Tailor-made therapy of gastrointestinal cancer targeting aberrant modification of biological molecules
| Project/Area Number |
17390221
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
TOYOTA Minoru Sapporo Medical University, First department of Internal Medicine, Assistant Professor, 医学部, 講師 (70270676)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Hiromu Sapporo Medical University, First department of Internal Medicine, Instructor, 医学部, 助手 (20381254)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2006: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 2005: ¥7,500,000 (Direct Cost: ¥7,500,000)
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| Keywords | Epigenetics / methylation / histone / Molecular target therapy / ubiquitin / DNAメチル化 / クロマチン / メチル化 |
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| Research Abstract |
Aberrant modification of various biological molecules is involved in development and progression of gastrointestinal cancer. Among these, epigenetic alterations of the genes play important role in gene silencing. It has been suggested that methylation-mediated inactivation of pro-aoptotic genes may lead to resistance of tumor cells to chemotherapeutic drugs. In the current study, we investigate DNA methylation and expression of the genes involved in hypoxia-mediated apoptosis. Among the genes analyzed, we identified aberrant methylation of BNIP3 in colorectal, gastric, and pancreatic cancer. Treatment of cancer cells with BNIP3 methylation restored its gene expression, which lead to induction of hypoxia-mediated apoptosis. We have previously reported that a subset of colorectal cancer showed genome-wide methylation defect. We have now found that gastric cancer with Epstein-Barr virus is closely associated with CpG island methylator phenotype. Finally, we examined epigenetic inactivation of genes involved in mitotic checkpoint, and found that CHFR is frequently inactivated by DNA methylation in colorectal, gastric and oral squamous cell cancers. Cancer cells which lack expression of CHFR are sensitive to microtubule inhibitors, indicating that methylation of CHFR can be a molecular marker to predict sensitivity to drugs. Knock-down of CHFR by shRNA disrupted checkpoint, and increased sensitivity of cancer cells to microtubule inhibitors. These results suggested that molecules that inhibit function of CHFR may be used to increased effect of microtubule inhibitors.
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Report
(3 results)
Research Products
(64 results)
