miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma

Chuyong Lin, Aibin Liu, Jinrong Zhu, Xin Zhang, Geyan Wu, Pengli Ren, Jueheng Wu, Mengfeng Li, Jun Li () and Libing Song ()
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Chuyong Lin: State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center
Aibin Liu: Zhongshan School of Medicine, Sun Yat-sen University
Jinrong Zhu: State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center
Xin Zhang: State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center
Geyan Wu: State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center
Pengli Ren: State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center
Jueheng Wu: Zhongshan School of Medicine, Sun Yat-sen University
Mengfeng Li: Zhongshan School of Medicine, Sun Yat-sen University
Jun Li: Zhongshan School of Medicine, Sun Yat-sen University
Libing Song: State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms5620

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