miR-93-directed downregulation of DAB2 defines a novel oncogenic pathway in lung cancer

• Published in: Oncogene Vol. 33; no. 34; pp. 4307 - 4315
• Main Authors: Du, L, Zhao, Z, Ma, X, Hsiao, T-H, Chen, Y, Young, E, Suraokar, M, Wistuba, I, Minna, J D, Pertsemlidis, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.08.2014; Nature Publishing Group
• Subjects: 3' Untranslated Regions; 631/337/384/331; 692/420/755; 692/699/67/1612; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Apoptosis Regulatory Proteins; Base Sequence; Binding Sites; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - mortality; Cell Biology; Cell growth; Cell Line, Tumor; Cell Proliferation; Disease-Free Survival; Female; G1 Phase Cell Cycle Checkpoints; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Human Genetics; Humans; Internal Medicine; Kaplan-Meier Estimate; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Medicine; Medicine & Public Health; Mice; Mice, Nude; MicroRNA; MicroRNAs - physiology; miRNA; mRNA; Neoplasm Transplantation; Oncogenes; Oncology; original-article; Patients; Physiological aspects; Promoter Regions, Genetic; Proportional Hazards Models; Ribonucleic acid; RNA; RNA Interference; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumorigenesis; lung cancer; miRNA; DAB2; miR-93
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.381

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.