title: Akt-p53-miR-365-cyclin D1/cdc25A axis contributes to gastric tumorigenesis induced by PTEN deficiency.
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.
authors.affiliation: 1] 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].
authors.forename: Shui-Long
authors.initials: SL
authors.lastname: Guo
authors.forename: Hui
authors.initials: H
authors.lastname: Ye
authors.forename: Yan
authors.initials: Y
authors.lastname: Teng
authors.forename: You-Liang
authors.initials: YL
authors.lastname: Wang
authors.forename: Guan
authors.initials: G
authors.lastname: Yang
authors.forename: Xiu-Bin
authors.initials: XB
authors.lastname: Li
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.forename: Xue
authors.initials: X
authors.lastname: Yang
authors.forename: Zhong-Zhou
authors.initials: ZZ
authors.lastname: Yang
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
mesh_terms: D000368:Aged; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000235:genetics* / Q000378:metabolism
chemical_list: C546819:MIRN365 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse