Malignant melanoma: Regulation by AP-2 and PAR-1

恶性黑色素瘤:AP-2 和 PAR-1 的调节

基本信息

  • 批准号:
    8259480
  • 负责人:
  • 金额:
    $ 26.29万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1999
  • 资助国家:
    美国
  • 起止时间:
    1999-04-01 至 2014-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The molecular changes associated with the transition of melanoma cells from Radial Growth Phase (RGP) to Vertical Growth Phase (VGP) and the acquisition of the metastatic phenotype is not very well-defined. Recent work from this laboratory demonstrated that this transition is associated with loss of nuclear expression of AP-2a in metastatic melanoma cells which resulted in deregulation of c-KIT, MCAM/MUC18, MMP-2, and VEGF, all of which are involved in the progression of human melanoma. However, the mechanisms for the lack of AP-2a expression in metastatic melanoma cells are not known. Using melanoma tissue microarrays combined with LSC and AQUA technologies, here, we further validated the lack of nuclear AP-2a expression in metastatic melanoma cells. In an effort to search for other target genes regulated by AP-2a, we have identified the thrombin receptor (PAR-1) and provided evidence for inverse correlation between AP-2a and PAR-1 expression in metastatic melanoma cells. Regulation of PAR-1 by AP-2a was demonstrated in vitro and in vivo, thus providing a unique link between the coagulation system and the progression of human melanoma. The role of PAR-1 in the progression of human melanoma is now established through the efforts of this continued research. We have used stable silencing of PAR-1 by lentiviral shRNA combined with cDNA chip arrays and cytokine membrane arrays to identify possible downstream genes regulated by the axis of thrombin/PAR-1. These genes include MCAM/MUC18, Connexin 43, Maspin, RUNX3, IL-8, Ang-2, GRO, ACRP30, and GITR-ligand. The hypothesis to be tested in this proposal is that loss of nuclear AP-2a results in upregulation of PAR-1 and contributes to the acquisition of the malignant phenotype in human melanoma. To test this hypothesis, we now propose: 1) To determine the mechanism(s) for the loss of nuclear AP-2a expression during melanoma progression; 2) To investigate how the axis of thrombin/PAR-1 contributes to the metastatic phenotype; and 3) To inhibit PAR-1 expression in vivo via delivery of siRNA packaged in neutral liposome nanoparticles as a possible new therapeutic modality. It is expected that the results obtained from this study will provide a better understanding of the role of AP-2a and PAR-1 in the progression of human melanoma that could thereby lead to new modalities to inhibit melanoma metastasis. PUBLIC HEALTH RELEVANCE: The molecular changes that are associated with the progression of human melanoma from radial growth phase into a vertical growth phase (metastatic phenotype) are largely unknown. Previously, we identified that the loss of the transcription factor AP-2a is associated with this transition. In this grant application, we will continue to investigate the role of AP-2a and its downstream target gene, the thrombin receptor (PAR-1), in the progression of human melanoma.
描述(由申请方提供):与黑色素瘤细胞从放射状生长期(RGP)向垂直生长期(VGP)转变以及获得转移表型相关的分子变化尚未明确。 该实验室最近的工作表明,这种转变与转移性黑色素瘤细胞中AP-2a的核表达丧失有关,这导致c-KIT、MCAM/MUC 18、MMP-2和VEGF的失调,所有这些都参与了人黑色素瘤的进展。 然而,在转移性黑素瘤细胞中缺乏AP-2a表达的机制尚不清楚。 使用黑色素瘤组织微阵列结合LSC和AQUA技术,在这里,我们进一步验证了转移性黑色素瘤细胞中缺乏核AP-2a表达。 为了寻找AP-2a调控的其他靶基因,我们鉴定了凝血酶受体(PAR-1),并为转移性黑色素瘤细胞中AP-2a和PAR-1表达之间的负相关性提供了证据。 在体外和体内证实了AP-2a对PAR-1的调节,从而提供了凝血系统与人黑色素瘤进展之间的独特联系。 PAR-1在人类黑色素瘤进展中的作用现在通过这项持续研究的努力而确立。 我们使用稳定沉默PAR-1的慢病毒shRNA结合cDNA芯片阵列和细胞因子膜阵列,以确定可能的下游基因调节凝血酶/PAR-1轴。 这些基因包括MCAM/MUC 18、连接蛋白43、Maspin、RUNX 3、IL-8、Ang-2、GRO、ACRP 30和GITR配体。 在该提议中待检验的假设是,核AP-2a的缺失导致PAR-1的上调,并有助于获得人黑色素瘤的恶性表型。 为了验证这一假设,我们现在提出:1)确定黑色素瘤进展期间核AP-2a表达丧失的机制; 2)研究凝血酶/PAR-1轴如何有助于转移表型;和3)通过递送包装在中性脂质体纳米颗粒中的siRNA来抑制PAR-1体内表达,作为可能的新治疗方式。 预期从本研究获得的结果将提供对AP-2a和PAR-1在人黑素瘤进展中的作用的更好理解,从而可能导致抑制黑素瘤转移的新模式。 公共卫生相关性:与人黑色素瘤从径向生长期进展到垂直生长期(转移表型)相关的分子变化在很大程度上是未知的。 以前,我们确定转录因子AP-2a的丢失与这种转变有关。 在本基金申请中,我们将继续研究AP-2a及其下游靶基因凝血酶受体(PAR-1)在人类黑色素瘤进展中的作用。

项目成果

期刊论文数量(40)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Fully human antibodies to MCAM/MUC18 inhibit tumor growth and metastasis of human melanoma.
  • DOI:
  • 发表时间:
    2002-09
  • 期刊:
  • 影响因子:
    11.2
  • 作者:
    L. Mills;C. Tellez;Suyun Huang;C. Baker;M. McCarty;L. Green;J. Gudas;Xiao Feng;M. Bar‐eli
  • 通讯作者:
    L. Mills;C. Tellez;Suyun Huang;C. Baker;M. McCarty;L. Green;J. Gudas;Xiao Feng;M. Bar‐eli
CREB inhibits AP-2alpha expression to regulate the malignant phenotype of melanoma.
  • DOI:
    10.1371/journal.pone.0012452
  • 发表时间:
    2010-08-27
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Melnikova VO;Dobroff AS;Zigler M;Villares GJ;Braeuer RR;Wang H;Huang L;Bar-Eli M
  • 通讯作者:
    Bar-Eli M
NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis.
  • DOI:
    10.1158/0008-5472.can-15-2511
  • 发表时间:
    2016-06-01
  • 期刊:
  • 影响因子:
    11.2
  • 作者:
    Shoshan E;Braeuer RR;Kamiya T;Mobley AK;Huang L;Vasquez ME;Velazquez-Torres G;Chakravarti N;Ivan C;Prieto V;Villares GJ;Bar-Eli M
  • 通讯作者:
    Bar-Eli M
Targeting the ATF-1/CREB transcription factors by single chain Fv fragment in human melanoma: potential modality for cancer therapy.
  • DOI:
    10.1615/critrevimmunol.v21.i1-3.180
  • 发表时间:
    2001
  • 期刊:
  • 影响因子:
    1.3
  • 作者:
    D. Jean;M. Bar‐eli
  • 通讯作者:
    D. Jean;M. Bar‐eli
Transcriptional control of melanoma metastasis: the importance of the tumor microenvironment.
  • DOI:
    10.1016/j.semcancer.2010.12.007
  • 发表时间:
    2011-04
  • 期刊:
  • 影响因子:
    14.5
  • 作者:
    Braeuer RR;Zigler M;Villares GJ;Dobroff AS;Bar-Eli M
  • 通讯作者:
    Bar-Eli M
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MENASHE BARELI其他文献

MENASHE BARELI的其他文献

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{{ truncateString('MENASHE BARELI', 18)}}的其他基金

AKT-Vimentin interaction; a potential role in soft tissue sarcoma progression and
AKT-波形蛋白相互作用;
  • 批准号:
    8249120
  • 财政年份:
    2009
  • 资助金额:
    $ 26.29万
  • 项目类别:
AKT-Vimentin interaction; a potential role in soft tissue sarcoma progression and
AKT-波形蛋白相互作用;
  • 批准号:
    8458614
  • 财政年份:
    2009
  • 资助金额:
    $ 26.29万
  • 项目类别:
Biology and Therapeutic Targeting of the Epidermal Growth Factor Receptor in Blad
Blad 表皮生长因子受体的生物学和治疗靶向
  • 批准号:
    7729507
  • 财政年份:
    2008
  • 资助金额:
    $ 26.29万
  • 项目类别:
Targeting Angiogenesis and the Tumor Microenvironment Utilizing si RNA
利用 si RNA 靶向血管生成和肿瘤微环境
  • 批准号:
    7895198
  • 财政年份:
    2004
  • 资助金额:
    $ 26.29万
  • 项目类别:
Targeting Angiogenesis and the Tumor Microenvironment Utilizing si RNA
利用 si RNA 靶向血管生成和肿瘤微环境
  • 批准号:
    8327828
  • 财政年份:
    2004
  • 资助金额:
    $ 26.29万
  • 项目类别:
Targeting Angiogenesis and the Tumor Microenvironment Utilizing si RNA
利用 si RNA 靶向血管生成和肿瘤微环境
  • 批准号:
    8728574
  • 财政年份:
    2004
  • 资助金额:
    $ 26.29万
  • 项目类别:
Targeting Angiogenesis and the Tumor Microenvironment Utilizing si RNA
利用 si RNA 靶向血管生成和肿瘤微环境
  • 批准号:
    8380914
  • 财政年份:
    2004
  • 资助金额:
    $ 26.29万
  • 项目类别:
BIOLOGY AND THERAPEUTIC TARGETING OF IL-8 AND MUC18/MCAM
IL-8 和 MUC18/MCAM 的生物学和治疗靶向
  • 批准号:
    6993431
  • 财政年份:
    2004
  • 资助金额:
    $ 26.29万
  • 项目类别:
Targeting Angiogenesis and the Tumor Microenvironment Utilizing si RNA
利用 si RNA 靶向血管生成和肿瘤微环境
  • 批准号:
    8541570
  • 财政年份:
    2004
  • 资助金额:
    $ 26.29万
  • 项目类别:
Malignant melanoma: Regulation by AP-2 and PAR-1
恶性黑色素瘤:AP-2 和 PAR-1 的调节
  • 批准号:
    8065375
  • 财政年份:
    1999
  • 资助金额:
    $ 26.29万
  • 项目类别:
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