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

Ching-Wen Lin; Yih-Leong Chang; Yu-Chiuan Chang; Jau-Chen Lin; Chun-Chi Chen; Szu-Hua Pan; Chen-Tu Wu; Hsuan-Yu Chen; Shuenn-Chen Yang; Tse-Ming Hong; Pan-Chyr Yang

doi:10.1038/ncomms2876

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

Nat Commun. 2013:4:1877. doi: 10.1038/ncomms2876.

Authors

Ching-Wen Lin¹, Yih-Leong Chang, Yu-Chiuan Chang, Jau-Chen Lin, Chun-Chi Chen, Szu-Hua Pan, Chen-Tu Wu, Hsuan-Yu Chen, Shuenn-Chen Yang, Tse-Ming Hong, Pan-Chyr Yang

Affiliation

¹ Graduate Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10043, Taiwan.

PMID: 23695671
DOI: 10.1038/ncomms2876

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
Hippo Signaling Pathway
Humans
Kaplan-Meier Estimate
Lung Neoplasms / genetics*
Lung Neoplasms / pathology*
Mice
Mice, Nude
MicroRNAs / genetics
MicroRNAs / metabolism*
Models, Biological
NF-kappa B / metabolism
Neoplasm Invasiveness
Neoplasm Metastasis
Protein Serine-Threonine Kinases / metabolism*
Real-Time Polymerase Chain Reaction
Signal Transduction*
Transcription, Genetic
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Up-Regulation / genetics
Xenograft Model Antitumor Assays

Substances

DNA-Binding Proteins
LZTS1 protein, human
MIRN135 microRNA, human
MicroRNAs
NF-kappa B
Tumor Suppressor Proteins
Protein Serine-Threonine Kinases