Faurschou Annesofie
Department of Dermatology, D92, Bispebjerg Hospital, University of Copenhagen, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark.
Dan Med Bull. 2010 Oct;57(10):B4179.
Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine produced in the skin in response to ultraviolet B radiation (UVB). TNF-α facilitates UVB-induced apoptosis and probably contributes to removal of damaged cells. Surprisingly, murine TNF-α-knockout models have demonstrated that TNF-α is necessary for the early stages of skin carcinogenesis and development of squamous cell carcinoma. In the present PhD thesis, we examined the effects of TNF-α on DNA repair and cell cycle regulation in UVB-irradiated keratinocytes. In the model of premalignant keratinocytes (HaCaT), TNF-α abolished the UVB-induced G2/M checkpoint and diminished the DNA repair despite induction of apoptosis. TNF-α activated the protein kinase B/Akt and regulation of its downstream targets, mTOR, Bad and FoxO3a. This effect was dependent on atypical protein kinase C species (aPKC) since a specific peptide blocking the activity of the PKCξ and ι/λ abrogated the activation of Akt by TNF-α. The aPKC-Akt axis was likely to be responsible for the TNF-α-induced decrease in DNA repair since blocking of Akt activity restored DNA repair. Since anti-TNF-α approaches are increasingly used in the therapy of autoimmune diseases and one of the safety concerns is the potential enhancement of skin carcinogenesis, we investigated the effect of the chimeric monoclonal anti-TNF-α antibody infliximab on UVB-irradiated HaCaT cells. Cells treated with infliximab had significantly increased levels of DNA damage despite enhanced G2/M checkpoint arrest, increased apoptosis and inhibition of Akt. In conclusion, we identified a possible novel mechanism by which TNF-α promotes UVB-induced skin carcinogenesis. This depends on aPKC-Akt activation and inhibition of DNA repair. TNF-α-treated cells are prone to escape checkpoint control and are possibly more likely to accumulate mutations, which may constitute a relevant mechanism enhancing tumor development. The effect of anti-TNF-α therapy on skin carcinogenesis warrants further investigation as our study indicates that, in contrast to what had been expected, infliximab may impair DNA repair.
肿瘤坏死因子-α（TNF-α）是皮肤在受到紫外线B辐射（UVB）后产生的一种促炎细胞因子。TNF-α促进UVB诱导的细胞凋亡，并可能有助于清除受损细胞。令人惊讶的是，小鼠TNF-α基因敲除模型表明，TNF-α在皮肤癌发生的早期阶段以及鳞状细胞癌的发展过程中是必需的。在本博士论文中，我们研究了TNF-α对UVB照射的角质形成细胞中DNA修复和细胞周期调控的影响。在癌前角质形成细胞（HaCaT）模型中，TNF-α消除了UVB诱导的G2/M期检查点，并减少了DNA修复，尽管诱导了细胞凋亡。TNF-α激活了蛋白激酶B/Akt及其下游靶点mTOR、Bad和FoxO3a的调控。这种效应依赖于非典型蛋白激酶C亚型（aPKC），因为一种阻断PKCξ和ι/λ活性的特异性肽消除了TNF-α对Akt的激活。aPKC-Akt轴可能是TNF-α诱导DNA修复减少的原因，因为阻断Akt活性可恢复DNA修复。由于抗TNF-α方法越来越多地用于自身免疫性疾病的治疗，其中一个安全问题是皮肤癌发生的潜在增强，我们研究了嵌合单克隆抗TNF-α抗体英夫利昔单抗对UVB照射的HaCaT细胞的影响。用英夫利昔单抗处理的细胞尽管G2/M期检查点阻滞增强、细胞凋亡增加和Akt受到抑制，但DNA损伤水平显著增加。总之，我们确定了一种可能的新机制，通过该机制TNF-α促进UVB诱导的皮肤癌发生。这依赖于aPKC-Akt激活和DNA修复抑制。TNF-α处理的细胞容易逃避检查点控制，并且可能更有可能积累突变，这可能构成促进肿瘤发展的相关机制。抗TNF-α治疗对皮肤癌发生的影响值得进一步研究，因为我们的研究表明，与预期相反，英夫利昔单抗可能会损害DNA修复。
