Role of alpha6beta4 integrin in epidermal carcinogenesis

描述（由申请人提供）：鳞状细胞癌（SCC）约占所有非黑色素瘤皮肤癌的20%，是最常见的人类恶性肿瘤类型。SCC具有相对较高的侵袭和转移倾向，尽管对皮肤SCC侵袭行为的生物学基础知之甚少。具有高肿瘤进展风险的上皮性肿瘤如SCC的一个特征是不适当的α 6 β 4整联蛋白表达。然而，在其他正常上皮中异常α 6 β 4表达对疾病的发生和病程的影响相对未知。α 6 β 4的基底上表达使表皮易于形成化学诱导的肿瘤，并通过需要E-钙粘蛋白介导的细胞间粘附和PI 3-激酶活性的机制扰乱基底细胞中的转化生长因子β（TGF β）信号传导。本研究的目的是确定基底层上α 6 β 4表达增强表皮肿瘤形成和破坏TGF β信号传导的分子机制。小GTP酶Rho家族的蛋白质介导肌动蛋白细胞骨架重组，并与上皮肿瘤进展有关。初步研究结果表明，基底上α 6 β 4与肌动蛋白细胞骨架和共定位与Rac 1和Rac激活改变转基因小鼠表皮和人类SCC表现出基底上α 6 β 4的表达。为了设想α 6 β 4整联蛋白、E-钙粘蛋白和PI 3-激酶都可以协同作用以操纵TGF β信号传导和表皮肿瘤形成的方式，该提议的目的将集中于Rho家族的小GTP酶的作用。 我们将描述转基因鼠表皮和表现出基底层上α 6 β 4表达的人SCC中Rho GT3表达和活性的变化。我们将在过表达α 6 β 4的细胞中操纵Rho GT3和PI 3-激酶信号传导，并确定其对TGF β介导的生长抑制的影响。为了确定Rho GT3活性对表皮肿瘤形成的影响，我们将产生Rho GT3活性缺陷并表现出基底上α 6 β 4表达的转基因鼠表皮。在该模型中，我们将测量消融的Rho GT3信号传导对基底细胞增殖和SCC诱导的影响。总的来说，我们计划确定表皮皮肤细胞相互交流方式的变化如何影响潜在致命的人类皮肤癌的发展。这些研究将说明正常功能所必需的细胞系统中的畸变如何强烈影响肿瘤的易感性，因此将对整个上皮癌领域产生广泛的影响。

DESCRIPTION (provided by applicant): Squamous cell carcinoma (SCC) constitutes approximately 20% of all nonmelanoma skin cancer, which is the most common type of human malignancy. SCC has a relatively high propensity for invasion and metastasis although the biological basis for the aggressive behavior of cutaneous SCCs is poorly understood. One characteristic of epithelial tumors such as SCC with a high risk of tumor progression is inappropriate alpha6beta4 integrin expression. However, the impact of aberrant alpha6beta4 expression in otherwise normal epithelium on the initiation and course of the disease is relatively unknown. Suprabasal expression of alpha6beta4 predisposes the epidermis to form chemically-induced tumors and perturbs transforming growth factor beta (TGFbeta) signaling in basal cells via a mechanism that requires E-cadherin-mediated intercellular adhesion and PI 3-kinase activity. The goal of this proposal is to define the molecular events by which suprabasal alpha6beta4 expression can enhance epidermal tumor formation and disrupt TGFbeta signaling. Proteins of the Rho family of small GTPases mediate actin cytoskeleton reorganization and are implicated in epithelial tumor progression. Preliminary findings indicate that suprabasal alpha6beta4 is linked to the actin cytoskeleton and co-localizes with Rac1 and that Rac activation is altered in transgenic murine epidermis and human SCCs that exhibit suprabasal alpha6beta4 expression. To envision a way that alpha6beta4 integrin, E-cadherin and PI 3-kinase could all act in concert to manipulate TGFbeta signaling and epidermal tumor formation, the aims of this proposal will focus on the role of the Rho family of small GTPases. We will characterize changes in Rho GTPase expression and activity in transgenic murine epidermis and human SCCs exhibiting suprabasal alpha6beta4 expression. We will manipulate Rho GTPase and PI 3-kinase signaling in cells overexpressing alpha6beta4 and determine its impact on TGFbeta-mediated growth inhibition. To define the effect of Rho GTPase activity on epidermal tumor formation, we will generate transgenic murine epidermis that is deficient in Rho GTPase activity and exhibits suprabasal alpha6beta4 expression. In this model we will measure the effect of ablated Rho GTPase signaling on basal cell proliferation and SCC induction. Overall, we plan to ascertain how changes in the way epidermal skin cells communicate with one another can impact on the development of potentially fatal human skin cancers. These studies will illustrate how aberrations in a cellular system essential for normal function can strongly influence the susceptibility for neoplasia, and therefore will have broad implications for the entire field of epithelial cancer.