658 HPV Oncoproteins Modulate Human β-defensin-3 Expression in Oral Epithelial Cells

Friday, March 23, 2012: 8 a.m. - 9:30 a.m.
Presentation Type: Oral Session
E.I. NWEZE1, B. CHOW2, J. BIAN3, J. DAYAN4, A. WEINBERG5, T.S. MCCORMICK6, and G. JIN2, 1Biological Sciences/Dental School, Case Western Reserve University, Cleveland, OH, 2Case Western Reserve University, Cleveland, OH, 3Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, 4School of Medicine, Case Western Reserve University, Cleveland, OH, 5Dept of Biosciences, Case Western Reserve University, Cleveland, OH, 6Dermatology, School of Medicine, Case Western Reserve University, Cleveland, OH
Objective: To elucidate mechanisms by which high-risk human papillomavirus (HPV) could evade immune detection and clearing via infected epithelial cells and the role of HPV-induced gene expression in orchestrating local immunity.

Method: Immunofluorescence microscopy was used to determine hBD-3 expression and E6 and E7 oncoproteins in normal and head and neck cancer biopsies. Expression of hBD-3 were determined by quantitative PCR and ELISA in primary oral epithelial cells transfected with each of expression vectors producing HPV-16 E6 and E7 as well as HPV-11 E6. The hBD-3 luciferase promoter constructs with serial promoter deletions were co-introduced with early genes of HPV-16 and HPV-11 for determination of transactivity.

Result: HPV-16 E6 and E7 are causal factors for a subset of oral cancer; while HPV-11 E6 protein may contribute to causing benign warts in the mouth. Cancer cells of HPV-related oral and oropharyngeal squamous cell carcinoma biopsies overproduce hBD-3. HPV-16 E6 or E7 increases the levels of hBD-3 mRNA and peptide in primary oral epithelial cells. However, HPV-11 E6 is significantly less potent in promoting hBD-3 expression. Combination of oncogenic E6 and E7 in oral epithelial cells also shows reduced induction of hBD-3. The transactivity of an hBD-3 luciferase promoter construct is differentially stimulated by oncogenic E6 and E7 compared with MEKK1, a known inducer of hBD-3 expression. Pharmacological inhibitors for MAPK and PI3K reduce the transactivity of a 2.5 kb hBD-3 promoter reporter; but not the reporter containing a 450 bp 3’-regulatory region.

Conclusion: Our previous work has suggested that overexpression of hBD-3 may contribute to oral cancer progression through modulating the immune response in the tumor microenvironment. These data suggest that early genes of high- and low-risk HPV types differentially modulate hBD-3 expression in oral epithelial cells, which may play a role in oral lesions related to HPV infection.

This abstract is based on research that was funded entirely or partially by an outside source: Pilot funding (P30CA043703) from the NCI/Case Comprehensive Cancer Center (GJ), R56DE021046-01A1 from NIH/NIDCR (GJ), and P01DE019759 from NIH/NIDCR (AW, TM)

Keywords: Carcinogenesis, Immune response, Inflammation, Oral biology and Oral mucosa
See more of: Infection
See more of: Microbiology / Immunology
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