An Activating β1 Integrin Mutation Increases the Conversion of Benign to Malignant Skin Tumors
An Activating β1 Integrin Mutation Increases the Conversion of Benign to Malignant Skin Tumors
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DOI：
10.1158/0008-5472.can-08-3051
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发表时间：
2009-02-15
期刊：
影响因子：
11.2
通讯作者：
Watt, Fiona M.
中科院分区：
文献类型：
--
作者：
Ferreira, Manuela;Fujiwara, Hironobu;Watt, Fiona M.
确定癌症相关基因多态的生理相关性是一项重大挑战。现在已经在人类肿瘤中描述了β整合素亚基编码序列的几个变化。其中，T188Iβ1基因在低分化鳞状细胞癌(SCC)中被鉴定为杂合子突变，并在体外激活细胞外基质黏附和抑制角质形成细胞分化。为了研究它在肿瘤发展中的作用，我们利用角蛋白14启动子在小鼠表皮的基底层过表达了突变型或野生型(WT)人β1亚单位。转基因整合素在细胞表面表达并具有一定的功能，其中T188Iβ1亚基对细胞扩散的促进作用强于WTβ1，对表皮的增殖和分化无影响，干细胞室未见扩张。在化学致癌过程中，两种转基因都促进了乳头状瘤的形成，但只有T188Iβ1转基因促进了乳头状瘤向鳞状细胞的转化。携带该突变的乳头状瘤表现为ERK活性增强，分化程度降低。表达T188Iβ1的SCC的分化程度低于表达WTβ1的SCCs。这些观察结果表明，β1整合素的类I区基因变异的表达不会影响正常的表皮动态平衡，但会增加肿瘤的敏感性，并影响肿瘤的类型。[癌症资源2009；69(4)：1334-42]
Identifying the physiologic relevance of cancer-associated genetic polymorphisms is a major challenge. Several changes in the coding sequence of beta integrin subunits have now been described in human tumors. One of these, T188I beta 1, was identified as a heterozygous mutation in a poorly differentiated squamous cell carcinoma (SCC) and shown to activate extracellular matrix adhesion and inhibit keratinocyte differentiation in vitro. To study its contribution to tumor development, we overexpressed the mutant or wild-type (WT) human beta 1 subunit in the basal layer of mouse epidermis using the keratin 14 promoter. The transgenic integrins were expressed at the cell surface and were functional, with the T188I beta 1 subunit promoting cell spreading to a greater extent than WT beta 1. Epidermal proliferation and differentiation were unaffected and no expansion of the stem cell compartment was detected. During chemical carcinogenesis, both transgenes increased papilloma formation, but only the T188I beta 1 transgene stimulated the conversion of papillomas to SCCs. Papillomas bearing the mutation showed increased Erk activity and reduced differentiation. SCCs expressing T188I beta 1 were less well-differentiated than those expressing WT beta 1. These observations establish that the expression of a genetic variant in the I-like domain of beta 1 integrins does not affect normal epidermal homeostasis, but increases tumor susceptibility and influences tumor type. [Cancer Res 2009;69(4):1334-42]