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

Shui-Long Guo1, Hui Ye, Yan Teng

  • 11] State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing 100071, China [2] Institute of Geriatrics, PLA Postgraduate School of Medicine, PLA General Hospital, Beijing 100853, China [3].

Nature Communications
|October 24, 2013
PubMed

Insights

Inactivating PTEN in mouse stomachs causes cancer by disrupting the p53-miR-365 pathway, increasing cell proliferation. Restoring miR-365 or Akt1 stops this gastric tumorigenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • PTEN/Akt signaling is often altered in human gastric cancers.
  • The direct role of PTEN/Akt dysregulation in gastric tumor development in vivo is unclear.

Purpose of the Study:

  • To investigate the in vivo causal link between PTEN/Akt signaling dysregulation and gastric tumorigenesis.
  • To elucidate the molecular mechanisms driving gastric cancer initiation and progression in response to PTEN loss.

Main Methods:

  • Inactivation of PTEN in mouse gastric epithelium.
  • Genetic ablation of Akt1 in PTEN-mutant mice.
  • Orthotopic restoration of miR-365.
  • Analysis of human gastric cancer tissues.

Main Results:

  • PTEN inactivation in mouse gastric epithelium led to spontaneous gastric carcinogenesis.
  • Akt activation suppressed p53, decreasing miR-365 and upregulating cyclin D1/cdc25A, promoting proliferation.
  • Genetic ablation of Akt1 or miR-365 restoration rescued tumorigenesis in PTEN-mutant mice.
  • Reduced miR-365 correlated with advanced human gastric cancer features and pathway deregulation.

Conclusions:

  • The PTEN-Akt-p53-miR-365-cyclin D1/cdc25A axis is a novel mechanism in gastric tumorigenesis.
  • This pathway represents potential therapeutic targets for gastric cancer treatment.

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