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首页> 外文期刊>BMC Medical Genomics >Characterization of global transcription profile of normal and HPV-immortalized keratinocytes and their response to TNF treatment
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Characterization of global transcription profile of normal and HPV-immortalized keratinocytes and their response to TNF treatment

机译：正常和HPV永生化角质形成细胞的整体转录谱的表征及其对TNF治疗的反应

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Background Persistent infection by high risk HPV types (e.g. HPV-16, -18, -31, and -45) is the main risk factor for development of cervical intraepithelial neoplasia and cervical cancer. Tumor necrosis factor (TNF) is a key mediator of epithelial cell inflammatory response and exerts a potent cytostatic effect on normal or HPV16, but not on HPV18 immortalized keratinocytes. Moreover, several cervical carcinoma-derived cell lines are resistant to TNF anti-proliferative effect suggesting that the acquisition of TNF-resistance may constitute an important step in HPV-mediated carcinogenesis. In the present study, we compared the gene expression profiles of normal and HPV16 or 18 immortalized human keratinocytes before and after treatment with TNF for 3 or 60 hours. Methods In this study, we determined the transcriptional changes 3 and 60 hours after TNF treatment of normal, HPV16 and HPV18 immortalized keratinocytes by microarray analysis. The expression pattern of two genes observed by microarray was confirmed by Northern Blot. NF-κB activation was also determined by electrophoretic mobility shift assay (EMSA) using specific oligonucleotides and nuclear protein extracts. Results We observed the differential expression of a common set of genes in two TNF-sensitive cell lines that differs from those modulated in TNF-resistant ones. This information was used to define genes whose differential expression could be associated with the differential response to TNF, such as: KLK7 ( kallikrein 7 ), SOD2 ( superoxide dismutase 2 ), 100P ( S100 calcium binding protein P ), PI3 ( protease inhibitor 3, skin-derived ), CSTA ( cystatin A ), RARRES1 ( retinoic acid receptor responder 1 ), and LXN ( latexin ). The differential expression of the KLK7 and SOD2 transcripts was confirmed by Northern blot. Moreover, we observed that SOD2 expression correlates with the differential NF-κB activation exhibited by TNF-sensitive and TNF-resistant cells. Conclusion This is the first in depth analysis of the differential effect of TNF on normal and HPV16 or HPV18 immortalized keratinocytes. Our findings may be useful for the identification of genes involved in TNF resistance acquisition and candidate genes which deregulated expression may be associated with cervical disease establishment and/or progression.
机译：背景技术高危HPV类型（例如HPV-16，-18，-31和-45）的持续感染是发展宫颈上皮内瘤变和宫颈癌的主要危险因素。肿瘤坏死因子（TNF）是上皮细胞炎症反应的关键介质，对正常或HPV16发挥有效的细胞抑制作用，但对HPV18永生化的角质形成细胞则无作用。此外，几种宫颈癌衍生的细胞系对TNF的抗增殖作用有抗性，这表明TNF抗性的获得可能构成HPV介导的癌变的重要步骤。在本研究中，我们比较了TNF治疗3或60小时之前和之后正常和HPV16或18种永生化的人类角质形成细胞的基因表达谱。方法在本研究中，我们通过微阵列分析确定了TNF治疗正常，HPV16和HPV18永生化角质形成细胞后3和60小时的转录变化。通过Northern Blot证实了通过微阵列观察到的两个基因的表达模式。还使用特定的寡核苷酸和核蛋白提取物通过电泳迁移率变动分析（EMSA）确定了NF-κB的活化。结果我们观察到在两种对TNF敏感的细胞系中一组共同基因的差异表达，这些基因与在TNF抗性的细胞系中调控的基因不同。该信息用于定义其差异表达可能与对TNF的差异反应相关的基因，例如：KLK7（激肽释放酶7），SOD2（超氧化物歧化酶2），100P（S100钙结合蛋白P），PI3（蛋白酶抑制剂3） ，皮肤来源的），CSTA（胱抑素A），RARRES1（视黄酸受体应答剂1）和LXN（乳胶）。通过Northern印迹证实了KLK7和SOD2转录物的差异表达。此外，我们观察到SOD2表达与TNF敏感性和TNF抵抗性细胞表现出的差异性NF-κB活化有关。结论这是首次深入分析TNF对正常和HPV16或HPV18永生化角质形成细胞的差异作用。我们的发现可能对鉴定参与TNF抗性获得的基因有用，而表达失调的候选基因可能与宫颈疾病的建立和/或发展有关。

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