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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.

项目总结