Human Papillomaviruses (HPVs) are implicated in the pathogenesis of a number of benign and malignant human epithelial neoplasms. Using in situ hybridization detection of nucleic acids, and other complementary techniques, we seek a comprehensive understanding of the role of these viruses in the pathogenesis of their associated neoplasms. We will continue to systematically identify the type and distribution of HPV DNAs and viral messenger RNAs (mRNAs) in the various neoplastic and preneoplastic epithelial proliferations with an emphasis on the female genital tract, particularly the uterine cervix. Having characterized a representative collection of each morphologic class of lesion, we will use exon-specific probes to determine the pattern of the expression of individual HPV and mRNA species in order to correlate the expression of each HPV gene with disease state and cellular differentiation. These studies are being extended to include a panel of host genes likely to be significant in the regulation of cell growth and differentiation including: several oncogenes growth factor receptors, anti-oncogenes, as well as genes potentially implicated in tumor progression and invasion such as type IV collagenase and the laminin receptor. Keratin mRNA probes will be used to evaluate the state of epithelial differentiation and proliferation. For selected genes the immunohistochemical evaluation of the mRNA encoded proteins will be compared to the mRNA distributions as a means of assessing the in situ regulation of gene expression at the level of RNA translation and protein accumulation. Other methods of HPV detection, notably the polymerase chain reaction, will be used as a method both for case selection as well as a means of reducing false negative results. The data generated in this project will be used to refine our evolving concepts of the molecular mechanism of HPV induced carcinogenesis.
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