PTEN公司
张力素
PI3K/AKT/mTOR通路
蛋白激酶B
癌症研究
磷酸酶
磷酸肌醇3激酶
生物
基因沉默
激酶
细胞生物学
肌醇
磷酸化
FOXO3公司
信号转导
受体
生物化学
基因
作者
Chuyong Lin,Aibin Liu,Jinrong Zhu,Xin Zhang,Geyan Wu,Pengli Ren,Jueheng Wu,Mengfeng Li,Jun Li,Libing Song
摘要
The strength and duration of phosphoinositide signalling from phosphatidylinositol-3-kinase (PI3K) activation to Akt is tightly balanced by phosphoinositide kinases and phosphatases. However, how phosphatase-mediated negative regulatory effects are concomitantly disrupted in cancers, which commonly exhibit constitutively activated PI3K/Akt signalling, remains undefined. Here we report that miR-508 directly suppresses multiple phosphatases, including inositol polyphosphate-5-phosphatase J (INPP5J), phosphatase and tensin homologue (PTEN) and inositol polyphosphate 4-phosphatase type I (INPP4A), resulting in constitutive activation of PI3K/Akt signalling. Furthermore, we find that overexpressing miR-508 promotes, while silencing miR-508 impairs, the aggressive phenotype of oesophageal squamous cell carcinoma (ESCC) both in vitro and in vivo. Importantly, the level of miR-508 correlates with poor survival and activated PI3K/Akt signalling in a large cohort of ESCC specimens. These findings uncover a mechanism for constitutive PI3K/Akt activation in ESCC, and support a functionally and clinically relevant epigenetic mechanism in cancer progression. The negative regulatory effects of phosphatases are sometimes altered in cancer, but the mechanisms that mediate this effect remain undefined. Here, the authors show that miR-508 suppresses multiple phosphatases, resulting in constitutive activation of the PI3K/Akt pathway.
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