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

• DOI: 10.1038/ncomms3544
• Publication Date: 2013-10-23T11:30:57Z
• Authors: Shui-Long Guo; Hui Ye; Yan Teng; You-Liang Wang; Guan Yang; Xiu-Bin Li; Chong Zhang; Xue Yang; Zhong-Zhou Yang; Xiao Yang
• Keywords: CDC25A

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