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Lung cancer has become the leading cause of cancer deaths in recent years. In the United States alone, there are more than 170,000 new lung cancer cases diagnosed every year, majority of which will eventually become lethal. Tobacco smoking is the major causal factor for the development of lung cancer, responsible for ~85% of the incidence. Although smoking cessation at an early age could substantially reduce lung cancer risk, for those who stopped smoking at an older age the lung cancer incidence still remains high. This observation suggests that the respiratory damages caused by tobacco smoking in early life persist for many years and ultimately contribute to the development of lung cancer. To date, the major challenge of lung cancer research is to identify and characterize the molecular network that regulate the onset and progression of lung cancer in human. We have previously identified a family of tumor suppressor microRNAs (miRNAs) as the bona fide p53 transcription targets. Using a mouse model for non-small cell lung cancer, we have preliminary data suggesting the role of mir-34 miRNAs in repressing lung cancer development. In this application, we propose to use mouse tumor models, cell culture studies and clinical studies to characterize the functions of mir-34 miRNAs in tumor suppression in lung cancer. We will investigate the effect of miR-34 deficiency during the initiation and progression of NSCLC and SCLC, examine the miR-34 functions on tumor maintenance, and elucidate the molecular mechanisms underlying the tumor suppression by miR-34 miRNAs. Given the small size of the miRNA molecules, these gene regulators can be easily detected and can be delivered in vivo with relative ease. Therefore, candidate tumor suppressor miRNAs, if functionally confirmed, can have great potentials for the development of novel diagnostic markers and therapeutic agents. The results from our proposed studies will undoubtedly provide fundamental insights into the molecular mechanisms for lung cancer regression downstream of p53. More importantly, these studies are likely to generate novel therapeutic approaches with profound impacts on cancer treatment in clinics. |
