| The work presented in this dissertation aims to characterize the molecular pathways involved in murine lung development, murine lung cancer development, and the processes that influence embryonic cancer development in order to better understand the complex processes involved in the development and progression of lung cancer, and potentially all cancers.; Oligonucleotide array-based analysis was conducted to examine the temporal pattern of gene expression across the various stages of lung development to identify regulatory pathways at key developmental time points. Whole-embryo total RNA or embryonic lung total RNA was harvested from A/J mice at seven developmental stages. To investigate changes in gene expression during lung development, four samples from each stage were examined using Affymetrix U74Av2 murine oligonucleotide microarrays. From the over 12,000 genes and ESTs represented on the array, 1,346 genes and ESTs were identified as having a significant change in expression between at least one time point and the others (p < 0.001, Kruskal-Wallis test). Within this group of ∼1,300 genes, 4 patterns of expression were seen: (1) upregulation during the embryonic period of development (up-down); (2) upregulation during the postnatal period of lung development (down-up); and (3) fluctuating expression, up initially, down for one or more time points and then up again (up-down-up); and (4) vice versa (down-up-down). Expression patterns of genes previously reported to be involved in pulmonary development were also examined. Using the pathway visualization tool, GenMapp, at least three regulatory pathways were found to contain clusters of differentially expressed genes: Wnt signaling, cell cycle, and apoptosis.; Furthermore, we have shown that many of the genes involved in lung development are either known oncogenes or tumor suppressor genes altered in lung cancer, such as Cyr61, Rassf1a, and Dutt1/Robo1 or putative lung cancer genes. In addition, the genes identified pertinent to early development may also serve as candidate susceptibility genes for various inherited lung cancer disorders as well as for various heritable disorders of lung development. These results will contribute to our understanding of novel aspects of the regulatory machinery for embryonic lung development and of the genes involved in lung tumorigenesis. (Abstract shortened by UMI.)... |
