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

• Published in: Nature communications 2013-10, Vol.4 (1), p.2544, Article 2544
• Main Authors: Guo, Shui-Long, Ye, Hui, Teng, Yan, Wang, You-Liang, Yang, Guan, Li, Xiu-Bin, Zhang, Chong, Yang, Xue, Yang, Zhong-Zhou, Yang, Xiao
• Format: Article
• Language: English
• Subjects: 631/80/86; 692/420/755; 692/699/67/1504/1829; Aged; Animals; Carcinogenesis; cdc25 Phosphatases - genetics; cdc25 Phosphatases - metabolism; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cyclin D1 - genetics; Cyclin D1 - metabolism; Deregulation; Female; Gene Expression Regulation, Neoplastic; Histology; Humanities and Social Sciences; Humans; Inactivation; Male; Mice; MicroRNAs - administration & dosage; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; multidisciplinary; Phosphorylation; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - deficiency; PTEN Phosphohydrolase - genetics; Science; Science (multidisciplinary); Signal Transduction; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Survival Analysis; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3544

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. The PTEN/Akt signalling pathway has been implicated in the pathogenesis of gastric cancer. Here, Guo et al . show that activation of Akt signalling results in the dysregulation of miR-365, which promotes tumorigenesis and that miR-365 reduction correlates with advance-stage tumours in gastric cancer patients.