HPV and Oral Innate Immunity: A Role for E5 Public Deposited

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  • June 7, 2019
Creator
  • Saladyanant, Thatsanee
    • Affiliation: School of Dentistry, Oral and Craniofacial Biomedicine PhD Program
Abstract
  • High (HR) and low-risk (LR) Human Papillomaviruses (HPVs) are known as the causative agents for benign and malignant lesions in the head and neck region. HR-and LR- infections differentially modify signal transduction and host immune responses. Of the HPV oncoproteins, HPVE5 is a small hydrophobic protein whose role is undefined in oral keratinocytes. We hypothesized that HR and LR-HPVE5 proteins differentially impact oral signal transduction, type I interferon responses, and cell differentiation processes. Our long-term goal is to elucidate the mechanisms of HPV integration. We generated pCMV plasmid vectors containing; whole genomes with E5 (HR-HPV16WT) or with E5 deleted (HPV16ΔE5), HPV16E5-tagged, transcribed but un-translated HPV16E5 (in the context of the whole genome or overexpressed), and LR-HPV6E5 genome. All constructs were transfected into oral keratinocytes and human primary foreskin keratinocytes. By growing cells on monolayer system, higher expression of phospho-p38 MAPK, phospho-MEK1/2 and phospho-Erk1/2 proteins were detected with HR-HPV16E5 but not with LR-HPV6E5 over-expression. Phospho-AKT and phospho-JNK levels were not different between HR and LR. The HR-E5 mRNA maintained MAPK activation implying a role for E5 transcripts in MAPK modulation. This effect was diminished in the absence of EGF and in the presence of terminal differentiation. HR-HPV16E5 demonstrated higher interferon promoter activity and ISG expression (ISG54 and 2’5’ OAS) that was inhibited with Cox-2 inhibitor. The HPV16ΔE5 behaved similarly to LR-HPV6E5. HPV16E5 also showed the suppressive effect on E6 splicing. By growing cells in organotypic raft culture, HPV16WT and HPV16E5 induced hyper-proliferation, activated spinous differentiation, and delayed terminal differentiation. HPV16E5 induced higher STAT1, and STAT3 expression compared to HPV6E5. In conclusion, cell proliferation and activation of intracellular immune responses are critical to transformation of oral keratinocytes and subsequent cancer development. HR-HPV16E5 increased MAPK proliferation signals, enhanced type I interferon responses and STAT3, delayed terminal differentiation, enhanced spinous differentiation, and control E6 and E7 expression whereas LR-HPV6E5 and HPV16ΔE5 barely did. In summary, HR-HPV16E5 may be a key facilitator of oncogenic progression in the head and neck region while LR-HPV6E5 is not.
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  • In Copyright
Advisor
  • Raab-Traub, Nancy
  • Heise, Mark
  • Arnold, Roland
  • Webster-Cyriaque, Jennifer
  • De Paris, Kristina
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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