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: Hong Cheng, Na Zhan, Dong Ding, Xiaoming Liu, Xiaoyan Zou, Ke Li, Yumin Xia
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 135 Issue 10 Pg. 2427-2436 (Oct 2015) ISSN: 1523-1747 [Electronic] United States
• PMID: 26016896 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Tumor Necrosis Factor
• TNFRSF12A protein, human
• TWEAK Receptor

Topics

• Apoptosis (genetics, physiology)
• Biopsy, Needle
• Blotting, Western
• Cell Proliferation
• Cells, Cultured
• Flow Cytometry
• Human papillomavirus 16 (isolation & purification)
• Humans
• Immunohistochemistry
• Keratinocytes (cytology, metabolism)
• Papillomavirus Infections (pathology)
• Real-Time Polymerase Chain Reaction (methods)
• Receptors, Tumor Necrosis Factor (genetics)
• Sensitivity and Specificity
• TWEAK Receptor
• Tissue Culture Techniques
• Transfection