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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要黑色素瘤是最致命的皮肤癌，据报告发病率不断增加每年。这种癌症起源于表皮基底层内的黑色素细胞并且可以迅速从新生肿瘤形成发展到远处转移。这进展受到多种因素的帮助，其中包括诱变，微环境变化以及细胞与细胞接触的丧失。正常条件下在皮肤，角质形成细胞和黑素细胞之间发生旁分泌信号（串扰）对于调节黑素细胞树突和增殖很重要。扰乱角质形成细胞介导的信号传导导致微环境改变，可能驱动黑色素瘤的发展。癌症数据库检查显示 17% 为黑色素瘤患者活检显示桥粒钙粘蛋白、桥粒糖蛋白 1 (Dsg1) 发生突变。然而，由于黑色素细胞和黑色素瘤细胞都不表达 Dsg1 或大多数桥粒蛋白，这表明邻近角质形成细胞在通过旁分泌信号机制调节黑色素瘤或黑色素细胞。损失角质形成细胞中的 Dsg1 揭示了白细胞介素 1 家族成员和促炎细胞因子、细胞因子以及其他信号分子长期以来一直致力于改变微环境并促进疾病的发展。黑素细胞仅表现出细胞因子显着增加与 Dsg1 沉默的角质形成细胞共培养后的生产。此外，Dsg1 已知可调节角质形成细胞中的表皮生长因子受体 (EGFR) 信号传导以一种不依赖于粘附的方式，对于产生亲的重要途径炎症细胞因子。基于这些观察，该提案检验了假设 Dsg1 通过角质形成细胞调节白细胞介素信号传导及其丢失或突变改变表皮微环境以促进黑色素瘤的发展。目标1将确定 Dsg1 突变对角质形成细胞细胞因子产生的影响。目标2将确定信号改变对黑色素细胞/黑色素瘤细胞行为的影响。这该项目将阐明 Dsg1 调节细胞的机制微环境以及这种调节如何改变之间的旁分泌信号角质形成细胞和黑色素细胞驱动黑色素瘤生成。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。