The role of E-cadherin in photocarcinogenesis

描述（由申请人提供）：本探索-发展（R21）研究资助提案的目的是调查基底角质形成细胞及其后代中E-钙粘蛋白的丢失是否有助于紫外线（UV）诱导的皮肤鳞状细胞癌（SCC）的发展，并检查UV辐射诱导E-钙粘蛋白下调的机制。我们的初步数据表明，在SKH-1无毛小鼠的慢性紫外线照射的结果在统计学上显着减少E-钙粘蛋白表达的病变进展，从早期原位癌与孤立地区的异型增生，通过小和大的浸润性SCC。因此，我们推测，E-钙粘蛋白表达的基础角质形成细胞的损失是至关重要的，在紫外线诱导的皮肤癌的早期发展和随后的进展。在这个建议中，我们将首先采用功能丧失的研究，以确定在一个时间调节和表皮特异性的方式是否E-钙粘蛋白下调促进SCC的发展。这将使用我们完善的光致癌模型来完成，该模型先前已被证明可以模拟人类皮肤致癌作用的发展。第二，我们将探讨靶向E-cadherin缺失引起的β-catenin动员是否通过激活TCF-LEF 1信号通路诱导角质形成细胞的改变。此外，由于我们最近证明，抑制PGE 2合成的吲哚美辛在体外，有针对性地删除EP 2在原代小鼠角质形成细胞（PMK）的文化或删除EP 2受体在体内或体外废除这种UV诱导的E-钙粘蛋白下调，我们还将研究的机制，其中PGE 2-EP 2信号诱导细胞表面E-钙粘蛋白的损失。由于上皮癌占所有人类癌症的80%，因此研究细胞表面E-cadherin的丢失如何促进一种上皮系统中的肿瘤转化可能在其他系统中很重要。此外，深入了解特定的降解途径如何促进UV诱导的E-钙粘蛋白下调也可能为抗侵袭治疗提供新的靶点。最后，EP 2信号通路和这些蛋白水解通路之间的“串扰”的发现可能会产生新的目标，用于癌症诊断和治疗的验证。 公共卫生相关性：由于上皮癌占所有人类癌症的80%，因此开发上皮中选择性缺失E-钙粘蛋白的小鼠模型系统可能会增强我们对重复UV损伤后原位病变如何早期形成并进展为SCC的理解。此外，深入了解特定的降解途径，通过PGE 2-EP 2信号，有助于UV诱导的E-钙粘蛋白下调可能会产生新的目标，在癌症诊断和治疗的验证。

DESCRIPTION (provided by applicant): The purpose of this exploratory-developmental (R21) research grant proposal is to investigate whether loss of E-cadherin in basal keratinocytes and their progeny is facilitative in the development of ultraviolet (UV) lightinduced skin squamous cell carcinomas (SCCs) and examine the mechanism(s) by which UV radiation induces E-cadherin down-regulation. Our preliminary data demonstrate that chronic UV-irradiation in SKH-1 hairless mice results in a statistically significant reduction of E-cadherin expression as lesions progress from early in situ carcinomas with isolated areas of dysplasia, through small and large invasive SCCs. Therefore we hypothesize that loss of E-cadherin expression in basal keratinocytes is critical in the early development and subsequent progression of UV-induced skin cancers. In this proposal, we will first employ loss of function studies to determine in a temporally regulated and epidermal-specific fashion whether E-cadherin down-regulation facilitates SCC development. This will be done using our well established model of photocarcinogenesis that has previously been shown to mimic the development of skin carcinogenesis in humans. Second, we will explore whether ¿-catenin mobilization, resulting from targeted E-cadherin deletion, induces alterations in keratinocytes by activating the TCF-LEF1 signaling pathway. Moreover, since we recently demonstrated that inhibition of PGE2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo or in vitro abrogated this UV-induced E-cadherin downregulation, we will also examine the mechanism by which PGE2-EP2 signaling induces this loss of cell surface E-cadherin. Since epithelial cancers comprise 80% of all human cancers, research that dissects how loss of cell surface E-cadherin facilitates neoplastic transformation in one epithelial system would likely be important in others. Moreover, in depth knowledge of how specific degradative pathways contribute to UV-induced E-cadherin downregulation might also provide new targets for anti-invasive therapy. Finally, the discovery of 'crosstalk' between the EP2 signaling pathway and these proteolytic pathways might yield new targets for validation in cancer diagnosis and therapy. PUBLIC HEALTH RELEVANCE: Since epithelial cancers comprise 80% of all human cancers, development of mouse model systems in which E-cadherin is selectively deleted in epithelium, may enhance our understanding of how early in situ lesions form and progress to SCCs after a repetitive UV injury. Moreover, in depth knowledge of how specific degradative pathways, via PGE2-EP2 signaling, contribute to UV-induced E-cadherin downregulation might yield new targets for validation in cancer diagnosis and therapy.