Ultraviolet responses of Gorlin syndrome primary skin cells
Ultraviolet responses of Gorlin syndrome primary skin cells
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DOI：
10.1111/j.1365-2133.2008.08650.x
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发表时间：
2008-08-01
影响因子：
10.3
通讯作者：
Magnaldo, T.
中科院分区：
文献类型：
--
作者：
Brellier, F.;Valin, A.;Magnaldo, T.
Gorlin综合征，或naevoid基底细胞癌综合征（NBCCS），是一种常染色体显性遗传病，与编码SONIC HEDGEHOG受体的PTCH1基因突变相关。除了发育异常外，NBCCS患者还容易发生基底细胞癌（BCC），这是人类中最常见的非黑色素瘤皮肤癌。由于紫外线（UV）暴露在散发性BCC的发展中起着重要作用，我们旨在确定原发性NBCCS皮肤细胞与野生型（WT）皮肤细胞相比，是否对紫外线暴露表现出不同的反应。方法从10例NBCCS特征性皮肤活检中分离原代成纤维细胞和角化细胞菌株。在确定PTCH1突变后，将NBCCS细胞修复紫外线诱导的DNA损伤的能力、紫外线照射后的存活能力以及p53的反应与WT皮肤细胞进行比较。结果首次发现c1763insG PTCH1突变。紫外线照射后的DNA修复和细胞存活分析显示，NBCCS和WT成纤维细胞和角化细胞的反应无明显差异。然而，与WT型角质形成细胞相比，紫外线照射后p53在所有NBCCS原代角质形成细胞株中异常持续积累。我们观察到NBCCS细胞在紫外线照射下具有正常的DNA修复和存活能力，这更好地解释了NBCCS患者的BCC倾向不仅仅与暴露在阳光下的身体部位有关，而可能是由于细胞周期的改变。
Background Gorlin syndrome, or naevoid basal cell carcinoma syndrome (NBCCS), is an autosomal dominant disorder associated with mutations in the PTCH1 gene, which encodes the receptor of SONIC HEDGEHOG. In addition to developmental abnormalities, patients with NBCCS are prone to basal cell carcinoma (BCC), the most frequent type of nonmelanoma skin cancer in humans.Objectives As ultraviolet (UV) exposure plays a prominent role in the development of sporadic BCC, we aimed to determine whether primary NBCCS skin cells exhibit differential responses to UV exposure compared with wild-type (WT) skin cells.Methods Primary fibroblast and keratinocyte strains were isolated from nonlesional skin biopsies of 10 patients with characteristic NBCCS traits. After identification of PTCH1 mutations, capacities of NBCCS cells to repair UV-induced DNA lesions and to survive after UV irradiation, as well as p53 responses, were compared with those of WT skin cells.Results The c1763insG PTCH1 mutation is described for the first time. DNA repair and cell survival analyses following UV irradiation revealed no obvious differences between responses of NBCCS and WT fibroblasts and keratinocytes. However, p53 accumulation after UV irradiation was abnormally persistent in all NBCCS primary keratinocyte strains compared with WT keratinocytes.Conclusions Our observations that NBCCS cells harbour normal DNA repair and survival capacities following UV irradiation better explain that BCC proneness of patients with NBCCS does not solely concern body areas exposed to sunlight and suggest rather that it might be due to cell cycle alterations.