Genetic correction of DNA repair-deficient/cancer-prone xeroderma pigmentosum group C keratinocytes
Genetic correction of DNA repair-deficient/cancer-prone xeroderma pigmentosum group C keratinocytes
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DOI：
10.1089/104303403766682241
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发表时间：
2003-07-01
影响因子：
4.2
通讯作者：
Magnaldo, T
中科院分区：
文献类型：
--
作者：
Arnaudeau-Bégard, C;Brellier, F;Magnaldo, T
着色性干皮病(XP)是一种罕见的光敏性和癌症易感性综合征，以常染色体隐性遗传遗传。XP患者发生的大多数癌症是基底细胞癌和鳞状细胞癌，明显局限于暴露在阳光下的皮肤部分。经典XP患者的细胞缺乏核苷酸切除修复，这是一种去除紫外线诱导的DNA损伤的多功能生化机制。在迄今已知的七个经典XP互补组(XP-A到XP-G)中，XP-C是欧洲和北非最常见的一个，XP-C患者仍然没有其他XP互补组中常见的神经问题。这促使我们对XP-C成纤维细胞，特别是角质形成细胞进行遗传纠正，角质形成细胞是与皮肤癌最相关的细胞，最近被证明能够在体外重建XP-C皮肤。在这项研究中，我们证明了通过稳定驱动野生型XPC蛋白表达的逆转录病毒载体转导XPC患者的角质形成细胞，DNA修复能力、细胞生存特性以及从增殖到流产的角质形成细胞集落向UVB辐射的转变可以完全恢复。此外，我们发现在没有紫外线的情况下，XP-C角质形成细胞表现出固有的细胞周期异常和β(1)-整合素的过度表达，这些缺陷在遗传校正后也完全逆转。随着XP-C矫正角质形成细胞缺陷的完全纠正，从这些细胞体外重建皮肤为XP组织治疗打开了一个理性的前景。
Xeroderma pigmentosum (XP) is a rare photosensitive and cancer-prone syndrome transmitted as an autosomal recessive trait. Most cancers developed by XP patients are basal and squamous cell carcinoma strikingly restricted to sun-exposed parts of the skin. Cells from patients with classic XP are deficient in nucleotide excision repair, a versatile biochemical mechanism for removal of ultraviolet-induced DNA lesions. Among the seven classic XP complementation groups known to date (XP-A to XP-G), XP-C is the most common one in Europe and North Africa and XP-C patients remain free of neurologic problems often seen in other XP complementation groups. This has prompted us to undertake genetic correction of XP-C fibroblasts and particularly keratinocytes, which are the most relevant cells in relation to skin cancer and have proven recently to be capable of reconstructing XP-C skin in vitro. In this study, we demonstrate that DNA repair capacity, cell survival properties, and transition from proliferative to abortive keratinocyte colonies toward UVB irradiation can be fully recovered in keratinocytes from patients with XPC transduced with a retroviral vector stably driving the expression of the wild-type XPC protein. In addition, we show that in the absence of UV, XP-C keratinocytes exhibit intrinsic cell cycle abnormalities, and beta(1)-integrin overexpression, defects that are also both fully reversed after genetic correction. Together with full correction of the defects in XP-C corrected keratinocytes, in vitro reconstruction of skin from these cells open a rational perspective to XP tissue therapy.