title: miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma.
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.
authors.affiliation: 1] State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China [2].
authors.forename: Chuyong
authors.initials: C
authors.lastname: Lin
authors.affiliation: 1] Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China [2].
authors.forename: Aibin
authors.initials: A
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Jinrong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Geyan
authors.initials: G
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Pengli
authors.initials: P
authors.lastname: Ren
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Libing
authors.initials: L
authors.lastname: Song
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D015331:Cohort Studies; D018450:Disease Progression; D044127:Epigenesis, Genetic; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism; D000077277:Esophageal Squamous Cell Carcinoma; D004947:Esophagus / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000737:chemistry*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; C571981:MIRN508 microRNA, human; C000599976:MIRN508 microRNA, mouse; D035683:MicroRNAs; D010716:Phosphatidylinositols; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; C581758:INPP5J protein, human; C000599977:INPP5J protein, mouse