Dohun Pyeon
Assistant Professor Ph.D., University of Wisconsin-MadisonCurrent Research
Virus-host interactions in human papillomavirus infection and oncogenesis Current Research Our research focuses on the human papillomavirus (HPV)-host interactions mediating infection and oncogenesis by this major human tumor virus. Human papillomaviruses (HPVs) are small DNA viruses associated with nearly all cervical cancers (CCs), 20-30% of head and neck cancers (HNCs), and other squamous cell carcinomas. Despite available vaccines, there remains an urgent need to develop new means of intervening in HPV infections, preventing cancer progression and developing more effective means for treating HPV-associated cancers. Using HPV16 virions (wild type and reporter-containing chimeras) produced by the our HiP technology, we recently developed high throughput genetics screens which led to the discovery that cell cycle progression through mitosis is required for early HPV infection, explaining one of the reasons why HPV can infect only undifferentiated, proliferating epithelial cells preferably during wound healing process. To expand our understanding how HPVs establish their early infection in host cells, we are studying (1) mechanisms of HPV- host cell cycle interactions during virus entry, and (2) HPV induction and modulation of host responses during early infection. This research will provide new leads for developing preventive and therapeutic strategies against HPV infection. While nearly all cervical cancers are caused by high risk HPVs, only 20-30% of head and neck cancers (HNCs) are associated with HPV. The remaining HNCs are linked to other risk factors including tobacco and alcohol. This varied etiology of HNCs provided us a unique opportunity to study the role of viral infection in cancer development by comparing HPV-associated and -independent cancers in the same anatomical sites. Using functional genomics approaches with primary human tissue samples from cancers of the head and neck and of the cervix, we found that HPV-positive cancers express a large number of cell cycle-related genes in early stages of cancer development and, consequently, are more proliferative than HPV-negative cancers. We also discovered that upregulation of many of these cell cycle-related genes is caused by the synergistic action of high risk HPV E6 and E7 oncoproteins. Unexpectedly, the deregulated cell cycle-related genes include testes-specific genes SYCP2 and STAG3, which function in meiosis, as well as more typical cell cycle activators such as cyclins, MCMs, and PCNA. We are further (1) studying these differentially regulated cell cycle-related genes to reveal important aspects of HPV oncogenesis, and (2) developing key targets for treatment of HPV-associated cancers and novel biomarkers for diagnosis and prognosis. In these studies we will advance understanding of the mechanisms by which HPVs utilize the host cell cycle machinery in early stages of infection and how this HPV-induced deregulation is connected to infection, host cell proliferation, genomic instability and, finally, cancer development.
Recent Publications
Pyeon D, Pearce SM, Lank SM, Ahlquist PG, Lambert PF. Establishment of Human Papillomavirus Infection Requires Cell Cycle Progression. PLoS Pathogens, 2009 Feb;5(2):e1000318.
Pyeon D, Newton MA, Lambert PF, den Boon JA, Sengupta S, Marsit CJ, Woodworth CD, Connor JP, Haugen TH, Smith EM, Kelsey KT, Turek LP, Ahlquist P. Fundamental differences in cell-cycle deregulation in human papillomavirus-positive and -negative head/neck and cervical cancers. Cancer Research 2007; 67:4605-4619.
Pyeon D, Lambert PF, Ahlquist P. Production of infectious human papillomavirus independently of viral replication and epithelial cell differentiation. Proceedings of National Academy of Science USA 2005; 102: 9311-9316.
Pyeon D, Diaz FJ, Splitter, GA. Prostaglandin E2 increases bovine leukemia virus tax and pol mRNA levels via cyclooxygenase 2: Regulation by interleukin-2, interleukin-10, and bovine leukemia virus. Journal of Virology 2000; 74:5740-5745.
Pyeon D, Splitter GA. Regulation of interleukin-2 and -10 on bovine leukemia virus tax and pol mRNA expression. Journal of Virology 1999; 73:8427-8434.
Pyeon D, Splitter GA. Interleukin-12 p40 mRNA expression in bovine leukemia virus-infected animals: increased in alymphocytosis but decrease in persistent lymphocytosis. Journal of Virology 1998; 72:6917-6921.
Pyeon D, O Reilly KL, Splitter GA. Increased interleukin-10 mRNA expression in tumor bearing or persistently lymphocytotic animals infected with bovine leukemia virus. Journal of Virology 1996; 70:5706-5710.