Development of molecular targeting therapy against p27^<Kip1> in oral squamous cell carcinoma.

口腔鳞状细胞癌中针对 p27^<Kip1> 的分子靶向治疗的发展。

基本信息

  • 批准号:
    15592116
  • 负责人:
  • 金额:
    $ 2.3万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 财政年份:
    2003
  • 资助国家:
    日本
  • 起止时间:
    2003 至 2004
  • 项目状态:
    已结题

项目摘要

p27^<Kip1> is a cyclin-dependent kinase inhibitor which regulates the progression of cell from the G1 into S phase in a cell cycle. Loss of p27^<Kip1> is associated with disease progression and an unfavorable outcome in several malignancies. We have now investigated the mechanism of molecular targeting therapy p27^<Kip1> gene in human oral squamous cell carcinoma using pcDNA3.1-p27^<Kip1> wt, pcDNA3.1-p27^<Kip1> mt and Skp2 or Jab1 antisense oligonucleotides (AS) in vitro and in vivo. We constructed an expression vector expressing mutant type p27^<Kip1> gene (pcDNA3.1-p27^<Kip1> mt), with mutation of Thr-187/Pro-188 (ACGCCC) to Met-187/Ile-188 (ATGATC), which is not influenced by ubiquitin-mediated degradation for increasing stability of p27^<Kip1> protein. In addition, we used the antisense Skp2 or Jab1 oligonucleotides for suppressing the degradation of p27^<Kip1> protein. We transfected them into oral cancer cells, B88 and HSY by electroporation. To estimate the reduction of each ca … More ncer xenograft by this method, we measured the size of xenografts in nude mice after electroporation with them. Apoptotic cells were investigated TUNEL method. Immunostaining of p27^<Kip1>, Skp2 and Jab1 protein was performed by immunohistochemistry.All of treatments inhibited the growth of B88 and HSY cells. The growth inhibition was mediated by pcDNA3.1-p27^<Kip1> mt or Skp2 AS or Jab1 AS specifically due to a significant induction of apoptosis characterized by an increase in fragmentation of nuclei and activation of caspase-3. pcDNA3.1-p27^<Kip1> mt, Skp2 AS and Jab1 AS induced a strong growth inhibition of xenograft tumors. Moreover, histological specimens revealed apoptotic cell death was increased in mutant type p27^<Kip1>-transfected tumors than wild type or empty vector only. In the same way, histological specimens revealed apoptotic cell death was increased in skp2 or Jab1 AS-treated tumors than each scramble control. During the experimental period, no loss of body weight was observed in each treatment group, and that no skin region including a burn also was observed.These findings suggest that p27^<Kip1>-mt, Skp2 AS and Jab1 AS have the potential to become a novel and powerful gene therapy tool, and stability of p27^<Kip1> protein offer therapeutic benefits in patients with oral squamous cell carcinoma cells. Less
p27 β<Kip1>是细胞周期蛋白依赖性激酶抑制剂,其调节细胞从细胞周期中的G1期进展到S期。p27 β的缺失<Kip1>与疾病进展和几种恶性肿瘤的不利结果相关。本研究<Kip1>利用pcDNA3.1-p27^<Kip1>wt、pcDNA3.1-p27^<Kip1>mt和Skp 2或Jab 1反义寡核苷酸(AS),在体内外研究了p27^基因分子靶向治疗人口腔鳞癌的机制。我们构建了突变型p27^基因的表达载体<Kip1>(pcDNA3.1-p27^<Kip1>mt),该基因由Thr-187/Pro-188(ACGCCC)突变为Met-187/Ile-188(ATGATC),不受泛素介导的降解的影响,从而提高了p27^蛋白的稳定性<Kip1>。此外,我们还使用了反义Skp 2或Jab 1寡核苷酸来抑制p27^蛋白的降解<Kip1>。我们通过电穿孔法将其转染到口腔癌细胞B88和HSY中。估计每个病例的减少 ...更多信息 通过这种方法,我们测量了电穿孔后裸鼠异种移植物的大小。TUNEL法检测凋亡细胞。免疫<Kip1>组化法检测p27^、Skp 2和Jab 1蛋白的表达。pcDNA3.1-p27^<Kip1>mt或Skp 2 AS或Jab 1 AS特异性介导的生长抑制是由于显著诱导凋亡,其特征在于细胞核碎裂和caspase-3活化的增加。pcDNA3.1-p27-<Kip1>mt、Skp 2 AS和Jab 1 AS对异种移植瘤有较强的生长抑制作用。此外,组织学标本显示,突变型p27^ -转染肿瘤中的凋亡细胞死亡<Kip1>比野生型或仅空载体增加。以同样的方式,组织学标本显示凋亡细胞死亡增加skp 2或Jab 1 AS治疗的肿瘤比每个乱序对照。实验期间,各治疗组均未观察到体重减轻,也未观察到包括烧伤在内的皮肤区域,这些结果表明,p27^<Kip1>-mt、Skp 2 AS和Jab 1 AS有可能成为一种新的、强有力的基因治疗工具,并且p27^蛋白的稳定性<Kip1>在口腔鳞状细胞癌细胞中具有治疗益处。少

项目成果

期刊论文数量(29)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Koji Harada: "Overexpression of iNOS Gene Suppresses the Tumorigenicity and Metastasis of Oral Cancer Cells"In Vivo. (in press).
Koji Harada:“iNOS 基因的过度表达抑制口腔癌细胞的致瘤性和转移”体内。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
佐藤光信: "口腔外科 YEAR BOOK"癌の遺伝子治療の最新の進歩 頭頸部癌""クインテッセンス出版株式会社. 4 (2003)
佐藤光信:《口腔外科年鉴》癌症头颈癌基因治疗最新进展》Quintessence Publishing Co., Ltd. 4 (2003)
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
S-1, an oral fluoropyrimidine anti-cancer agent, enhanced radiosensitivity in a human oral cancer cell line in vivo and in vitro: involvement possibility of inhibition of survival signal, Akt/PKB
  • DOI:
    10.1016/j.canlet.2004.12.048
  • 发表时间:
    2005-08-26
  • 期刊:
  • 影响因子:
    9.7
  • 作者:
    Harada, K;Kawaguchi, S;Sato, M
  • 通讯作者:
    Sato, M
Koji Harada: "Combined effects of the oral fluoropyrimidine anticancer agent, S-1 and radiation on human oral cancer cells"Oral Oncology. (in press).
Koji Harada:“口服氟嘧啶抗癌剂、S-1 和辐射对人类口腔癌细胞的综合作用”口腔肿瘤学。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Koji Harada: "Antitumor effect of cepharanthine on human oral squamous cell carcinoma cell lines by induction of cyclin-dependent kinase inhibitor p27^<Kipl>"Anticancer Research. 23. 1441-1448 (2003)
Koji Harada:“千金藤素通过诱导细胞周期蛋白依赖性激酶抑制剂 p27^<Kipl> 对人口腔鳞状细胞癌细胞系产生抗肿瘤作用”抗癌研究。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
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HARADA Koji其他文献

HARADA Koji的其他文献

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{{ truncateString('HARADA Koji', 18)}}的其他基金

Development of novel treatment against refractory oral cancer by uptake inhibition of iron or induction of ferroptosis
通过抑制铁的摄取或诱导铁死亡来开发针对难治性口腔癌的新疗法
  • 批准号:
    18K09814
  • 财政年份:
    2018
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Development of new oral cancer treatments focused on mTOR inhibition leading to the anti-aging prevention and the healthy life-span extension
开发新的口腔癌治疗方法,重点关注 mTOR 抑制,从而实现抗衰老预防和健康寿命延长
  • 批准号:
    15K11292
  • 财政年份:
    2015
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Development of a novel functional preservation therapy against advanced, recurrent or unresectable oral cancers.
开发一种针对晚期、复发性或不可切除口腔癌的新型功能保留疗法。
  • 批准号:
    24593034
  • 财政年份:
    2012
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Examination of the physical pictures of the field theories with nonlinearly realized symmetries by the Wilsonian renormalization group method
用威尔逊重正化群方法检验具有非线性实现对称性的场论的物理图像
  • 批准号:
    22540286
  • 财政年份:
    2010
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A fundamental research on a new AIDS treatment based on an error rate control of HIV-1 reverse transcriptase
基于HIV-1逆转录酶错误率控制的艾滋病新疗法的基础研究
  • 批准号:
    22500273
  • 财政年份:
    2010
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Identification of new predictive factors for chemo-radiation against oral cancers and setting of individualized medicine based on their expressions
口腔癌放化疗新预测因素的鉴定以及基于其表达的个体化医疗设置
  • 批准号:
    21592555
  • 财政年份:
    2009
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Development of the therapy for oral cancer by S-1 and proteasome inhibitor in combination with concurrent radiotherapy
S-1和蛋白酶体抑制剂联合同步放疗治疗口腔癌的进展
  • 批准号:
    19592339
  • 财政年份:
    2007
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Understanding a mechanism of HIV-1 drug resistance development under the RTI pressure and the development of a medication scheduling system
了解RTI压力下HIV-1耐药性发展的机制以及药物调度系统的开发
  • 批准号:
    18700293
  • 财政年份:
    2006
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Development of molecular targeting therapy against stability of p27^<Kip1> protein in oral squamous cell carcinoma.
针对口腔鳞状细胞癌中 p27^<Kip1> 蛋白稳定性的分子靶向治疗的发展。
  • 批准号:
    17592089
  • 财政年份:
    2005
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Relationship between p27^<Kip1> expression and tumor differention and prognosis in human oral squamous cell carcinoma.
人口腔鳞癌p27^<Kip1>表达与肿瘤分化及预后的关系。
  • 批准号:
    11671990
  • 财政年份:
    1999
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
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