2004 Fiscal Year Final Research Report Summary
Development of a novel therapy for gastrointestinal cancer using epigenetic alterations as a target.
| Project/Area Number |
15390234
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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) |
IMAI Kohzoh Sapporo Medical University, 学長 (60117603)
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| Project Period (FY) |
2003 – 2004
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| Keywords | DNA methylation / histone acetyiation / chromatin / tumor suppressor gene / epigenetics |
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| Research Abstract |
It has been suggested that DNA methylation plays a role in silencing of genes associated with cell cycle regulation and apoptosis. Because DNA methylation is an epigenetic changes, gene expression can be restored using methyltransferase inhibitors. In the current study, we tried to develop a novel therapy using DNA methylation as a molecular target. For this purpose, we examined methylation mediated gene silencing of pro-apoptotic genes. We investigated the expression of one inducible MHC class II molecule, HLA-DR, and its coactivators in a panel of colorectal and gastric cancer cell lines. Interferon-y induced expression of HLA-DR in 14 of 20 cell lines tested; the remaining six cell lines did not express HLA-DR. Analysis of the expression of transcription factors and coactivators associated with HLA-DR revealed that the loss of CIITA expression was closely associated with the absence of HLA-DR induction. Moreover, DNA methylation of the 5' CpG island of CIITA-PIV was detected in all
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cancer cells that lacked CIITA. It thus appears that CIITA methylation is a key mechanism that enables some gastrointestinal cancer cells to escape immune surveillance. BNIP3 protein is a pro-apoptotic member of the Bcl-2 family that is expressed in hypoxic regions of tumors. To examine its role in the progression of gastrointestinal cancer, we examined the expression and DNA methylation status of BNIP3 gene in a panel of colorectal and gastric cancer cell lines. BNIP3 was not expressed in 14 of the 24 cell lines tested. Methylation of BNIP3's 5' CpG island was closely correlated with silencing the gene. Moreover, treating methylated cells with the methyltransferase inhibitor 5-aza-dC restored hypoxia-induced expression of BNIP3 mRNA and protein, which in turn led to cell death. Aberrant methylation of BNIP3 was also detected in 66% of primary colorectal and 49% of primary gastric cancers, but not in normal tissue samples collected from areas adjacent to the tumors. Inactivation of BNIP3 plays a key role in the progression of some gastrointestinal cancers, and that it may be a useful molecular target for therapy. Less
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