汇报者：吕红莉 www.book118.com  阿斯匹林与多发性家族性毛发上皮瘤疾病简介：概况临床表现治疗阿斯匹林治疗多发性家族性毛发上皮瘤（MFT) 的疗效。MFT 致病基因CYLD 编码蛋白CYLD 蛋白功能。阿斯匹林治疗MFT 的机制。毛发上皮瘤分型：家族性多发性非家族性单发性多发性家族性毛发上皮瘤（Multiple Familial Trichoepithelioma ） 多发性家族性毛发上皮瘤（MFT ）是一种常染色体显性遗传的皮肤附属器肿瘤1996 年，Harada 等对三个美国MFT 家系进行连锁分析，将其致病基因定位于染色体9p21 2004 年，我科收集中国一家三代MFT 家系，并将其致病基因定位于染色体16q12-q13, 为CYLD 基因MFT 具有遗传异质性Clinical Feature 临床表现Grouped tiny pearly papules and nodules on the face, especially,the upper lip and nasolabial folds. Occasionally on the scalp,neck,and upper trunk . color: skin color or yellowish generally begin during early childhood or at puberty. Histological Feature 组织病理Treatment 治疗There is no effective therapeusis. Laser Refrigeration Dermabrasion  Treatment of MFT With Aspirin 口服阿斯匹林治疗多发性家族性毛发上皮瘤Case Report  病例报道41-year-old white woman with clinically apparent MFT Physical examination: numerous skin-colored,  dome-shaped papules on her entire face and scattered throughout her scalp.  During the 15 years she has undergone mumerous laser, but the papales always recurred. numerous skin-colored, dome-shaped papules on her entire face and scattered throughout her scalp. Oral aspirin(325mg twice daily)  Subcutaneous adalimumab(40mg every other week) After 2 months: Oral aspirin(325mg twice daily)  Subcutaneous adalimumab(40mg every week) 口服阿斯匹林（325mg 2 次/日）皮下注射adalimumab （40mg 1 次/2 周）两个月后：口服阿斯匹林（325mg 2 次/日）皮下注射adalimumab （40mg 1 次/周）Eight months later  八个月后The trichoepitheliomas were smaller and her skin was less indurated.  皮疹变小，皮肤也较前变软。 Question 存在的问题The regimen included 2 drugs,the author cannot discern the contribution of either drug alone.  此疗法包含两种药物，无法确定每种药的单独疗效。Aspirin and MFT The disease gene of MFT and its  encoded protein. Why can aspirin treat MFT? Disease Gene 致病基因We had identify that the disease gene of MFT was CYLD gene.  CYLD protein is a member of the family of deubiquitinating enzymes(DUBs),it plays an indispensible role in the NF-kB signalling pathway. The Role of NF-κB NF-κB is a key transcription factor that sits at the end of the TNF-αpathway and inhibits apoptosis,increased lever of NF-κB can prevent cell death,causing MFT. NF-κB 是一种重要的转录因子，它位于TNF-α途径末端，可抑制细胞凋亡。NF-κB 过度表达则阻止细胞凋亡，导致细胞异常增生，最终形成MFT. What is NF-κB signalling pathway ？NF-κB is normally found in the cell cytoplasm, where it is kept inactive by association with inhibitor (IκB) proteins. 静息状态下，NF-κB 与抑制蛋白IκB 结合，NF-κB 以无活性的状态存在细胞质中。When TNF-αbind its receptor ,a molecule called TNF-receptor-associated factor 2 (TRAF-2) binds to the cytoplasmic end of the receptor,where it is ubiquitinated. Ubiquitination of TRAF-2 leads to the activation of the inhibitor of IκB kinase （IKK) complex,which In turn leads to the activation of NF-κB , NF-κB is than free to move into the nucleus and activate gene and ,thus ,to cell survival. TNF-α与其受体结合后，TRAF-2 则结合到TNF-α受体末端，TRAF-2 可发生多聚泛素化，IκB 激酶（IKK) 复合体活化。活化的IKK 则使IκB 磷酸化。NF-κB 被释放出来，进入细胞核内，启动特异基因的转录，而抑制了细胞凋亡。CYLD de-ubiquitinates TRAF-2 and thus prevents theactivation of the IκB kinase complex(and hence of NF-κB). 一旦CYLD 活性丧失，就不能抑制TRAF-2 的信号转导功能，从而引起NF-κB 信号转导途径的过度活化，导致细胞的异常增生，形成肿瘤。可见，CYLD 在NF-κB 信号转导途径起负调节功能。What does aspirin do in NF-κB signalling pathway ？阿斯匹林在NF-κB 信号途径中的作用Aspirin and CYLD have a similar effect on NF-κB levels,but they act on different parts of the pathway.  和CYLD 类似，阿斯匹林对NF-κB 水平也起作用。但阿斯匹林和CYLD 在NF-κB 信号途径中发挥作用的部位不同。Aspirin and its derivatives can inhibit the release of NF-κB and its translocation to the nucleus, hence preventing cell proliferation. Aspirin acts on parts of the pathway downstream of that engaged by CYLD,it may compensate for CYLD dysfunction.  Now we have a more accurate conception of the disease process and we hope there is a mechanism-driven therapy. * Aspirin and Multiple Familial Trichoepitheliomas 成群出现的小的类似珍珠样的丘疹或结节，好发于面部，特别是上唇附近，鼻唇沟。偶见于头皮,颈部,和躯干。呈肤色或淡黄色常发生于儿童或青少年。真皮内出现嗜碱性基底细胞性肿瘤团块。 上皮性肿瘤团块可呈实性，花边样网状、筛状、放射状、及小梁状等。无确切有效的治疗方法。激光冷冻（小皮损）皮肤磨削术患者为41 岁的白种女性，临床表现为典型MFT 。皮损为遍布面部、头部的大量呈肤色、半球形丘疹。15 年内多次行激光治疗，但是皮损易于复发。多发性家族性毛发上皮瘤的致病基因为CYLD 基因。CYLD 蛋白是去泛素化酶家族中成员之一，具去泛素化酶活性，可负向调节NF-κB 信号途径。What does CYLD do there?  CYLD 在NF-κB 信号途径中的作用CYLD 可去除TRAF-2 上的多聚 泛素链，阻止了IκB 激酶复合体的活化，抑制NF-κB 的过度活化。 阿斯匹林及其衍生物可抑制NF-κB 的释放，且阻止NF-κB 进入细胞核，阻止细胞增殖。阿斯匹林作用于NF-κB 通路的下游，一定程度上可代偿CYLD 的功能障碍。* * *