Type VII collagen is required for Ras-driven human epidermal tumorigenesis
Type VII collagen is required for Ras-driven human epidermal tumorigenesis
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DOI：
10.1126/science.1106209
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发表时间：
2005-03-18
期刊：
影响因子：
56.9
通讯作者：
Khavari, PA
中科院分区：
文献类型：
--
作者：
Ortiz-Urda, S;Garcia, J;Khavari, PA
VII型胶原蛋白缺陷导致隐性营养不良性大疱性表皮病（RDEB），这是一种起泡性皮肤病，通常伴有表皮癌。为了研究VII型胶原在这些癌症中的作用，我们研究了RDEB角质形成细胞中Ras驱动的肿瘤发生。缺乏VII型胶原的细胞在小鼠中不形成肿瘤，而保留特定VII型胶原片段（氨基末端非胶原结构域NC 1）的细胞具有致瘤性。强迫NC 1表达恢复成瘤性胶原VII-空表皮中的非细胞自主的方式。NC 1内的纤连蛋白样序列（FNC 1）以层粘连蛋白5依赖的方式促进肿瘤细胞侵袭，并且是肿瘤发生所需的。因此，由VII型胶原介导的肿瘤-间质相互作用促进肿瘤形成，并且RDEB患者亚组中NC 1序列的保留可能导致其对鳞状细胞癌的易感性增加。
Type VII collagen defects cause recessive dystrophic epidermolysis bullosa (RDEB), a blistering skin disorder often accompanied by epidermal cancers. To study the role of collagen VII in these cancers, we examined Ras-driven tumorigenesis in RDEB keratinocytes. Cells devoid of collagen VII did not form tumors in mice, whereas those retaining a specific collagen VII fragment (the amino-terminal noncollagenous domain NC1) were tumorigenic. Forced NC1 expression restored tumorigenicity to collagen VII-null epidermis in a non-cell-autonomous fashion. Fibronectin-like sequences within NC1 (FNC1) promoted tumor cell invasion in a laminin 5-dependent manner and were required for tumorigenesis. Tumor-stroma interactions mediated by collagen VII thus promote neoplasia, and retention of NC1 sequences in a subset of RDEB patients may contribute to their increased susceptibility to squamous cell carcinoma.