HPV Type 16 Infection Switches Keratinocytes from Apoptotic to Proliferative Fate under TWEAK/Fn14 Interaction
HPV Type 16 Infection Switches Keratinocytes from Apoptotic to Proliferative Fate under TWEAK/Fn14 Interaction
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在 TWEAK/Fn14 相互作用下，HPV 16 型感染将角质形成细胞从凋亡命运转变为增殖命运。
DOI：
10.1038/jid.2015.201
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发表时间：
2015-10-01
影响因子：
6.5
通讯作者：
Xia, Yumin
中科院分区：
文献类型：
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作者：
Cheng, Hong;Zhan, Na;Xia, Yumin
以前，已知肿瘤坏死因子（TNF）样细胞凋亡弱诱导剂（TWEAK）是通过接合Fn 14受体的角质形成细胞凋亡的诱导剂。然而，高风险的人乳头瘤病毒（HPV）感染赋予角质形成细胞增殖优势，从而可能具有致瘤性。本研究旨在研究角质形成细胞中TWEAK/Fn 14信号传导和HPV 16型感染之间的串扰，这可能在调节细胞周期进程中起作用。TWEAK和Fn 14的表达在肛门生殖器疣和正常皮肤中测定。原代角质形成细胞和HaCaT细胞均转染HPV 16 E6/E7基因。结果表明，Fn 14在HPV 16转染后高表达，并伴随Ras GT3活性和TNF受体相关因子2（TRAF 2）表达的增加。与正常对照组相比，转染E6/E7基因的角质形成细胞的TNF受体谱由1型转变为2型，对TNF-α刺激的凋亡反应减弱。令人惊讶的是，在E6/E7阳性角质形成细胞中观察到增殖的显著增加，而不是凋亡，因为另外补充了TWEAK。总之，角质形成细胞中的HPV 16感染在TWEAK/Fn 14相互作用下引起凋亡向增殖命运的转变，这可能是通过促进Ras和TRAF 2活化并调节TNF受体表达。
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.