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

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.
项目摘要 黑色素瘤是最致命的皮肤癌,据报道发病率正在上升。 每年一次。这种癌症起源于表皮基底层的黑素细胞。 并且可以迅速从新生的肿瘤形成发展到远处转移。这 进展是由几个因素推动的,其中可能包括突变, 微环境改变,细胞与细胞之间的接触丧失。在正常情况下 皮肤,角质形成细胞和黑素细胞之间的旁分泌信号(串扰)发生 并且对调节黑素细胞的树突状和增殖很重要。中断 角质形成细胞介导的信号转导导致微环境改变,可能导致 黑色素瘤的发展。对癌症数据库的检查发现17%的黑色素瘤 患者活组织检查显示桥粒钙粘蛋白1(DSG1)发生突变。 然而,由于黑素细胞和黑色素瘤细胞都不表达DSG1或大多数 桥粒蛋白,这表明邻近的角质形成细胞可能在 通过旁分泌信号机制调节黑色素瘤或黑素细胞。损失 角质形成细胞中的DSG1显示白介素1家族成员和 促炎细胞因子和细胞因子以及其他信号分子 长期以来一直与改变微环境有关,并对 疾病的发展。黑素细胞只有细胞因子显著增加。 与角质形成细胞共培养后产生的DSG1被沉默。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 以不依赖黏附的方式,对生产亲和素很重要的一条途径 炎性细胞因子。在这些观察的基础上,这项提议检验了假设 DSG1通过角质形成细胞调节白细胞介素性信号及其缺失或突变 改变表皮微环境,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 微环境及其调控对旁分泌信号的影响 角质形成细胞和黑素细胞驱动黑色素瘤的形成。这些研究将是第一次 探讨DSG1在黑色素瘤中的信号转导作用。

项目成果

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Christopher R. Arnette其他文献

Keratinocyte desmoglein 1 regulates the epidermal microenvironment and tanning response
角质形成细胞桥粒芯糖蛋白 1 调节表皮微环境和晒黑反应
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Christopher R. Arnette;J. Koetsier;Joshua A. Broussard;P. Gerami;Jodi L. Johnson;K. Green
  • 通讯作者:
    K. Green

Christopher R. Arnette的其他文献

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{{ truncateString('Christopher R. Arnette', 18)}}的其他基金

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
  • 财政年份:
    2016
  • 资助金额:
    $ 0.07万
  • 项目类别:

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