Papillomaviruses and cervical cancer
Human papillomaviruses (HPVs) cause neoplasia of infected epithelia. Some HPV types cause only benign lesions, for example common warts. However, several “high-risk” HPV types, such as HPV-16 and HPV-18, are important public health problems, since they are the primary cause of cancer of the cervix and other anogenital and oral sites. Most men and women become infected during part of their lives by “high-risk” HPV types, but with few exceptions, the virus is carcinogenic only in women and only in a fraction of the infected individuals.
Several still poorly understood mechanisms determine whether HPV infections remain latent, benign, or progress malignantly. Some of these mechanisms are based on the regulation of the HPV oncogene transcription. The gene expression of HPVs is regulated in a very complex manner, in spite of the small size of viral DNA genomes, and involves many sequence specific transcription factors, which determine properties like epithelial specificity of HPV transcription, hormonal regulation, and negative feedback loops. Beyond regulation by these factors, there is now increasing evidence that the viral life cycle as well as HPV dependent tumor progression are governed by phenomena that are independent of sequence specific factors but rather determined by epigenetic mechanisms such as DNA methylation.
HPV DNA often becomes methylated and thereby transcriptionally repressed, and we are studying how HPV genomes are recognized by the cellular methylation machinery and how methylation and demethylation correlate with the viral life cycle and cancer progression. Specifically, we observed that the HPV L1 gene becomes hyper-methylated in cancers and high-grade precursor lesions, and we are investigating in collaborative etiological and epidemiological studies the power of this biomarker for monitoring disease progression.
Additional recent directions of the lab include research of the synergistic effects of tobacco smoking and HPVs in carcinogenesis, and collaboration with other groups at UCI to understand the humoral immune response against HPV infections.
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