title: HPV Type 16 Infection Switches Keratinocytes from Apoptotic to Proliferative Fate under TWEAK/Fn14 Interaction.
abstract: Previously, tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) had been known to be an inducer of apoptosis of keratinocytes by engaging the Fn14 receptor. However, the high-risk human papillomavirus (HPV) infection confers a proliferation advantage on keratinocytes that may consequently harbor tumorigenicity. This study was designed to investigate the cross-talk in keratinocytes between TWEAK/Fn14 signaling and HPV type 16 infection, which may cooperate in regulating cell-cycle progression. TWEAK and Fn14 expression was determined in anogenital warts and normal skin. Both primary keratinocytes and HaCaT cells were transfected with HPV16 E6/E7 genes. The results showed that Fn14 is highly expressed upon HPV16 transfection and accompanied by an increase in Ras GTPase activity and TNF-receptor-associated factor 2 (TRAF2) expression. Moreover, the E6/E7-transfected keratinocytes exhibit a shift of TNF receptor profile from type 1 to type 2 and weakened apoptotic response to TNF-α stimuli, when compared with the normal control. Surprisingly, significant increase in proliferation but not apoptosis was seen in E6/E7-positive keratinocytes, as TWEAK was additionally supplemented. In conclusion, the HPV16 infection in keratinocytes causes a switch of apoptotic to proliferative fate under TWEAK/Fn14 interaction, possibly by favoring Ras and TRAF2 activation and modulating TNF receptor expression.
authors.affiliation: Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China; Department of Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhan
authors.affiliation: Department of Gynecology, Hubei Maternity and Child Health Hospital, Wuhan, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Ding
authors.affiliation: Department of Dermatology, The Third Affiliated Hospital of Soochow University, Changzhou, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Hubei Maternity and Child Health Hospital, Wuhan, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zou
authors.affiliation: Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China. Electronic address: xiayumin1202@163.com.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Xia
mesh_terms: D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D001707:Biopsy, Needle; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D052162:Human papillomavirus 16 / Q000302:isolation & purification*; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D030361:Papillomavirus Infections / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D012680:Sensitivity and Specificity; D000074050:TWEAK Receptor; D046509:Tissue Culture Techniques; D014162:Transfection
chemical_list: D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor