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。尽管皮肤SCC侵袭性行为的生物学基础尚不清楚，但SCC具有相对较高的侵袭和转移倾向。具有肿瘤进展高风险的上皮性肿瘤（如SCC）的一个特征是不适当的alpha6beta4整合素表达。然而，在正常上皮中异常的alpha6beta4表达对疾病发生和发展的影响相对未知。在基底上表达alpha6beta4使表皮容易形成化学诱导的肿瘤，并通过e -cadherin介导的细胞间粘附和PI 3-激酶活性的机制干扰基底细胞中的转化生长因子β (tgf β)信号。本研究的目的是确定基底上alpha6beta4表达促进表皮肿瘤形成和破坏tgf - β信号传导的分子事件。小gtpase的Rho家族蛋白介导肌动蛋白细胞骨架重组，并参与上皮肿瘤的进展。初步研究结果表明，基底上alpha6beta4与肌动蛋白细胞骨架相连，并与Rac1共定位，并且在表现出基底上alpha6beta4表达的转基因小鼠表皮和人SCCs中，Rac激活发生改变。为了设想一种方法，alpha6beta4整合素，E-cadherin和PI 3-kinase都可以协同作用，操纵tgf - β信号和表皮肿瘤的形成，本提案的目的将集中在Rho家族的小GTPases的作用上。

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.