MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1

• Published in: Nature communications Vol. 4; no. 1; p. 1877
• Main Authors: Lin, Ching-Wen, Chang, Yih-Leong, Chang, Yu-Chiuan, Lin, Jau-Chen, Chen, Chun-Chi, Pan, Szu-Hua, Wu, Chen-Tu, Chen, Hsuan-Yu, Yang, Shuenn-Chen, Hong, Tse-Ming, Yang, Pan-Chyr
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.05.2013; Nature Publishing Group
• Subjects: 631/337/384/331; 631/67/1612; 631/67/322; 631/80/86; Animals; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation; DNA Methylation - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epithelial-Mesenchymal Transition - genetics; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Kaplan-Meier Estimate; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Models, Biological; multidisciplinary; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B - metabolism; Protein-Serine-Threonine Kinases - metabolism; Real-Time Polymerase Chain Reaction; Science; Science (multidisciplinary); Signal Transduction; Transcription, Genetic; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Up-Regulation - genetics; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2876

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. Lung cancers have a high potential to become metastatic, which is a major cause of treatment failure. Here, the authors identify a microRNA that is upregulated in non-small-cell lung cancer and is associated with Hippo pathway modulation metastasis and poor clinical outcome.