| Project/Area Number |
13357013
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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 | 展開研究 |
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| Research Field |
Digestive surgery
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
YAMAOKA Yoshio Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (90089102)
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| Co-Investigator(Kenkyū-buntansha) |
IKAI Iwao Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (60263084)
YAMAMOTO Yuzou Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (70281730)
YAMAMOTO Naritaka Kyoto University, Graduate School of Medicine, Instructor, 医学研究科, 助手 (30253298)
TERAJIMA Hiroaki Kyoto University, Graduate School of Medicine, Instructor, 医学研究科, 助手 (40314215)
SATOH Segi Kyoto University, Graduate School of Medicine, Instructor, 医学研究科, 助手 (00303834)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥47,580,000 (Direct Cost: ¥36,600,000、Indirect Cost: ¥10,980,000)
Fiscal Year 2002: ¥24,570,000 (Direct Cost: ¥18,900,000、Indirect Cost: ¥5,670,000)
Fiscal Year 2001: ¥23,010,000 (Direct Cost: ¥17,700,000、Indirect Cost: ¥5,310,000)
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| Keywords | Hepatocellular carcinoma / Gastric cancer / cDNA microarray / TaqMan PCR / LOH / Rucurrence / Lymph node metastasis / SIAH1 / PEG10 / 肝癌細胞 |
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| Research Abstract |
Results 1
Through a genome-wide cDNA microarray of hepatocellular carcinomas (HCCs), we identified a number of genes associated with tumor progression. Thus, to analyze expression profiles more precisely and to establish a predictive system of intrahepatic recurrence after surgery, we performed second screening of 47 HCCs by TaqMan PCR consisting of 120 genes. Then we divided 47 HCCs into two groups, 25 HCCs are for training and 22 HCCs are blinded sets for validation. We identified 27 genes that associated with intrahepatic recurrence within 1 year after curative resection. A predictive score, based on expression profiles of 15 of the genes, correctly predicted the recurrent status in 16 of 22 HCCs in the blinded sets. A positive predictive value was 75% and negative predictive value was 71.4%. Accumulation of such data will make it possible to define the nature of individual tumors, to provide clues for identifying new therapeutic targets, and ultimately to optimize treatment of each
… More
patient.
Results 2
In a previous study, we observed a high frequency of LOH on chromosome 16, which correlated with vascular invasiveness of tumors. We performed deletion mapping of chromosome 16 and then identified SIAHI as a putative tumor suppressor gene for HCC and found a correlation between its suppressed expression and tumor size and differentiation, suggesting an important role of SIAHI in the development of HCC. Through a genome-wide cDNA microarray, we identified that the paternally expressed gene 10 (PEG10) was highly expressed in a great majority of HCCs. Exogenous expression of PEG 10 conferred oncogenic activity and transfection of hepatoma cells with antisense S-oligonucleotides **ppressing PEG10 resulted in their growth inhibition. Additional experiments revealed that PEG10 protein associated with SIAHI and **erexpression of PEG 10 decreased the cell death mediated by SIAH1. These findings suggested that development of drug(s) inhibiting PEG10 activity could be a novel approach for the treatment of HCCs.
Results 3
We analyzed expression profiles of 20 intestinal type gastric tumors by a cDNA microarray and identified a number of genes that are commonly up-regulated or down-regulated in the cancer tissues. A predictive score, based on expression profiles of 5 genes, correctly diagnosed the lymph node status of 9 additional gastric cancers. It may help clinicians predict metastasis to lymph nodes and assist researchers in understanding molecular changes during the development of intestinal type gastric cancers and identifying novel therapeutic targets for this type of cancer. VEGF-C/D Al VEGFR-3 pathway is said to play an important role in tumor lymphangiogenesis and lymphatic metastasis. We identified that by administrating anti-VEGFR-3 blocking antibodies in murine orthotopic gastric cancer models, regional lymph node metastasis and lymphatic vessel density in the primary tumors are reduced. In addition, increased density of LYVE-1-positive lymphatic vessels of primary tumors was closely correlated with lymph node metastasis in human samples of gastric cancer. Anti-lymphangiogenesis by inhibiting VEGFR-3 signaling could provide a potential strategy for the prevention of lymph node metastasis in gastric cancer. Less
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