title: miR-205 targets PTEN and PHLPP2 to augment AKT signaling and drive malignant phenotypes in non-small cell lung cancer.
abstract: AKT signaling is constitutively activated in various cancers, due in large part to loss-of-function in the PTEN and PHLPP phosphatases that act as tumor suppressor genes. However, AKT signaling is activated widely in non-small cell lung cancers (NSCLC) where genetic alterations in PTEN or PHLPP genes are rare, suggesting an undefined mechanism(s) for their suppression. In this study, we report upregulation of the oncomir microRNA (miR)-205 in multiple subtypes of NSCLC, which directly represses PTEN and PHLPP2 expression and activates both the AKT/FOXO3a and AKT/mTOR signaling pathways. miR-205 overexpression in NSCLC cells accelerated tumor cell proliferation and promoted blood vessel formation in vitro and in vivo. Conversely, RNA interference-mediated silencing of endogenous miR-205 abrogated these effects. The malignant properties induced by miR-205 in NSCLC cells were reversed by AKT inhibitors, FOXO3a overexpression, rapamycin treatment, or restoring PHLPP2 or PTEN expression. Mechanistic investigations revealed that miR-205 overexpression was a result of NF-κB-mediated transactivation of the miR-205 gene. Taken together, our results define a major epigenetic mechanism for suppression of PTEN and PHLPP2 in NSCLC, identifying a pivotal role for miR-205 in development and progression of this widespread disease.
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, Guangdong 510080, China.
authors.forename: Junchao
authors.initials: J
authors.lastname: Cai
authors.forename: Lishan
authors.initials: L
authors.lastname: Fang
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Huang
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Yuan
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Xun
authors.initials: X
authors.lastname: Zhu
authors.forename: Baixue
authors.initials: B
authors.lastname: Chen
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000230:Adenocarcinoma / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018196:Carcinoma, Adenosquamous / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D020413:3' Untranslated Regions; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C499517:FOXO3 protein, human; C534425:MIR205, human; C546842:MTOR protein, human; C541572:PHLPP2 protein, human; C494929:PTEN protein, human