Apigenin restores TSP-1 expression in UVB-irradiated keratinocytes

芹菜素恢复 UVB 照射的角质形成细胞中 TSP-1 的表达

基本信息

  • 批准号:
    9012025
  • 负责人:
  • 金额:
    $ 46.17万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-03-06 至 2017-01-01
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Non-melanoma skin cancer (NMSC) is a major health problem in the United States, with over two million new cases diagnosed yearly, making it the most common cancer in this country (1). Ultraviolet B (UVB) radiation is the major carcinogen for non-melanoma skin cancer. Like all solid tumors, NMSC promotes growth of new blood vessels (angiogenesis) in order to grow and metastasize. Thrombospondin-1 (TSP-1) is the first protein inhibitor of angiogenesis to be identified (2), and its expression is markedly downregulated in epidermis following UVB irradiation and throughout distinct steps of skin carcinogenesis (3-6). Apigenin (Api, 4', 5, 7- trihydroxyflavone), a nonmutagenic flavonoid found in fruits and vegetables, inhibits NMSC induced by UV exposure and chemical carcinogens (7,8). We and others have shown that Api induces many antitumorigenic and chemopreventive actions in multiple cell types (9-14), however, the role of TSP-1 in chemoprevention by Api has never been reported. Our preliminary results show that Api blocks downregulation of TSP-1 by UVB in cultured keratinocytes and skin in vivo. We show that regulation of TSP-1 expression in UVB/Api-treated keratinocytes occurs post-transcriptionally and is mediated by RNA-binding protein HuR. Importantly, HuR has recently been demonstrated to play an important role in translation of TSP-1 mRNA. In addition we have shown that Api promotes nuclear to cytoplasmic translocation of HuR (15), where polyribosomal translation of TSP-1 occurs. Furthermore, we have shown that siRNA knockdown of HuR expression abrogates the ability of Api to restore normal TSP-1 levels in UVB-irradiated keratinocytes. Our compelling preliminary results in an established in vivo model of UVB-induced skin carcinogenesis, confirms in vivo that UVB inhibited TSP-1 protein expression in epidermis and Api restored TSP-1 expression. Furthermore, Api inhibited UVB-induced up-regulation of stromal inflammation and microvascular density (MVD) in superficial dermis. Given the well-known anti-angiogenic and less studied anti-inflammatory action of TSP-1, it is likely that induction of TSP-1 expression by Api is the cause of decreased MVD and inflammatory infiltrates. Based on these findings, we propose to test the novel hypothesis that Api restores TSP-1 expression in UVB-irradiated epidermis via upregulation of TSP-1 translation. We further hypothesize that this induction of TSP-1 expression by Api leads to inhibition of inflammation and angiogenesis in the stromal compartment, with overall chemoprevention of NMSC. We propose to test this hypothesis in cell-based and in vivo studies using wild- type and Thrombospondin-1-null (TSP-1 -/-) mice and keratinocytes exposed to UVB and/or Api. Identifying TSP-1 as a key target of apigenin and demonstrating its important role in chemoprevention by Api will provide a new target and rationale for improved treatment and prevention strategies for NMSC.
描述(由申请人提供):非黑色素瘤皮肤癌 (NMSC) 是美国的一个主要健康问题,每年诊断出超过 200 万例新病例,使其成为该国最常见的癌症 (1)。紫外线 B (UVB) 辐射是非黑色素瘤皮肤癌的主要致癌物。与所有实体瘤一样,NMSC 促进新血管生长(血管生成)以生长和转移。 Thrombospondin-1 (TSP-1) 是第一个被鉴定的血管生成蛋白抑制剂 (2),在 UVB 照射后以及整个皮肤癌发生的不同步骤中,其表达在表皮中显着下调 (3-6)。芹菜素 (Api, 4', 5, 7- 三羟基黄酮) 是一种存在于水果和蔬菜中的非诱变类黄酮,可抑制由紫外线照射和化学致癌物诱导的 NMSC (7,8)。我们和其他人已经证明,Api 在多种细胞类型中诱导许多抗肿瘤发生和化学预防作用 (9-14),然而,TSP-1 在 Api 化学预防中的作用从未有过报道。我们的初步结果表明,Api 可阻断 UVB 在体内培养的角质形成细胞和皮肤中对 TSP-1 的下调。我们发现,经 UVB/Api 处理的角质形成细胞中 TSP-1 表达的调节发生在转录后,并由 RNA 结合蛋白 HuR 介导。重要的是,HuR 最近被证明在 TSP-1 mRNA 的翻译中发挥重要作用。此外,我们还发现 Api 促进 HuR (15) 从核到细胞质的易位,在此发生 TSP-1 的多核糖体翻译。此外,我们还发现,HuR 表达的 siRNA 敲低会消除 Api 在 UVB 照射的角质形成细胞中恢复正常 TSP-1 水平的能力。我们在 UVB 诱导皮肤癌的体内模型中取得了令人信服的初步结果,证实了 UVB 抑制了表皮中 TSP-1 蛋白的表达,而 Api 恢复了 TSP-1 表达。此外,Api 还能抑制 UVB 诱导的真皮浅层基质炎症和微血管密度 (MVD) 的上调。鉴于 TSP-1 众所周知的抗血管生成作用和较少研究的抗炎作用,Api 诱导 TSP-1 表达很可能是 MVD 减少和炎症浸润的原因。基于这些发现,我们建议测试 Api 通过上调 TSP-1 翻译来恢复 UVB 照射表皮中 TSP-1 表达的新假设。我们进一步假设 Api 对 TSP-1 表达的诱导导致基质室中炎症和血管生成的抑制,并对 NMSC 进行全面化学预防。我们建议使用暴露于 UVB 和/或 Api 的野生型和 Thrombospondin-1-null (TSP-1 -/-) 小鼠和角质形成细胞在基于细胞和体内的研究中检验这一假设。确定 TSP-1 作为芹菜素的关键靶点并证明其在 Api 化学预防中的重要作用将为改进 NMSC 的治疗和预防策略提供新的靶点和原理。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

OLGA Valery VOLPERT其他文献

OLGA Valery VOLPERT的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('OLGA Valery VOLPERT', 18)}}的其他基金

Apigenin restores TSP-1 expression in UVB-irradiated keratinocytes
芹菜素恢复 UVB 照射的角质形成细胞中 TSP-1 的表达
  • 批准号:
    8633023
  • 财政年份:
    2013
  • 资助金额:
    $ 46.17万
  • 项目类别:
Maximization of anti-angiogenesis by thrombospondin-1
血小板反应蛋白-1 最大限度地抑制血管生成
  • 批准号:
    6969494
  • 财政年份:
    2005
  • 资助金额:
    $ 46.17万
  • 项目类别:
Maximization of anti-angiogenesis by thrombospondin-1
血小板反应蛋白-1 最大限度地抑制血管生成
  • 批准号:
    7260287
  • 财政年份:
    2005
  • 资助金额:
    $ 46.17万
  • 项目类别:
Maximization of anti-angiogenesis by thrombospondin-1
血小板反应蛋白-1 最大限度地抑制血管生成
  • 批准号:
    7471438
  • 财政年份:
    2005
  • 资助金额:
    $ 46.17万
  • 项目类别:
Maximization of anti-angiogenesis by thrombospondin-1
血小板反应蛋白-1 最大限度地抑制血管生成
  • 批准号:
    7093581
  • 财政年份:
    2005
  • 资助金额:
    $ 46.17万
  • 项目类别:
Regulation of angiogenic balance by thrombospondin-1
血小板反应蛋白-1 调节血管生成平衡
  • 批准号:
    6364673
  • 财政年份:
    2001
  • 资助金额:
    $ 46.17万
  • 项目类别:
Regulation of angiogenic balance by thrombospondin-1
血小板反应蛋白-1 调节血管生成平衡
  • 批准号:
    6779791
  • 财政年份:
    2001
  • 资助金额:
    $ 46.17万
  • 项目类别:
Regulation of angiogenic balance by thrombospondin-1
血小板反应蛋白-1 调节血管生成平衡
  • 批准号:
    6527785
  • 财政年份:
    2001
  • 资助金额:
    $ 46.17万
  • 项目类别:
Regulation of angiogenic balance by thrombospondin-1.
血小板反应蛋白-1 调节血管生成平衡。
  • 批准号:
    7390374
  • 财政年份:
    2001
  • 资助金额:
    $ 46.17万
  • 项目类别:
Regulation of angiogenic balance by thrombospondin-1.
血小板反应蛋白-1 调节血管生成平衡。
  • 批准号:
    7216270
  • 财政年份:
    2001
  • 资助金额:
    $ 46.17万
  • 项目类别:

相似海外基金

Development of Novel Lung Cancer Therapy Using Tumor-Specific Angiogenesis Inhibitors and Drug Repositioning
使用肿瘤特异性血管生成抑制剂和药物重新定位开发新型肺癌疗法
  • 批准号:
    21H03019
  • 财政年份:
    2021
  • 资助金额:
    $ 46.17万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of biomarkers related to drug resistance of angiogenesis inhibitors
血管生成抑制剂耐药性相关生物标志物的开发
  • 批准号:
    20K08542
  • 财政年份:
    2020
  • 资助金额:
    $ 46.17万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Structural and Functional Studies of Brain Angiogenesis Inhibitors (BAIs/ADGRBs)
脑血管生成抑制剂 (BAIs/ADGRB) 的结构和功能研究
  • 批准号:
    9813883
  • 财政年份:
    2019
  • 资助金额:
    $ 46.17万
  • 项目类别:
Elucidation of proteinuria expression mechanism by angiogenesis inhibitors and research on adverse effect avoidance
血管生成抑制剂蛋白尿表达机制的阐明及不良反应避免的研究
  • 批准号:
    17K08457
  • 财政年份:
    2017
  • 资助金额:
    $ 46.17万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Evaluation of cardiotoxicity and elucidation of cardiotoxic molecular mechanisms in cancer patients receiving angiogenesis inhibitors
接受血管生成抑制剂的癌症患者的心脏毒性评估和心脏毒性分子机制的阐明
  • 批准号:
    26461102
  • 财政年份:
    2014
  • 资助金额:
    $ 46.17万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Minimally invasive response evaluation in vivo for the dual therapy of the angiogenesis inhibitors
血管生成抑制剂双重治疗的体内微创疗效评价
  • 批准号:
    23591763
  • 财政年份:
    2011
  • 资助金额:
    $ 46.17万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
ANGIOGENESIS INHIBITORS IN THE MULTIMODAL TREATMENT OF PEDIATRIC SOLID TUMORS
血管生成抑制剂在小儿实体瘤多模式治疗中的应用
  • 批准号:
    8309814
  • 财政年份:
    2011
  • 资助金额:
    $ 46.17万
  • 项目类别:
Discovery and Investigation of Novel Angiogenesis Inhibitors Among Existing Drugs
现有药物中新型血管生成抑制剂的发现和研究
  • 批准号:
    7351352
  • 财政年份:
    2008
  • 资助金额:
    $ 46.17万
  • 项目类别:
Discovery and Investigation of Novel Angiogenesis Inhibitors Among Existing Drugs
现有药物中新型血管生成抑制剂的发现和研究
  • 批准号:
    8002099
  • 财政年份:
    2008
  • 资助金额:
    $ 46.17万
  • 项目类别:
Novel Angiogenesis Inhibitors Targeting the Anthrax Toxin Receptors
针对炭疽毒素受体的新型血管生成抑制剂
  • 批准号:
    7615664
  • 财政年份:
    2008
  • 资助金额:
    $ 46.17万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了