The role of E-cadherin in photocarcinogenesis

描述(申请人提供)：这项探索性发展(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-钙粘附素的缺失是否有助于紫外线(UV)光诱导的皮肤鳞状细胞癌(SCCs)的发展，并研究紫外线辐射诱导E-钙粘附素下调的机制(S)。我们的初步数据显示，在SKH-1无毛小鼠中，随着病变从早期原位癌伴孤立的异型增生区域进展到小的和大的侵袭性鳞状细胞，慢性紫外线照射导致E-钙粘附素的表达在统计学上显著降低。因此，我们假设E-钙粘附素在基底层角质形成细胞中的表达缺失在紫外线诱导的皮肤癌的早期发展和随后的进展中起关键作用。在这项提案中，我们将首先利用功能丧失研究，以时间调节和表皮特异性的方式确定E-钙粘素下调是否促进鳞癌的发展。这将使用我们已建立的光癌模型来完成，该模型之前已被证明模拟人类皮肤癌的发展。其次，我们将探索E-钙粘附素靶向缺失导致的连环蛋白动员是否通过激活TCF-LEF1信号通路而导致角质形成细胞的改变。此外，由于我们最近证明了吲哚美辛在体外抑制PGE2的合成，在原代小鼠角质形成细胞(PMK)中靶向删除EP2，或者在体内或体外删除EP2受体，取消了紫外线诱导的E-钙粘蛋白下调，我们还将研究PGE2-EP2信号导致细胞表面E-钙粘素丢失的机制。由于上皮性癌症占人类所有癌症的80%，研究细胞表面E-钙粘附素的缺失如何促进一个上皮系统的肿瘤转化可能在其他上皮系统中也很重要。此外，深入了解特定的降解途径如何有助于紫外线诱导的E-钙粘素下调也可能为抗侵入性治疗提供新的靶点。最后，EP2信号通路和这些蛋白分解通路之间“串扰”的发现可能为癌症诊断和治疗的验证提供新的靶点。公共卫生相关性：由于上皮性癌症占人类所有癌症的80%，建立E-钙粘附素选择性缺失的小鼠模型系统，可能会增强我们对重复紫外线损伤后早期原位病变形成和发展为鳞状细胞的理解。此外，深入了解特定的降解途径如何通过PGE2-EP2信号对紫外线诱导的E-钙粘素下调起作用，可能会为癌症诊断和治疗提供新的验证靶点。

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.