title: MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1.
abstract: Dysregulation of microRNAs has a critical role in cancer progression. Here we identify an intronic microRNA, miR-135b that is upregulated in highly invasive non-small-cell lung cancer cells. Expression of miR-135b enhances cancer cell invasive and migratory abilities in vitro and promotes cancer metastasis in vivo, while specific inhibition of miR-135b by a miR-135b-specific molecular sponge and antagomirs suppresses cancer cell invasion, orthotopic lung tumour growth and metastasis in a mouse model. miR-135b targets multiple key components in the Hippo pathway, including LATS2, β-TrCP and NDR2, as well as LZTS1. Expression of miR-135b, LZTS1, LATS2 and nuclear TAZ predicts poor outcomes of non-small-cell lung cancer. We find that miR-135b is dually regulated by DNA demethylation and nuclear factor-kappaB signalling, implying that abnormal expression of miR-135b in cancer may result from inflammatory and epigenetic modulations. We conclude that miR-135b is an oncogenic microRNA and a potential therapeutic target for non-small-cell lung cancer.
authors.affiliation: Graduate Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10043, Taiwan.
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Lin
authors.forename: Yih-Leong
authors.initials: YL
authors.lastname: Chang
authors.forename: Yu-Chiuan
authors.initials: YC
authors.lastname: Chang
authors.forename: Jau-Chen
authors.initials: JC
authors.lastname: Lin
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Chen
authors.forename: Szu-Hua
authors.initials: SH
authors.lastname: Pan
authors.forename: Chen-Tu
authors.initials: CT
authors.lastname: Wu
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Chen
authors.forename: Shuenn-Chen
authors.initials: SC
authors.lastname: Yang
authors.forename: Tse-Ming
authors.initials: TM
authors.lastname: Hong
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D000090683:Hippo Signaling Pathway; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C118711:LZTS1 protein, human; C544965:MIRN135 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases