Desmosomal Cadherin Regulation of Pro-inflammatory Cytokine Production in Melanomagenesis

桥粒钙粘蛋白对黑色素瘤发生中促炎细胞因子产生的调节

• 批准号: 9192220
• 负责人: Christopher R. Arnette
• 金额: $ 5.61万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192220
• 关键词: Adhesions; Affect; Attenuated; Automobile Driving; Binding; Binding Proteins; Biological Assay; Biopsy; C-terminal; Cadherins; Carcinogens; Cell Adhesion Molecules; Cell-Cell Adhesion; Cells; Clinical Data; Coculture Techniques; Complex; Conditioned Culture Media; Coupling; Data; Databases; Dermatitis; Development; Disease; Distant Metastasis; E-Cadherin; Engineering; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor Receptor; Epidermis; Epithelium; Exhibits; Exposure to; Family member; Human; Hypersensitivity; IL8 gene; Immunoblotting; Immunoprecipitation; Immunotherapy; In Vitro; Incidence; Inflammation; Inflammatory; Interleukin-1; Interleukin-15; Interleukin-2; Interleukin-7; Interleukins; Lesion; Ligation; Link; Malignant Neoplasms; Mediating; Melanoma Cell; Messenger RNA; Metabolic; Modeling; Mutagenesis; Mutation; P-Cadherin; Paracrine Communication; Pathway interactions; Patient-Focused Outcomes; Patients; Production; Proteins; Publishing; Ras/Raf; Receptor Signaling; Regulation; Reporting; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Skin Cancer; Specimen; Staging; Stratum Basale; Syndrome; Testing; Therapeutic; Time; Tissue Microarray; Tissues; Ultraviolet Rays; base; cancer type; cell behavior; cytokine; desmoglein 1; insight; keratinocyte; melanocyte; melanoma; mutant; paracrine; programs; research study; scaffold; tumor; tumor progression; tumorigenic; wasting

Project Summary Melanoma is the deadliest skin cancer, with an increasing incidence reported annually. This cancer originates from melanocytes within the basal layer of the epidermis and can quickly progress from nascent tumor formation to distant metastases. This progression is aided by several factors, which can include mutagenesis, microenvironment changes, and loss of cell-cell contact. Under normal conditions within the skin, paracrine signaling between keratinocytes and melanocytes (crosstalk) occurs and is important for regulating melanocyte dendricity and proliferation. Disruption of keratinocyte-mediated signaling results in an altered microenvironment, possibly driving melanoma development. Examination of cancer databases revealed 17% of melanoma patient biopsies showed mutations in desmosomal cadherin, Desmoglein 1 (Dsg1). However, as neither melanocytes nor melanoma cells express Dsg1 or the majority of desmosomal proteins, this suggests a potential role for neighboring keratinocytes to regulate melanoma or melanocytes through a paracrine signaling mechanism. Loss of Dsg1 in keratinocytes revealed significant changes in interleukin 1 family members and pro-inflammatory cytokines, and cytokines, as well as other signaling molecules, have long been implicated in altering the microenvironment and contributing to the development of disease. Melanocytes only exhibited significant increases in cytokine production following co-culture with keratinocytes silenced for Dsg1. Furthermore, Dsg1 is known to regulate epidermal growth factor receptor (EGFR) signaling in keratinocytes in an adhesion-independent manner, a pathway important for the production of pro- inflammatory cytokines. Based on these observations, this proposal tests the hypothesis that Dsg1 regulates interleukin signaling by keratinocytes and that its loss or mutation alters the epidermal microenvironment to promote melanoma development. Aim 1 will determine the effect of mutations of Dsg1 on keratinocyte cytokine production. Aim 2 will determine the effects of altered signaling on melanocyte/melanoma cell behavior. This project will elucidate the mechanisms by which Dsg1 regulates the cellular microenvironment and how this regulation alters the paracrine signaling between keratinocytes and melanocytes to drive melanomagenesis. These studies will be the first to implicate a signaling role for Dsg1 in melanoma.

项目摘要 黑色素瘤是最致命的皮肤癌，报告率越来越多 每年。该癌症起源于表皮基底层内的黑素细胞 并可以迅速从新生的肿瘤形成到远处转移。这 进展得到了几个因素的帮助，这些因素可能包括诱变， 微环境会改变和细胞接触的丧失。在正常情况下 角质形成细胞和黑素细胞（串扰）之间的皮肤，旁分泌信号传导发生 对于调节黑素细胞树突和增殖很重要。破坏 角质形成细胞介导的信号传导导致微环境改变，可能驱动 黑色素瘤发育。癌症数据库的检查显示了17％的黑色素瘤 患者活检显示在脱乳小蛋白，脱木质1（DSG1）中突变。 但是，由于黑色素细胞和黑色素瘤细胞都不表达DSG1或大多数 脱染色体蛋白，这表明相邻角质形成细胞的潜在作用 通过旁分泌信号传导机制调节黑色素瘤或黑素细胞。损失 角质形成细胞中的DSG1揭示了白介素1个家庭成员的重大变化， 促炎性细胞因子，细胞因子以及其他信号分子具有 长期以来一直涉及改变微环境，并为 疾病的发展。黑素细胞仅显示细胞因子显着增加 与角质形成细胞共培养后，生产DSG1沉默。此外，DSG1 已知可以调节角质形成细胞中表皮生长因子受体（EGFR）信号传导 以与附着力无关的方式，这对于生产前的途径很重要 炎症细胞因子。基于这些观察结果，该提案检验了假设 DSG1调节角质形成细胞的白介素信号传导，其损失或突变 改变表皮微环境以促进黑色素瘤的发展。目标1意志 确定DSG1突变对角质形成细胞细胞因子产生的影响。 AIM 2意志 确定信号改变对黑色素/黑色素瘤细胞行为的影响。这 项目将阐明DSG1调节细胞的机制 微环境以及该调节如何改变旁分泌信号 角质形成细胞和黑素细胞驱动黑素作仿。这些研究将是第一个 暗示DSG1在黑色素瘤中的信号传导作用。