365, thus causing upregulation of cyclin D1 and cdc25A, which promotes gastric cell proliferation. Importantly, genetic ablation of Akt1 restores miR-365 expression and effectively rescues gastric tumorigenesis in PTEN-mutant mice. Moreover, orthotopic restoration of miR-365 represses PTEN-deficient-induced hyperplasia. In human gastric cancer tissues, miR-365 reduction correlates with poorly differentiated histology, deep invasion and advanced stage, as well as the deregulation of PTEN, phosphorylated Akt, p53, cyclin D1 and cdc25A. These data demonstrate that the PTEN-Akt-p53-miR-365-cyclin D1/cdc25A axis serves as a new mechanism underlying gastric tumorigenesis, providing potential new therapeutic targets.

Suggested Citation

  • Shui-Long Guo & Hui Ye & Yan Teng & You-Liang Wang & Guan Yang & Xiu-Bin Li & Chong Zhang & Xue Yang & Zhong-Zhou Yang & Xiao Yang, 2013. "Akt-p53-miR-365-cyclin D1/cdc25A axis contributes to gastric tumorigenesis induced by PTEN deficiency," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3544
    DOI: 10.1038/ncomms3544
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