| Co-Investigator(Kenkyū-buntansha) |
OKUDA Tsukasa Kyoto prefectural University of Medicine, Department of Digestive Surgery, Subprofessor, 医学研究科, 助教授 (30291587)
HAGIWARA Akeo Kyoto prefectural University of Medicine, Department of Digestive Surgery, Subprofessor, 医学研究科, 助教授 (90198648)
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| Budget Amount *help |
¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2003: ¥3,200,000 (Direct Cost: ¥3,200,000)
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| Research Abstract |
Our previous results suggest that a lack of RUNX3 function is causally related to the genesis of human gastric cancer, but the role of RUNX3 in progression and metastases has not yet been clarified. We examined the expression of RUNX3 in clinical samples of peritoneal metastases in gastric cancers. Furthermore, change of metastatic potential in animal experiments using RUNX3-stable transfectants of gastric cancer cells and global expression changes using cDNA microarray was analyzed.
Significant downregulation of RUNX3 through methylation on the promoter region was observed in all clinical samples of peritoneal metastases (14/14, 100%) by quantitative RT-PCR and methylation specific PCR(MSP). Although stable transfection of RUNX3 did not inhibit cell proliferation, TGF-β induced antiproliferative effect and apoptosis was slightly observed. Interestingly, it strongly inhibited peritoneal metastases of gastric cancers in animal model (p<0.01). Furthermore, we performed globally analyzed e
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xpression profiles of approximately 21000 genes in parent cells and stable transfectant of RUNX3 using a cDNA microarray. Microarray analysis identified approximately 28 candidate genes (known genes and ESTs) under the possible down-stream control of RUNX3, some of these genes were considered to be possibly involved in peritoneal metastases, which were related to signal transduction (vav3, toll-like receptor, MAPKK, MET, S100A11, Cathepsin E), apoptosis (caspase 9), immune response (CD55, TLR10), and cell adhesion (sialyltransferase1, galectin 4). Some of them are known to be involved in TGF-β signaling pathway. Same expression pattern with cDNA microarray in some of the selected genes are confirmed using quantitative RT-PCR in clinical samples of peritoneal metastases.
These results indicate that silencing of RUNX3 affect the expression of important genes involved in metastases including cell adhesion, proliferation and apoptosis, and promote the peritoneal metastases of gastric cancer. Identification of such genes could then lead to new therapeutic modalities as well as therapeutic targets. Less
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