权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The Profiling of Cholangiocarcinoma and the Development of Molecular targeted therapy

胆管癌的概况和分子靶向治疗的发展

基本信息

批准号：
16209039
负责人：
NIMURA Yuji
金额：
$ 32.2万
依托单位：
Aichi Cancer Center Research Institute (2007)Nagoya University (2004-2006)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16209039/
关键词：
Nek2 molecular targeted therapy siRNA

项目摘要

Cholangiocarcinoma, one of the most common liver tumors in South-east Asian countries, is a primary malignancy derived from the bile duct epithelium. Despite the progress of the combined therapy, its prognosis is still extremely miserable among all malignancies. To search for the molecular targets for the treatment of cholangiocarcinoma, we compared the gene expression pattern of cholangiocarcinoma with those of a normal liver using cDNA expression array containing 1176 unique genes. Among these explored genes, we identified Nek2 as a candidate that showed high expression in a tumor-specific manner. We investigated the role of Nek2, a member of the serine/threonine kinase family, Nek, in the tumorigenic growth of cholangiocarcinoma cells. Expression of Nek2 is elevated in cholangiocarcinoma in a tumor-specific manner as compared with that of normal fibroblast cells. While expression of exogenous Nek2 did not perturb the growth of cholangiocarcinoma cells, suppression of the Nek2 expression with siRNA resulted in the inhibition of cell proliferation and induced cell death. In xenograft-nude mouse model, subcutaneous injection of Nek2 siRNA around the tumor nodules resulted in reduction of tumor size as compared with those of control siRNA injection. In peritoneal dissemination model, Nek2 siRNA-treated mice showed statistically longer survival periods in comparison with those of the control siRNA-treated mice. In summary, this is the first demonstration that Nek2 plays a critical role in tumorigenic growth of cholangiocarcinoma, and inhibition of Nek2 expression with its siRNA causes suppression of cholangiocarcinoma growth and survival. Our data in vivo provides a strong rationale for the further investigation of Nek2 inhibitors as a new cancer therapy, holding the potential to provide regression of multiple human malignancies.

胆管细胞癌是东南亚国家最常见的肝脏肿瘤之一，是起源于胆管上皮细胞的原发恶性肿瘤。尽管综合治疗取得了进展，但在所有恶性肿瘤中，其预后仍然极其悲惨。为了寻找治疗胆管细胞癌的分子靶点，我们利用包含1176个独特基因的基因表达阵列，比较了胆管细胞癌和正常肝脏的基因表达谱。在这些探索的基因中，我们发现Nek2是一个以肿瘤特异性方式高表达的候选基因。我们研究了丝氨酸/苏氨酸激酶家族成员Nek2在胆管癌细胞致瘤生长中的作用。与正常成纤维细胞相比，Nek2在胆管细胞癌中的表达具有肿瘤特异性。外源性Nek2的表达不影响胆管癌细胞的生长，但siRNA抑制Nek2的表达可抑制细胞增殖，诱导细胞死亡。在裸鼠移植瘤模型中，瘤结节周围皮下注射Nek2 siRNA可使肿瘤体积缩小。在腹膜扩散模型中，与对照组相比，Nek2 siRNA处理组小鼠的存活时间显著延长。综上所述，这是首次证明Nek2在胆管癌细胞的致瘤生长中起关键作用，抑制Nek2的表达及其siRNA可以抑制胆管癌细胞的生长和生存。我们在体内的数据为Nek2抑制剂作为一种新的癌症治疗方法的进一步研究提供了强有力的理论基础，具有提供多种人类恶性肿瘤消退的潜力。