Analysis of TGF-β/BMP signaling during bone metastasis and development of cancer therapy

骨转移过程中TGF-β/BMP信号传导分析及癌症治疗发展

基本信息

  • 批准号:
    17390422
  • 负责人:
  • 金额:
    $ 10.72万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
  • 财政年份:
    2005
  • 资助国家:
    日本
  • 起止时间:
    2005 至 2007
  • 项目状态:
    已结题

项目摘要

Members of the transforming growth factor-b (TGF-β) superfamily, including TGF-β and bone morphogenetic proteins (BMPs), are multifunctional cytokines that regulate a wide range of cellular responses, including cell proliferation, differentiation, adhesion, migration, and apoptosis. TGF-β signaling facilitates tumor growth and metastasis in advanced cancer. The TGF-β signaling pathway has correspondingly become an attractive target for drug development in the field of oncology.We investigated the roles of TGF-β and BMP signaling during bone metastasis. We first established a highly bone-metastatic variant of human breast cancer MDA-MB-231 cells, termed MDA-MB-231-5a-D (MDA-231-D). Next, we examined the effects of a novel TGF-β type I receptor (TBR-I) kinase inhibitor, Ki26894, on bone metastasis of MDA-231-D cells. Ki26894 blocked TGF-β signaling in MDA-231-D cells, as detected by suppression of phosphorylation of Smad2 and inhibition of TGF-β-responsive reporter activity. Moreover, Ki … More 26894 decreased the motility and the invasion of MDA-231-D cells induced by TGF-β in vitro. Ki26894 also suppressed transcription of plasminogen activator inhibitor-1 (PAI-1), parathyroid hormone-related protein (PTHrP), and interleukin-11 (IL-11) mRNA of MDA-231-D cells, which were stimulated by TGF-β. X-ray radiography revealed that systemic Ki26894 treatment initiated 1 day before the inoculation of MDA-231-D cells into the left ventricle of BALB/c nu/nu female mice resulted in decreased bone metastasis of breast cancer cells. Moreover, Ki26894 prolonged the survival of mice inoculated with MDA-231-D cells compared to vehicle-treated mice. These findings suggest that TβR-I kinase inhibitors such as Ki26894 may be useful for blocking the progression of advanced cancers.In addition, we identified differentially expressed in chondrocytes 1 (DEC1, also known as SHARP2 and Stral3) as a downstream target of TGF-β signaling, which promotes the survival of breast cancer cells. In the mouse mammary carcinoma cell lines JygMC (A) and 4T1, the TBR-β kinase inhibitors A-44-03 and SB431542 induced apoptosis of cells under serum-free conditions. Oligonucleotide microarray and real-time reverse transcription-PCR analyses revealed that TGF-β induced DEC1 in these cells, and the increase of DEC1 was suppressed by the TβR-I kinase inhibitors as well as by expression of dominant-negative TGF-β type II receptor. Overexpression of DEC1 prevented the apoptosis of JygMC (A) cells induced by A-44-03, and knockdown of endogenous DEC1 abrogated TGF-β-promoted cell survival. Moreover, a dominant-negative mutant of DEC1 prevented lung and liver metastasis of JygMC (A) cells in vivo. Our observations thus provide new insights into the molecular mechanisms governing TGF-β-mediated cell survival and metastasis of cancer. Less
转化生长因子-b (TGF-β) 超家族的成员,包括 TGF-β 和骨形态发生蛋白 (BMP),是调节多种细胞反应的多功能细胞因子,包括细胞增殖、分化、粘附、迁移和凋亡。 TGF-β信号传导促进晚期癌症的肿瘤生长和转移。 TGF-β信号通路相应地成为肿瘤学领域药物开发的一个有吸引力的靶点。我们研究了TGF-β和BMP信号通路在骨转移过程中的作用。我们首先建立了人乳腺癌 MDA-MB-231 细胞的高度骨转移变体,称为 MDA-MB-231-5a-D (MDA-231-D)。接下来,我们研究了新型 TGF-β I 型受体 (TBR-I) 激酶抑制剂 Ki26894 对 MDA-231-D 细胞骨转移的影响。 Ki26894 阻断 MDA-231-D 细胞中的 TGF-β 信号传导,通过抑制 Smad2 磷酸化和抑制 TGF-β 响应报告基因活性来检测。此外,Ki … 更多 26894 降低了体外 TGF-β 诱导的 MDA-231-D 细胞的运动和侵袭。 Ki26894 还抑制受 TGF-β 刺激的 MDA-231-D 细胞的纤溶酶原激活剂抑制剂-1 (PAI-1)、甲状旁腺激素相关蛋白 (PTHrP) 和白细胞介素 11 (IL-11) mRNA 的转录。 X射线照相显示,在将MDA-231-D细胞接种到BALB/c nu/nu雌性小鼠的左心室前1天开始全身Ki26894治疗,导致乳腺癌细胞的骨转移减少。此外,与媒介物处理的小鼠相比,Ki26894 延长了接种 MDA-231-D 细胞的小鼠的存活时间。这些发现表明,Ki26894等TβR-I激酶抑制剂可能有助于阻止晚期癌症的进展。此外,我们发现软骨细胞1(DEC1,也称为SHARP2和Stral3)中差异表达的蛋白是TGF-β信号传导的下游靶标,可促进乳腺癌细胞的存活。在小鼠乳腺癌细胞系 JygMC (A) 和 4T1 中,TBR-β 激酶抑制剂 A-44-03 和 SB431542 在无血清条件下诱导细胞凋亡。寡核苷酸微阵列和实时逆转录PCR分析表明,TGF-β在这些细胞中诱导DEC1,并且TβR-I激酶抑制剂以及显性失活TGF-β II型受体的表达抑制DEC1的增加。 DEC1 的过度表达可阻止 A-44-03 诱导的 JygMC (A) 细胞凋亡,而内源性 DEC1 的敲除可消除 TGF-β 促进的细胞存活。此外,DEC1 的显性失活突变体可阻止 JygMC (A) 细胞体内的肺和肝转移。因此,我们的观察结果为控制 TGF-β 介导的细胞存活和癌症转移的分子机制提供了新的见解。较少的

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)
乳癌骨転移におけるTGF-βシグナルとインビボイメージング
乳腺癌骨转移中的TGF-β信号和体内成像
  • DOI:
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Moren A;Imamura T (他3名;2番目);Takeshi Imamura;Takeshi Imamura;今村健志
  • 通讯作者:
    今村健志
癌研究におけるインビボバイオイメージングの応用
体内生物成像在癌症研究中的应用
  • DOI:
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Moren A;Imamura T (他3名;2番目);Takeshi Imamura;Takeshi Imamura;今村健志;今村健志
  • 通讯作者:
    今村健志
Visualizing spatiotemporal dynamics of multicellular cell-cycle progression
  • DOI:
    10.1016/j.cell.2007.12.033
  • 发表时间:
    2008-02-08
  • 期刊:
  • 影响因子:
    64.5
  • 作者:
    Sakaue-Sawano, Asako;Kurokawa, Hiroshi;Miyawaki, Atsushi
  • 通讯作者:
    Miyawaki, Atsushi
Modulation of the functional binding sites for TGF-β on the type II receptor leads to suppression of TGF-β signaling
  • DOI:
    10.1038/sj.onc.1210123
  • 发表时间:
    2007-05-17
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Shimanuki, T.;Hara, T.;Miyazono, K.
  • 通讯作者:
    Miyazono, K.
がん研究におけるインビボ光イメージング
癌症研究中的体内光学成像
  • DOI:
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Moren A;Imamura T (他3名;2番目);Takeshi Imamura;Takeshi Imamura;今村健志;今村健志;今村健志;今村健志;今村健志;今村健志
  • 通讯作者:
    今村健志
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IMAMURA Takeshi其他文献

Limb fitting and cloud tracking for the study of the Venus atmosphere
用于金星大气研究的肢体拟合和云跟踪
  • DOI:
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    0
  • 作者:
    OGOHARA Kazunori;KASHIMURA Hiroki;KOUYAMA Toru;SATO Naoki;TAKAGI Masahiro;IMAMURA Takeshi;HORINOUCHI Takeshi
  • 通讯作者:
    HORINOUCHI Takeshi

IMAMURA Takeshi的其他文献

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{{ truncateString('IMAMURA Takeshi', 18)}}的其他基金

The mechanisms of Galectin3-induced stem cell dysfunction and the effects of anti-galectin3 therapy
Galectin3诱导干细胞功能障碍的机制及抗Galectin3治疗的效果
  • 批准号:
    19H03378
  • 财政年份:
    2019
  • 资助金额:
    $ 10.72万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Microscale processes in the Venus atmosphere revealed by radio occultation
射电掩星揭示金星大气层中的微观过程
  • 批准号:
    24540482
  • 财政年份:
    2012
  • 资助金额:
    $ 10.72万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Effects of insulin resistance-related factors on the stem cell functions in vivo.
胰岛素抵抗相关因素对体内干细胞功能的影响。
  • 批准号:
    23390056
  • 财政年份:
    2011
  • 资助金额:
    $ 10.72万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of advanced fluorescent imaging systems for the study of bone remodeling
开发用于骨重塑研究的先进荧光成像系统
  • 批准号:
    23390368
  • 财政年份:
    2011
  • 资助金额:
    $ 10.72万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of advanced in vivo EMT imaging system and its application for the study of cancer metastasis
先进体内EMT成像系统的开发及其在癌症转移研究中的应用
  • 批准号:
    23650600
  • 财政年份:
    2011
  • 资助金额:
    $ 10.72万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Sturm und Drang in the history of European culture
欧洲文化史上的狂飙突进
  • 批准号:
    22520328
  • 财政年份:
    2010
  • 资助金额:
    $ 10.72万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Study of TGFβ signaling during angiogenesis in bone metastasis sites by using in vivo optical imaging
利用体内光学成像研究骨转移部位血管生成过程中的 TGFβ 信号传导
  • 批准号:
    20390407
  • 财政年份:
    2008
  • 资助金额:
    $ 10.72万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Improvements of radio occultations of lunar and planetary atmospheres
月球和行星大气射电掩星的改进
  • 批准号:
    20740289
  • 财政年份:
    2008
  • 资助金额:
    $ 10.72万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Screening of novel signal transducers for BMP using DNA affinity purification
使用 DNA 亲和纯化筛选新型 BMP 信号转导器
  • 批准号:
    15591611
  • 财政年份:
    2003
  • 资助金额:
    $ 10.72万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Screening and characterization of BMP-specific R-Smads binding proteins
BMP 特异性 R-Smads 结合蛋白的筛选和表征
  • 批准号:
    13671554
  • 财政年份:
    2001
  • 资助金额:
    $ 10.72万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)

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The Expanded Repertoire of cGAMP Signal Transduction During Innate Immune Responses
先天免疫反应期间 cGAMP 信号转导的扩展库
  • 批准号:
    10183204
  • 财政年份:
    2019
  • 资助金额:
    $ 10.72万
  • 项目类别:
The Expanded Repertoire of cGAMP Signal Transduction During Innate Immune Responses
先天免疫反应期间 cGAMP 信号转导的扩展库
  • 批准号:
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Signal Transduction Enzyme Inhibitors from Extremophilic Microbes as Anticancer A
嗜极微生物信号转导酶抑制剂作为抗癌 A
  • 批准号:
    8052902
  • 财政年份:
    2009
  • 资助金额:
    $ 10.72万
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Signal Transduction Enzyme Inhibitors from Extremophilic Microbes as Anticancer A
嗜极微生物信号转导酶抑制剂作为抗癌 A
  • 批准号:
    7807157
  • 财政年份:
    2009
  • 资助金额:
    $ 10.72万
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Signal Transduction Enzyme Inhibitors from Extremophilic Microbes as Anticancer A
嗜极微生物信号转导酶抑制剂作为抗癌 A
  • 批准号:
    7636059
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    2009
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Signal Transduction Pathways in Glioblastoma
胶质母细胞瘤的信号转导途径
  • 批准号:
    7060073
  • 财政年份:
    2005
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    $ 10.72万
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Signal Transduction Pathways in Glioblastoma
胶质母细胞瘤的信号转导途径
  • 批准号:
    6924086
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    2005
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Signal Transduction in Lymphoma
淋巴瘤的信号转导
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    6544833
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    2002
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    $ 10.72万
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Signal Transduction in Lymphoma
淋巴瘤的信号转导
  • 批准号:
    6765305
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Signal Transduction in Lymphoma
淋巴瘤的信号转导
  • 批准号:
    6603588
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    $ 10.72万
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