The role of E-cadherin in photocarcinogenesis

E-钙粘蛋白在光致癌作用中的作用

• 批准号: 7531243
• 负责人: Sabine M Brouxhon
• 金额: $ 4.79万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531243
• 关键词: Acute; Adhesives; Agonist; Applications Grants; Area; Awareness; Biological Models; Cancer Etiology; Carcinoma in Situ; Cell Surface Proteins; Cell membrane; Cell surface; Cells; Chronic; Cytoplasm; Data; Deformity; Degradation Pathway; Depth; Development; Dinoprostone; Dose; Down-Regulation; Dysplasia; E-Cadherin; Epithelial; Epithelial Cells; Epithelium; Exposure to; Generations; Healthcare; Human; In Situ Lesion; In Vitro; Inbred HRS Mice; Incidence; Indomethacin; Injury; Invasive; Knowledge; Lead; Lesion; Link; Loss of E-cadherin Expression; Lysosomes; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Medical; Modeling; Molecular; Morbidity - disease rate; Mus; Neoplastic Cell Transformation; Oncogenic; Pathway interactions; Process; Prostaglandin-Endoperoxide Synthase; Public Health; Purpose; Reporting; Research Project Grants; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinogenesis; Squamous cell carcinoma; Statistically Significant; System; Testing; Time; Ultraviolet Rays; Validation; anticancer research; butaprost; cancer diagnosis; cost; cyclooxygenase 1; cyclooxygenase 2; improved; in vivo; keratinocyte; loss of function; mortality; mouse model; multicatalytic endopeptidase complex; prostaglandin EP2 receptor; skin squamous cell carcinoma; tumor; tumorigenesis; ultraviolet; ultraviolet irradiation

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.

描述（由申请人提供）：本探索性发展（R21）研究拨款申请的目的是研究基底角化细胞及其后代中E-cadherin的缺失是否促进了紫外线（UV）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-cadherin下调的机制。我们的初步数据表明，在SKH-1无毛小鼠中，慢性紫外线照射导致E-cadherin表达的统计学显著降低，因为病变从早期原位癌和孤立的发育不良区域发展到小的和大的侵袭性SCCs。因此，我们假设基底角质形成细胞中E-cadherin表达的缺失在紫外线诱导的皮肤癌的早期发展和随后的进展中至关重要。在本提案中，我们将首先采用功能丧失研究，以临时调节和表皮特异性的方式确定e -钙粘蛋白下调是否促进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的发展。其次，我们将探讨定向E-cadherin缺失导致的¿-catenin动员是否通过激活TCF-LEF1信号通路诱导角质形成细胞的改变。此外，由于我们最近证明了吲哚美辛在体外抑制PGE2合成，在原代小鼠角质形成细胞（PMK）培养中靶向删除EP2或在体内或体外删除EP2受体可消除紫外线诱导的e -钙粘蛋白下调，我们还将研究PGE2-EP2信号传导诱导细胞表面e -钙粘蛋白缺失的机制。由于上皮癌占所有人类癌症的80%，解剖细胞表面e -钙粘蛋白如何促进一种上皮系统的肿瘤转化的研究可能对其他上皮系统很重要。此外，深入了解特定降解途径如何促进紫外线诱导的e -钙粘蛋白下调也可能为抗侵入性治疗提供新的靶点。最后，发现EP2信号通路和这些蛋白水解通路之间的“串扰”可能会产生新的靶点，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%，因此在上皮中选择性删除e -钙粘蛋白的小鼠模型系统的发展，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SCCs的理解。此外，深入了解通过PGE2-EP2信号传导的特定降解途径如何促进紫外线诱导的e -钙粘蛋白下调，可能会为癌症诊断和治疗的验证提供新的靶点。