? ? MicroRNAs (miRNAs) are noncoding small RNAs that regulate gene expression. There is intense interest in miRNAs given their emerging clinical relevance in cancer. Expression profiles of miRNAs have proven useful to improve the classification, diagnosis, and prognostic information of specific human malignancies. This includes lung cancer, the most common lethal malignancy for men and women in our society. Yet, which miRNAs are deregulated during the lung carcinogenesis continuum is largely unknown. Knowing this is relevant to cancer chemoprevention. This NIH RO-3 application responds to PAR-06-313: """"""""Small Grants in Cancer Chemoprevention"""""""" and explores comprehensively which miRNAs are preferentially expressed or repressed in pulmonary pre-malignancy and malignancy (relative to normal lung) using comprehensive arrays containing currently known miRNAs. Novel murine transgenic cyclin E lines that we engineered permit mechanistic studies in lung carcinogenesis as these recapitulate frequent features of human preneoplastic and neoplastic lung lesions. These are unique tools to probe involvement of miRNAs in lung carcinogenesis. Intriguingly, our preliminary work not only has found miRNAs already linked to human lung cancers, but also discovered previously unrecognized miRNAs as deregulated in these transgenic lines that reproduce in the mouse pre-malignant and malignant lesions reminiscent of those found in the clinic. After prioritization of miRNAs for further study through Specific Aim #1 using real-time RT-PCR, in situ hybridization and other expression assays, Specific Aim #2 translates this work into the clinic first using a paired normal-malignant lung tissue bank with over 200 consecutive cases accrued for these studies and then will validate highlighted miRNAs by over-expressing the most prominently repressed ones and targeting for repression the most highly expressed miRNAs, respectively, in immortalized and malignant lung epithelial cells to discover their functional roles in lung carcinogenesis. We assembled an interdisciplinary team with a successful track record for productive collaborations. There is a major public health interest in improved early detection of neoplastic lung lesions and to identify candidate targets to prevent progression of these lesions. For this reason, our team is excited to pursue the Specific Aims. ? ? ?
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