2007 Fiscal Year Final Research Report Summary
The Profiling of Cholangiocarcinoma and the Development of Molecular targeted therapy
| Project/Area Number |
16209039
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Aichi Cancer Center Research Institute (2007)
Nagoya University (2004-2006) |
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Principal Investigator |
NIMURA Yuji Aichi Cancer Center Research Institute, Aichi Cancer Center (Research Institute), President (80126888)
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| Co-Investigator(Kenkyū-buntansha) |
HAMAGUCHI Michinari Nagoya University Graduate School of Medicine, Department of Cancer Biology, Professor (90135351)
NAGINO Masato Nagoya University Graduate School of Medicine, Division of Surgical Oncology, Professor (20237564)
ODA Koji Nagoya University Graduate School of Medicine, Division of Surgical Oncology, Associated Professor (30311715)
YOKOYAMA Yukihiro Nagoya University Graduate School of Medicine, Division of Surgical Oncology, Assistant Professor (80378091)
KOKURYO Toshio Nagoya University Graduate School of Medicine, Division of Surgical Oncology, Assistant Professor (60378023)
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| Project Period (FY) |
2004 – 2007
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| Keywords | Nek2 / molecular targeted therapy / siRNA |
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| Research Abstract |
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.
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