miR-93-directed downregulation of DAB2 defines a novel oncogenic pathway in lung cancer
| Autor: | Ignacio I. Wistuba, John D. Minna, Milind Suraokar, Tzu-Hung Hsiao, Yi Chen, Liqin Du, Alexander Pertsemlidis, Xiuye Ma, Zhenze Zhao, Emily M. Young |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Lung Neoplasms Tumor suppressor gene DAB2 Mice Nude Kaplan-Meier Estimate Biology medicine.disease_cause Disease-Free Survival Article Mice Downregulation and upregulation RNA interference Carcinoma Non-Small-Cell Lung Cell Line Tumor microRNA Genetics medicine Animals Humans RNA Messenger Lung cancer Promoter Regions Genetic Molecular Biology 3' Untranslated Regions Adaptor Proteins Signal Transducing Cell Proliferation Proportional Hazards Models miRNA miR-93 Regulation of gene expression Binding Sites Base Sequence Cell growth Tumor Suppressor Proteins Oncogenes medicine.disease G1 Phase Cell Cycle Checkpoints Gene Expression Regulation Neoplastic MicroRNAs lung cancer Cancer research Female RNA Interference Carcinogenesis Apoptosis Regulatory Proteins Neoplasm Transplantation |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 |
| Popis: | The disabled homolog 2 (DAB2) gene was recently identified as a tumor suppressor gene with its expression downregulated in multiple cancer types. The role of DAB2 in lung tumorigenesis, however, is not fully characterized, and the mechanisms of DAB2 dysregulation in lung cancer are not defined. Here we show that low DAB2 levels in lung tumor specimens are significantly correlated with poor patient survival, and that DAB2 overexpression significantly inhibits cell growth in cultured lung cancer cells, indicating its potent tumor suppressor function. We next identify that microRNA miR-93 functions as a potent repressor of DAB2 expression by directly targeting the 3'UTR of the DAB2 mRNA. Using in vitro and in vivo approaches, we demonstrate that miR-93 overexpression has an important role in promoting lung cancer cell growth, and that its oncogenic function is primarily mediated by downregulating DAB2 expression. Our clinical investigations further indicate that high tumor levels of miR-93 are correlated with poor survival of lung cancer patients. The correlations of both low DAB2 and high miR-93 expression levels with poor patient survival strongly support the critical role of the miR-93/DAB2 pathway in determining lung cancer progression. |
| Databáze: | OpenAIRE |
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