title: Activation of the interleukin-32 pro-inflammatory pathway in response to human papillomavirus infection and over-expression of interleukin-32 controls the expression of the human papillomavirus oncogene.
abstract: High-risk variants of human papillomavirus (HPV) induce cervical cancer by persistent infection, and are regarded as the principal aetiological factor in this malignancy. The pro-inflammatory cytokine interleukin-32 (IL-32) is present at substantial levels in cervical cancer tissues and in HPV-positive cervical cancer cells. In this study, we identified the mechanism by which the high-risk HPV-16 E7 oncogene induces IL-32 expression in cervical cancer cells. We used antisense transfection, over-expression, or knock-down of IL-32 to assess the effects of the HPV-16 E7 oncogene on IL-32 expression in cervical cancer cells. Cyclo-oxygenase 2 (COX-2) inhibitor treatment was conducted, and the expression levels, as well as the promoter activities, of IL-32 and COX-2 were evaluated in human HPV-positive cervical cancer cell lines. E7 antisense treatment reduced the expression levels and promoter activities of COX-2, which is constitutively expressed in HPV-infected cells. Constitutively expressed IL-32 was also inhibited by E7 antisense treatment. Moreover, IL-32 expression was blocked by the application of the selective COX-2 inhibitor, NS398, whereas COX-2 over-expression resulted in increased IL-32 levels. These results show that the high-risk variant of HPV induces IL-32 expression via E7-mediated COX-2 stimulation. However, E7 and COX-2 were down-regulated in the IL-32γ over-expressing cells and recovered by IL-32 small interfering RNA, indicating that E7 and COX-2 were feedback-inhibited by IL-32γ in cervical cancer cells.
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Centre, Seoul, Korea.
authors.forename: Sojung
authors.initials: S
authors.lastname: Lee
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Heejong
authors.initials: H
authors.lastname: Kim
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Kang
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Young
authors.initials: Y
authors.lastname: Yang
authors.forename: Jinman
authors.initials: J
authors.lastname: Kim
authors.forename: JongSup
authors.initials: J
authors.lastname: Park
authors.forename: SurNie
authors.initials: S
authors.lastname: Park
authors.forename: JinTae
authors.initials: J
authors.lastname: Hong
authors.forename: Do-Young
authors.initials: DY
authors.lastname: Yoon
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000276:immunology / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D052162:Human papillomavirus 16 / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins / Q000096:biosynthesis* / Q000276:immunology; D030361:Papillomavirus Infections / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000378:metabolism / Q000821:virology
chemical_list: C496971:IL32 protein, human; D007378:Interleukins; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D051546:Cyclooxygenase 2