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:9404521
- 负责人:
- 金额:$ 0.07万
- 依托单位:
- 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:
- 关键词:AdhesionsAffectAlpha CellAnnual ReportsAttenuatedAutomobile DrivingBindingBiological AssayBiopsyC-terminalCadherinsCarcinogensCell Adhesion MoleculesCellsClinical DataCoculture TechniquesComplexCouplingDataDatabasesDermatitisDevelopmentDiseaseDistant MetastasisE-CadherinERBB2 geneEngineeringEnzyme-Linked Immunosorbent AssayEpidermal Growth Factor ReceptorEpidermisEpitheliumExhibitsExposure toFamily memberHumanHypersensitivityIL8 geneImmunoblottingImmunoprecipitationImmunotherapyIn VitroIncidenceInflammationInflammatoryInterleukin-1Interleukin-15Interleukin-2Interleukin-7InterleukinsLesionLigationLinkMalignant NeoplasmsMediatingMelanoma CellMessenger RNAMetabolicModelingMutagenesisMutationP-CadherinParacrine CommunicationPathway interactionsPatient-Focused OutcomesPatientsPhenotypeProductionProteinsPublishingQuantitative Reverse Transcriptase PCRRas/RafReceptor SignalingRegulationRoleSamplingSignal PathwaySignal TransductionSignaling MoleculeSkinSkin CancerSpecimenStratum BasaleSyndromeTestingTherapeuticTimeTissue MicroarrayTissuesTumorigenicityUltraviolet Raysbasecancer typecell behaviorcytokinedesmoglein 1experimental studyinsightkeratinocytemelanocytemelanomamutantparacrineprogramsscaffoldsmall hairpin RNAtumortumor progressiontumorigenicwasting
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。这种癌症起源于表皮基底层内的黑素细胞
并且可以迅速从新生肿瘤形成进展到远处转移。这
几个因素有助于进展,这些因素可以包括诱变,
微环境的改变和细胞间接触的丧失。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传导(串扰)发生
并且对于调节黑素细胞的密度和增殖是重要的。破坏
角质形成细胞介导的信号转导导致微环境改变,可能驱动
黑色素瘤发展。对癌症数据库的检查显示,17%的黑色素瘤
患者活检显示桥粒钙粘蛋白,桥粒芯糖蛋白1(Dsg 1)突变。
然而,由于黑素细胞和黑色素瘤细胞都不表达Dsg 1,
桥粒蛋白,这表明邻近角质形成细胞的潜在作用,
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Dsg 1揭示了白细胞介素1家族成员的显著变化,
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,
疾病的发展。黑素细胞仅表现出细胞因子的显着增加
与Dsg 1沉默的角质形成细胞共培养后的产量。此外,Dsg 1
已知调节角质形成细胞中表皮生长因子受体(EGFR)信号传导
以不依赖于粘附的方式,一种重要的用于产生亲-
炎性细胞因子根据这些观察,本提案检验了以下假设:
Dsg 1通过角质形成细胞调节白细胞介素信号传导,
改变表皮微环境促进黑色素瘤的发展。目标1将
确定Dsg 1突变对角质形成细胞细胞因子产生的影响。目标2将
确定改变的信号传导对黑素细胞/黑素瘤细胞行为的影响。这
该项目将阐明Dsg 1调节细胞凋亡的机制。
微环境,以及这种调节如何改变旁分泌信号之间
角质形成细胞和黑素细胞来驱动黑色素瘤的发生。这些研究将是第一个
暗示Dsg 1在黑色素瘤中的信号作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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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