title: Human papillomavirus oncogenic E6 protein regulates human β-defensin 3 (hBD3) expression via the tumor suppressor protein p53.
abstract: Human β-defensin-3 (hBD3) is an epithelial cell-derived innate immune regulatory molecule overexpressed in oral dysplastic lesions and fosters a tumor-promoting microenvironment. Expression of hBD3 is induced by the epidermal growth factor receptor signaling pathway. Here we describe a novel pathway through which the high-risk human papillomavirus type-16 (HPV-16) oncoprotein E6 induces hBD3 expression in mucosal keratinocytes. Ablation of E6 by siRNA induces the tumor suppressor p53 and diminishes hBD3 in HPV-16 positive CaSki cervical cancer cells and UM-SCC-104 head and neck cancer cells. Malignant cells in HPV-16-associated oropharyngeal cancer overexpress hBD3. HPV-16 E6 induces hBD3 mRNA expression, peptide production and gene promoter activity in mucosal keratinocytes. Reduction of cellular levels of p53 stimulates hBD3 expression, while activation of p53 by doxorubicin inhibits its expression in primary oral keratinocytes and CaSki cells, suggesting that p53 represses hBD3 expression. A p53 binding site in the hBD3 gene promoter has been identified by using electrophoretic mobility shift assays and chromatin immunoprecipitation (ChIP). In addition, the p63 protein isoform ΔNp63α, but not TAp63, stimulated transactivation of the hBD3 gene and was co-expressed with hBD3 in head and neck cancer specimens. Therefore, high-risk HPV E6 oncoproteins may stimulate hBD3 expression in tumor cells to facilitate tumorigenesis of HPV-associated head and neck cancer.
authors.affiliation: Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA.
authors.forename: Twishasri
authors.initials: T
authors.lastname: DasGupta
authors.affiliation: Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA.|Present Address: University of Nigeria, Nsukka, Nigera.
authors.forename: Emeka I
authors.initials: EI
authors.lastname: Nweze
authors.affiliation: Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yue
authors.affiliation: Center for Molecular Cancer Diagnosis Inc., Twinsburg, OH, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.affiliation: Human Developmental and Regenerative Biology, Harvard University, Cambridge, MA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Ghosh
authors.affiliation: Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA.|Present Address: St. Luke's Hospital, Chesterfield, MO, USA.
authors.forename: Hameem I
authors.initials: HI
authors.lastname: Kawsar
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Zender
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Androphy
authors.affiliation: Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Weinberg
authors.affiliation: Department of Dermatology, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: McCormick
authors.affiliation: Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Jin
mesh_terms: D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D023083:beta-Defensins / Q000235:genetics* / Q000378:metabolism
chemical_list: C422950:DEFB103A protein, human; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D023083:beta-Defensins
keywords: head and neck cancer; human papillomavirus; human β-defensins; microenvironment; p53